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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. [ABSTRACT FROM AUTHOR]

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]). Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? 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. 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. 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. ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rationale: Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance, recurrent respiratory infections, and progressive airway damage and obstructive lung disease. While the association of ciliary ultrastructure defect/genotype with 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: ODA (outer dynein arm), ODA/IDA (outer and inner dynein arm), IDA/MTD (inner dynein arm and microtubular disorganization), and Normal/Near Normal ultrastructure with associated genotypes. CTs were scored utilizing the Melbourne-Rotterdam Annotated Grid Morphometric Analysis for PCD (MERAGMA-PCD), evaluating airway abnormalities in a hierarchical order: atelectasis, bronchiectasis, bronchial wall thickening, mucus plugging/tree in bud opacities. Volume fraction of each component was expressed as % of total lung volume. %Disease was computed as the sum of all components. Regression analyses were utilized 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, 24 Normal/Near Normal. Mean (SD) age was 8.5 (4.6) years, forced expiratory volume in 1 second (FEV1) % predicted was 82.4 (19.5), and %Disease was 4.6 (3.5). Children with IDA/MTD defects had higher %Disease compared to children with ODA defects (2.71% higher (95%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 BMI, and lower FEV1 were associated with higher %Disease (0.23%, 95%CI: 0.11-0.35, p<0.001; 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 to children with ODA defects. [ABSTRACT FROM AUTHOR]

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/type of laterality abnormality and ciliary ultrastructural defect and 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 this 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 inversus totalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%). Compared to group with inner dynein arm defects with microtubular disorganization, laterality defects were more likely in the outer dynein arm defects group (OR 2.07, 95% 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 zero 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 ultrastructure defect. Pathophysiologic mechanisms underlying these differences require further exploration. [ABSTRACT FROM AUTHOR]

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-1b (interleukin-1b), IL-8, and TNF-a (tumor necrosis factor a) 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 20.32 (95% confidence interval, 20.51 to 20.10) and 0.46 (0.14 to 0.69), respectively. Sputum neutrophil elastase, IL-1b, and TNF-a 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article presents the issue of Critical Care Medicine including a new consensus document for developing, validating, updating, and reporting prediction models. Topics include receiving a diverse collection of manuscripts asking a wide variety of scientific questions; providing an accessible summary and reference guide for authors exploring questions using causal inference methods; and providing an estimate of the average increase in the risk of lung cancer for each year of smoking.

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. [ABSTRACT FROM AUTHOR]

Ciliopathy insights: Primary ciliary dyskinesia (PCD) results from genetic mutations and structural defects that impair the motility of cilia, the cellular protrusions that sweep mucus along the surface of the airway. Here, Liu and colleagues developed a quantitative imaging workflow to improve the diagnosis of PCD. Using super-resolution microscopy on nasal airway cells isolated from patients with PCD, the authors detected mislocalized PCD-related proteins, cellular structural defects, and impairments in ciliary beating. These imaging and analysis methods could help complement standard methods of diagnosis, such as genetic testing, and could provide insight into pathology caused by variants of uncertain significance. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective We sought to determine the prevalence of, and identify factors associated with, parent questions about physical activity for their child with a chronic cardiac, respiratory, or rheumatologic condition. Methods This cross-sectional study of 56 children (32 [57%] female), 3 to 18 years of age, with chronic cardiac (n=21), respiratory (n=18), or rheumatologic (n=17) conditions involved a parent questionnaire about their child's physical activity participation and measurement of the child's activity with an omni-directional accelerometer for 1 week. Results Parents of 20 (36%) children had at least one question about their child's physical activity participation, and the prevalence of questions did not vary by age (Wald chi square = 0.77, P=0.38), gender (Wald chi square = 0.11, P=0.74), or clinic (Wald chi square = 1.77, P=0.41). Parent questions were associated (P = 0.04) with lower levels of activity for boys (95% confidence interval [CI] for estimated marginal means: With questions: 197, 395; Without questions: 346, 500) and higher levels of activity for girls (95% CI for estimated marginal means: With questions: 268, 448; Without questions: 239, 369). A multivariable logistic regression model found that parents with questions had higher odds of having a child who was less well (odds ratio [OR]=19.9 for unwell, OR=5.6 for generally well with some symptoms versus well and asymptomatic) and had a history of cardiac arrhythmia (OR=7.6). Conclusions Over one-third of parents reported having questions about physical activity for their child with a chronic medical condition, suggesting substantial uncertainty even among children reported as active. Presence of parent uncertainty is associated with parent reports of the child being unwell or a history of cardiac arrhythmia. By asking parents if they have questions about their child's activity, health care professionals may be better able to identify inactive boys and overprotective attitudes toward active girls. [ABSTRACT FROM AUTHOR]

