Sharon D. Dell

Background: Childhood interstitial lung diseases (chILD) are a heterogeneous group of rare disorders. In 2013, the American Thoracic Society (ATS) developed a guideline regarding the classification, evaluation, and management of children <2 years old with chILD. The current guideline provides updated recommendations regarding genetic testing, chest imaging, lung biopsy, and lung transplant referral. Methods: The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to form clinical questions, summarize evidence, and develop recommendations, following ATS policies and procedures. A multidisciplinary panel with expertise in chILD formulated recommendations addressing diagnostic tools and referral for lung transplant evaluation. Results: Rapid and broad genetic testing is recommended for infants with chILD and respiratory failure (strong recommendation). Chest computed tomography (CT) remains an important part of the diagnostic evaluation (conditional recommendation). Surgical lung biopsy is recommended when there is urgency to identify a specific chILD disorder and genetic testing is not feasible, timely, or inconclusive; to identify histopathologic “treatable traits”; or to inform prognosis (strong recommendation). Referral for lung transplant evaluation is recommended for children with specific chILD disorders with predictable poor outcomes (strong recommendation). Repeat chest CT to aid decision-making, prognosis, and/or change therapies is suggested for children with chILD diagnosed before age 2 years (conditional recommendation). Conclusions: This guideline provides evidence-based recommendations for genetic testing, chest imaging, lung biopsy, and referral for lung transplant evaluation to improve the diagnostic evaluation and management of children <2 years with chILD. Implementing this guideline will hopefully increase genetic testing for chILD, inform the diagnostic evaluation and disease monitoring of chILD, and identify future research priorities for chILD.

Asthma affects approximately 13% of Canadian children.1 Severe asthma, whose control requires high-dose inhaled corticosteroids (ICS) and a second controller medication or daily systemic corticoste...

Cilia are cellular organelles that extrude from the surface of various cell types, serving either sensory or motile functions. Retinitis pigmentosa GTPase regulator ( RPGR ) variants affect both photoreceptor sensory cilia and airway motile cilia, leading to retinitis pigmentosa (RP) and primary ciliary dyskinesia (PCD), respectively. Not all patients develop PCD, and it remains unclear which RPGR variants predispose patients to PCD. Here, we leverage 2D organoids, super-resolution microscopy, and live-cell imaging to characterize the multiciliated cells (MCCs) from patients with different RPGR variants and CRISPR-modified RPGR KO MCCs. We demonstrate that MCCs with RPGR variants have reduced ciliation, shorter cilia, impaired cilia beat, or cilia beat incoordination, potentially resulting in compromised mucociliary clearance and lung diseases. Moreover, we show that RPGR regulates motile cilia through interfering with F-actin dynamics, evidenced by the undissolved F-actin meshwork in RPGR -deficient MCCs, and the defects can be ameliorated with either latrunculin A or Y27632 treatment. Though PCD was observed only in patients with variants that affect both isoforms, patients with RPGR ^ORF15 variants also had cilia and airway anomalies. All RPGR variants affected motile cilia in some way, and the mechanisms involved the accumulation of apical F-actin. Loss of RPGR, through apical F-actin accumulation in airway cells, leads to reduced ciliation with short cilia that have an impaired beat, leading to defective mucociliary clearance.

Rationale: The 2012 Global Lung Function Initiative (GLI) spirometry reference equations rely on race to predict pulmonary function, which may disproportionately affect diagnosis and management of respiratory conditions in certain groups. However, the impacts of newly endorsed race-neutral GLI Global equations have been understudied in pediatric populations. Objectives: To evaluate differences in percentage and severity of pediatric lung function impairments identified using the race-specific 2012 GLI equations compared to the race-neutral GLI Global equations. Methods: Retrospective spirometry data for British Columbia Children’s Hospital patients aged 5-18 years from August 2022 to June 2024 was interpreted using the race-specific and race-neutral GLI equations. Impairment severity was assessed with forced expiratory volume in 1 second (FEV1) z-scores. FEV1, forced vital capacity (FVC), and FEV1/FVC lower limits of normal were used to classify tests as normal, obstructive, suspected restrictive, or suspected mixed. Results: Spirometry results from 1759 Caucasian, 44 Black, 31 North East Asian, 421 South East Asian, and 691 Other/Mixed individuals were analyzed. Compared to the race-specific, the race-neutral equations identified a mean decrease in FEV1 z-score of 0.77 (95% CI, 0.67-0.86) in the Black population, corresponding to increased impairment severity in 22.7% (95% CI, 11.5%-37.8%) of this group. In contrast, the Caucasian population showed a mean increase in FEV1 z-score of 0.36 (95% CI, 0.35-0.37), with decreased severity observed in 13.5% (95% CI, 11.9%-15.2%). Percentage of suspected restriction increased in Black individuals from 20.5% (95% CI, 9.8%-35.3%) to 43.2% (95% CI, 28.3%-59.0%) and decreased in Caucasian from 14.4% (95% CI, 12.8%-16.2%) to 9.0% (95% CI, 7.7%-10.5%). The South East Asian group experienced the largest increase in mean FEV1/FVC z-score using the race neutral equations, rising by 0.45 (95% CI, 0.44-0.46), which corresponded to a reduction in obstructive impairments from 17.1% (95% CI, 13.6%-21.0%) to 7.8% (95% CI, 5.5%-10.8%). Conclusions: The race-neutral GLI equations produced the greatest decrease in obstruction in the South East Asian population, while the largest increases in severity and suspected restriction were found in the Black population. The diagnostic and management implications of these changes will require consideration as the race-neutral equations are implemented clinically for pediatric patients.