Respiratory distress occurs in 5% to 7% of live births at term gestation. Most cases are mild and transient and can be attributed to transient tachypnea of the newborn or "wet lung." Severe respiratory distress is often due to nonpulmonary causes such as sepsis or congenital heart disease. Occasionally, term neonatal respiratory distress is associated with an inherited primary lung disease such as primary ciliary dyskinesia or surfactant metabolism defects. These lung diseases have characteristic presentations in the neonatal period and are important to recognize, as they necessitate different management approaches and have lifelong implications. Suspicion for these diseases should prompt referral to a pediatric pulmonologist. [Pediatr Ann. 2019;48(4):e175-e181.]. [ABSTRACT FROM AUTHOR]

Background: Despite remarkable advances in our understanding of asthma, there are still several unmet needs associated with the management of pediatric asthma. Methods: A two‐day, face‐to‐face meeting was held in London, United Kingdom, on October 28 and 29, 2017, involving a group of international expert clinicians and scientists in asthma management to discuss the challenges and unmet needs that remain to be addressed in pediatric asthma. Results: These unmet needs include a lack of clinical efficacy and safety evidence, and limited availability of non‐steroid‐based alternative therapies in patients <6 years of age. An increased focus on children is needed in the context of clinical practice guidelines for asthma; current pediatric practice relies mostly on extrapolations from adult recommendations. Furthermore, no uniform definition of pediatric asthma exists, which hampers timely and robust diagnosis of the condition in affected patients. Conclusions: There is a need for a uniform definition of pediatric asthma, clearly distinguishable from adult asthma. Furthermore, guidelines which provide specific treatment recommendations for the management of pediatric asthma are also needed. Clinical trials and real‐world evidence studies assessing anti‐immunoglobulin E (IgE) therapies and other monoclonal antibodies in children <6 years of age with asthma may provide further information regarding the most appropriate treatment options in these vulnerable patients. Early intervention with anti‐IgE and non‐steroid‐based alternative therapies may delay disease progression, leading to improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) can manifest in the neonatal period with severe respiratory distress. We describe a child with PCD who presented at term with severe neonatal respiratory distress, persistent right upper lobe collapse and failure to thrive who underwent lobectomy prior to the diagnosis of PCD at the age of 3 years. This case report illustrates the severe spectrum of lung disease associated with coiled-coil domain containing protein 40 (CCDC40) gene variants in patients with PCD. [ABSTRACT FROM AUTHOR]

Background: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD).Target Audience: Clinicians investigating adult and pediatric patients for possible PCD.Methods: Systematic reviews and, when appropriate, meta-analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by a multidisciplinary panel with expertise in PCD. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript.Results: After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD.Conclusions: The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD. [ABSTRACT FROM AUTHOR]

Rationale: Childhood asthma has shown variable associations with children's physical activity. Neighborhood walkability captures community features that promote walking and is protective against some chronic conditions, such as obesity and diabetes.Objectives: We evaluated associations between home neighborhood walkability and incident and ongoing childhood asthma.Methods: In this population-based cohort study, we used prospectively collected administrative healthcare data for the Province of Ontario housed at the Institute for Clinical Evaluative Sciences. We followed an administrative data cohort of 326,383 Toronto children born between 1997 and 2003, inclusive, until ages 8-15 years. Home neighborhood walkability quintile was measured using a validated walkability index with four dimensions: population density, dwelling density, access to retail and services, and street connectivity. Incident asthma was defined by time of entry into the validated Ontario Asthma Surveillance Information System database, which requires two outpatient visits for asthma within two consecutive years or any hospitalization for asthma and follows children with asthma longitudinally starting at any age. Associations between walkability and incident asthma were examined using Cox proportional hazards models. Associations between ongoing asthma and walkability in each year of life were examined using generalized linear mixed models.Results: Twenty-one percent of children (n = 69,628) developed incident asthma and were followed longitudinally in the Ontario Asthma Surveillance Information System database. Low birth home neighborhood walkability was associated with an increased incidence of asthma (hazard ratio, 1.11; 95% confidence interval, 1.08-1.14). Among children with asthma, low walkability in a given year of a child`s life was associated with greater odds of ongoing asthma in the same year (odds ratio, 1.12; 95% confidence interval, 1.09-1.14).Conclusions: Children living in neighborhoods with low walkability were at increased risk of incident and ongoing asthma. Neighborhood walkability improvement, such as by adding pedestrian paths to improve street connectivity, offers potential strategies to contribute to primary asthma prevention. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia is a genetically heterogeneous disorder of motile cilia that is predominantly inherited in an autosomal-recessive fashion. It is associated with abnormal ciliary structure and/or function leading to chronic upper and lower respiratory tract infections, male infertility, and situs inversus. The estimated prevalence of primary ciliary dyskinesia is approximately one in 10,000-40,000 live births. Diagnosis depends on clinical presentation, nasal nitric oxide, high-speed video-microscopy analysis, transmission electron microscopy, genetic testing, and immunofluorescence. Here, we review its clinical features, diagnostic methods, molecular basis, and available therapies. [ABSTRACT FROM AUTHOR]

Background: Quality of life (QOL)-primary ciliary dyskinesia (PCD) is the first disease-specific, health-related QOL instrument for PCD. Psychometric validation of QOL-PCD assesses the performance of this measure in adults, including its reliability, validity and responsiveness to change.Methods: Seventy-two adults (mean (range) age: 33 years (18-79 years); mean (range) FEV1% predicted: 68 (26-115)) with PCD completed the 49-item QOL-PCD and generic QOL measures: Short-Form 36 Health Survey, Sino-Nasal Outcome Test 20 (SNOT-20) and St George Respiratory Questionnaire (SGRQ)-C. Thirty-five participants repeated QOL-PCD 10-14 days later to measure stability or reproducibility of the measure.Results: Multitrait analysis was used to evaluate how the items loaded on 10 hypothesised scales: physical, emotional, role and social functioning, treatment burden, vitality, health perceptions, upper respiratory symptoms, lower respiratory symptoms and ears and hearing symptoms. This analysis of item-to-total correlations led to 9 items being dropped; the validated measure now comprises 40 items. Each scale had excellent internal consistency (Cronbach's α: 0.74 to 0.94). Two-week test-retest demonstrated stability for all scales (intraclass coefficients 0.73 to 0.96). Significant correlations were obtained between QOL-PCD scores and age and FEV1. Strong relationships were also found between QOL-PCD scales and similar constructs on generic questionnaires, for example, lower respiratory symptoms and SGRQ-C (r=0.72, p<0.001), while weak correlations were found between measures of different constructs.Conclusions: QOL-PCD has demonstrated good internal consistency, test-retest reliability, convergent and divergent validity. QOL-PCD offers a promising tool for evaluating new therapies and for measuring symptoms, functioning and QOL during routine care. [ABSTRACT FROM AUTHOR]