Background: Managing patients with primary ciliary dyskinesia (PCD) is challenging due to limited therapeutic options and lack of sensitive, disease-specific outcome measures. Hyperpolarised 129-xenon magnetic resonance imaging (Xe MRI) is an emerging imaging modality that quantifies ventilation heterogeneity using the ventilation defect per cent (VDP). In other obstructive lung diseases, VDP has demonstrated increased sensitivity compared to conventional lung function measures; however, its utility in PCD has not been established. In PCD, we aimed to: 1) determine the feasibility of Xe MRI; 2) evaluate the same-day repeatability of VDP; and 3) explore the relationship between VDP with lung clearance index 2.5% (LCI _2.5 ) and forced expiratory volume in 1 s z-score (FEV ₁ z). Methods: In this cross-sectional observational study, participants >6 years old with confirmed PCD were recruited from two Canadian PCD centres. Participants underwent lung function testing to measure FEV ₁ z and LCI _2.5 . Xe MRI was performed twice within 30–60 min to measure VDP. Intraclass correlation coefficient (ICC) and Bland–Altman plots (B&A) were used to assess same-day repeatability of VDP. Linear correlation between VDP with FEV ₁ z and LCI _2.5 evaluated their relationships. Results: 16 participants completed the study. In all participants, the VDP was elevated (VDP>2.3) with a median VDP of 11.05% (IQR: 4.83–13.67%). Same-day repeat Xe MRI VDP had an ICC>0.95 and B&A showed good agreement. VDP positively correlated with LCI _2.5 (r=0.89, p < 0.05) and negatively correlated with FEV ₁ z (r=0.6, p < 0.05). Conclusions: Xe MRI is a feasible imaging modality to capture lung disease in PCD. VDP has excellent same-day repeatability and correlated strongly with LCI _2.5 . Moreover, VDP was more sensitive at detecting lung function impairments than LCI _2.5 and FEV ₁ z, demonstrating its potential as a sensitive outcome measure in PCD.

Xenon 129 MRI and MR spectroscopy are safe, sensitive, and robust tools for measuring pulmonary ventilation, gas exchange, and microstructure, providing regional structure-function information for treatment planning and monitoring of disease progression and treatment response.

Background: Primary ciliary dyskinesia (PCD) is a motile ciliopathy characterized by abnormal mucociliary clearance and progressive lung disease. Spirometry is commonly used to monitor lung health and response to treatment, but it is known to be insensitive to early subclinical lung disease in PCD. Multiple breath washout is more sensitive than spirometry, but its repeatability in PCD has not been assessed. Objectives: To evaluate the (i) same‐day and (ii) 28‐day repeatability of lung clearance index 2.5% (LCI) in PCD. Methods: Participants > 6 years old with a confirmed PCD diagnosis were recruited from two Canadian PCD centers. Participants completed baseline lung function tests to measure their forced expiratory volume in 1‐second, z ‐score (FEV1z), and LCI. Tests were repeated either on the same day or after 28 days. No clinical interventions were performed during the same‐day repeat testing. Outpatient therapies were unchanged during 28‐day repeat testing. Repeatability was assessed using intraclass correlation (ICC), and Bland−Altman plots (B&A). Results: Twenty‐three participants were enrolled (same‐day: 16; 28‐day: 13). The same‐day and 28‐day repeat testing ICC for FEV1z were 0.9 and 0.92, and LCI were 0.95 and 0.71, respectively. Baseline testing showed that most participants had abnormal LCI (18 of 29 tests), even in those with FEV1z in the normal range. FEV1z and LCI exhibited a weak inverse correlation. Conclusions: LCI is a repeatable and sensitive lung function measure in PCD patients, and may be a suitable outcome metric for clinical trials, particularly in patients with early subclinical lung disease.