Rationale: Primary ciliary dyskinesia (PCD) is a rare disease. There are no available data on disease-specific pediatric patient-reported outcomes.Objectives: Our objective was to create developmentally appropriate, health-related quality-of-life questionnaires (QOL-PCD) for children (6-12 yr) and adolescents (13-17 yr) with PCD and a parent proxy measure.Methods: The QOL-PCD was developed using a cross-cultural protocol-driven approach satisfying both North American and European drug regulatory agency guidelines. A conceptual framework was generated by literature review, focus groups (expert clinicians and patients/parents), and open-ended interviews with children, adolescents, and parents of patients with PCD. We recruited participants from international research consortiums, PCD clinics, and patient advocacy groups, aiming for representation of a wide spectrum of disease severity, sociodemographic status, and ethnicity. Qualitative interviews were conducted by trained and experienced research assistants and psychologists. Transcripts were content-analyzed with Atlas.ti/NVivo to assess saturation of content. A self-completed item relevance survey was administered to E.U.Participants: Qualitative and quantitative data were used to construct draft instruments. Questionnaires were further refined after cognitive interviews.Measurements and Main Results: Focus groups (n = 62 experts; n = 20 patients/parents) and open-ended interviews with patients/parents (n = 69; 34 males; age at diagnosis, 0-15 yr; FEV1, 58-118% predicted) revealed a wide spectrum of issues unique to this population. Content analysis of transcripts identified the following domains, depending on age: Respiratory Symptoms, Physical Functioning, Emotional Functioning, Treatment Burden, Ears and Hearing, Sinus Symptoms, Social Functioning, Role Functioning, Vitality, Health Perceptions, School Functioning, and Eating and Weight. Various items were retained in questionnaires, based on age and role of respondent: 37, 43, and 41 items for children, adolescents, and parent proxy, respectively. The item relevance survey (n = 57) yielded results similar to those of open-ended interviews. Cognitive testing (n = 47; 20 males; age at diagnosis, 0-11 yr; FEV1, 49-124% predicted) confirmed that items and response choices were clear and understood by respondents, and that all relevant items were included.Conclusions: The QOL-PCD measures, developed using rigorous, protocol-driven methods and international collaborations, have demonstrated content validity and cross-cultural equivalence for implementation in English-speaking populations. Psychometric testing is underway to determine their measurement properties for evaluating clinical interventions and informing quality of care. [ABSTRACT FROM AUTHOR]

Rationale: Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations.Objectives: To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents.Methods: Investigators at seven North American sites in the Genetic Disorders of Mucociliary Clearance Consortium prospectively and systematically assessed individuals (aged 0-18 yr) referred due to high suspicion for PCD. The investigators defined specific clinical questions for the clinical report form based on expert opinion. Diagnostic testing was performed using standardized protocols and included nasal nitric oxide measurement, ciliary biopsy for ultrastructural analysis of cilia, and molecular genetic testing for PCD-associated genes. Final diagnoses were assigned as "definite PCD" (hallmark ultrastructural defects and/or two mutations in a PCD-associated gene), "probable/possible PCD" (no ultrastructural defect or genetic diagnosis, but compatible clinical features and nasal nitric oxide level in PCD range), and "other diagnosis or undefined." Criteria were developed to define early childhood clinical features on the basis of responses to multiple specific queries. Each defined feature was tested by logistic regression. Sensitivity and specificity analyses were conducted to define the most robust set of clinical features associated with PCD.Measurements and Main Results: From 534 participants 18 years of age and younger, 205 were identified as having "definite PCD" (including 164 with two mutations in a PCD-associated gene), 187 were categorized as "other diagnosis or undefined," and 142 were defined as having "probable/possible PCD." Participants with "definite PCD" were compared with the "other diagnosis or undefined" group. Four criteria-defined clinical features were statistically predictive of PCD: laterality defect; unexplained neonatal respiratory distress; early-onset, year-round nasal congestion; and early-onset, year-round wet cough (adjusted odds ratios of 7.7, 6.6, 3.4, and 3.1, respectively). The sensitivity and specificity based on the number of criteria-defined clinical features were four features, 0.21 and 0.99, respectively; three features, 0.50 and 0.96, respectively; and two features, 0.80 and 0.72, respectively.Conclusions: Systematically defined early clinical features could help identify children, including infants, likely to have PCD. Clinical trial registered with ClinicalTrials.gov (NCT00323167). [ABSTRACT FROM AUTHOR]

Asthma often starts before six years of age. However, there remains uncertainty as to when and how a preschool-age child with symptoms suggestive of asthma can be diagnosed with this condition. This delays treatment and contributes to both short- and long-term morbidity. Members of the Canadian Thoracic Society Asthma Clinical Assembly partnered with the Canadian Paediatric Society to develop a joint working group with the mandate to develop a position paper on the diagnosis and management of asthma in preschoolers. In the absence of lung function tests, the diagnosis of asthma should be considered in children one to five years of age with frequent (≥8 days/month) asthma-like symptoms or recurrent (≥2) exacerbations (episodes with asthma-like signs). The diagnosis requires the objective document of signs or convincing parent-reported symptoms of airflow obstruction (improvement in these signs or symptoms with asthma therapy), and no clinical suspicion of an alternative diagnosis. The characteristic feature of airflow obstruction is wheezing, commonly accompanied by difficulty breathing and cough. Reversibility with asthma medications is defined as direct observation of improvement with short-acting ß2-agonists (SABA) (with or without oral corticosteroids) by a trained health care practitioner during an acute exacerbation (preferred method). However, in children with no wheezing (or other signs of airflow obstruction) on presentation, reversibility may be determined by convincing parental report of a symptomatic response to a three-month therapeutic trial of a medium dose of inhaled corticosteroids with as-needed SABA (alternative method), or as-needed SABA alone (weaker alternative method). The authors provide key messages regarding in whom to consider the diagnosis, terms to be abandoned, when to refer to an asthma specialist and the initial management strategy. Finally, dissemination plans and priority areas for research are identified. [ABSTRACT FROM AUTHOR]

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4+ T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease. [ABSTRACT FROM AUTHOR]

Background: Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied.Methods: In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD.Results: Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P < .001; year-round nasal congestion, P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P < .001).Conclusions: At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects.Trial Registry: ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

The article discusses a research study which investigated the prevalence of laterality defects other than situs inversus totalis in primary ciliary dyskinesia (PCD). Study results are presented including the presence of electron microscopic defects and PCD-causing gene mutations. Data provided shows the laterality defects included in situs ambiguus (SA) subgroups, the demographics and clinical features of participants with SA, and the diagnostic testing of participants with classic PCD and SA.

ABSTRACT Primary ciliary dyskinesia ( PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects. Advances in genetic testing have been crucial in addressing the diagnostic challenge. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine subjects with PCD (seven families). Loss-of-function was confirmed with quantitative ciliary ultrastructural analysis, measurement of ciliary beat frequency and waveform, and transcript analysis. All nine individuals carrying c.921+3_6del AAGT splice-site mutation in RSPH4A were Hispanic with ancestry tracing to Puerto Rico. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent. [ABSTRACT FROM AUTHOR]

To review outcome of children post-allogeneic (allo) and autologous (auto) SCT with severe lung injury who had lung biopsy and to determine whether the diagnoses provided by lung biopsy had an impact on outcome. Retrospective study was carried out from January 2000 to June 2010. Nine hundred and eighteen children (0-18 yr) received SCT (allo 476, auto 442), and 59 biopsies were performed in 48 patients. Most common result of lung biopsy was non-infectious inflammation and recurrent disease in allo- and autorecipients, respectively. In a multivariate analysis, survival of allorecipients who had management change was inferior (p = 0.002 ; HR: 3.12). These patients were extremely sick, and management change was the last attempt to stabilize their respiratory status. There was a trend toward superior survival for children who had biopsy after 100 days following SCT (p = 0.09 ; HR: 0.55) and a trend toward inferior survival for those with proven infections within two wk of biopsy (p = 0.07; HR: 2.14). Only 31% of allorecipients and 25% of autorecipients survived. There were no biopsy-related complications. Lung biopsy itself appears to be well tolerated, although requiring a biopsy seems to carry a poor prognosis; this seems to be due to different causes, auto (relapse), allo (non-infectious inflammation). [ABSTRACT FROM AUTHOR]