M. Boon

Primary ciliary dyskinesia: critical evaluation of clinical symptoms and diagnosis in patients with normal and abnormal ultrastructure

BackgroundPrimary ciliary dyskinesia (PCD) is a rare disorder with variable disease progression. To date, mutations in more than 20 different genes have been found. At present, PCD subtypes are described according to the ultrastructural defect on transmission electron microscopy (TEM) of the motile cilia. PCD with normal ultrastructure (NU) is rarely reported because it requires additional testing. Biallelic mutations in DNAH11 have been described as one cause of PCD with NU.The aim of our study was to describe the clinical characteristics of a large population of patients with PCD, in relation to the ultrastructural defect. Additionally, we aimed to demonstrate the need for biopsy and cell culture to reliably diagnose PCD, especially the NU subtype.MethodsWe retrospectively analyzed data from 206 patients with PCD. We compared the clinical characteristics, lung function, microbiology and imaging results of 68 patients with PCD and NU to those of 90 patients with dynein deficiencies and 41 patients with central pair abnormalities. In addition, we aimed to demonstrate the robustness of the diagnosis of the NU subtype in cell culture by data from genetic analysis.ResultsPCD with NU comprised 33% (68/206) of all patients with PCD. Compared to other subtypes, patients with PCD and NU had a similar frequency of upper and lower respiratory tract problems, as well as similar lung function and imaging. With the currently widely applied approach, without cell culture, the diagnosis would have been missed in 16% (11/68) of patients with NU. Genetic analysis was performed in 29/68 patients with PCD and NU, and biallelic mutations were found in 79% (23/29) of tested patients.ConclusionsWe reported on the clinical characteristics of a large population of patients with PCD and NU. We have shown that systematic performance of biopsy and cell culture increases sensitivity to detect PCD, especially the subtype with NU.PCD with NU has similar clinical characteristics as other PCD types and requires biopsy plus ciliogenesis in culture for optimal diagnostic yield.

Pulmonary alveolar microlithiasis: a case report and review of the literature.

A 12-year-old girl of Turkish descent was referred 6xa0weeks after an influenza A infection because of persistent chest X-ray abnormalities compatible with interstitial lung disease. The clinically suspected diagnosis of pulmonary alveolar microlithiasis (PAM) supported by pathognomonic radiological abnormalities was confirmed by genetic analysis. The clinical presentation of PAM is illustrated by a case and review of the current literature on this subject: you only see what you know.

WS13.6 Structural alterations in the end-stage cystic fibrosis lung: comparing histopathology to microCT

WS13.5 Visualising ventilation heterogeneity in mild CF using hyperpolarised 3He MRI, and comparison with lung clearance index (LCI) A. Horsley1,2, H. Marshall1, L. Smith3, D. Hughes4, F. Horn1, L. Armstrong1, J. Parra-Nobles1, S. Cunningham5, I. Aldag3, J. Wild1, C. Taylor3. 1University of Sheffield, Department of Academic Radiology, Sheffield, United Kingdom; 2University of Manchester, Manchester Adult Cystic Fibrosis Centre, Manchester, United Kingdom; 3Sheffield Children’s Hospital NHS Foundation Trust, Department of Respiratory Medicine, Sheffield, United Kingdom; 4Sheffield Children’s Hospital NHS Foundation Trust, Department of Radiology, Sheffield, United Kingdom; 5Royal Hospital for Sick Children, Edinburgh, Department of Respiratory Medicine, Edinburgh, United Kingdom

Monocytes from patients with Primary Ciliary Dyskinesia show enhanced inflammatory properties and produce higher levels of pro-inflammatory cytokines

Patients with Primary Ciliary Dyskinesia (PCD) suffer from recurrent upper and lowerxa0airway infections due to defects in the cilia present on the respiratory epithelium. Since chronic inflammatory conditions can cause changes in innate immune responses, we investigated whether monocytes isolated from the peripheral blood of pediatric PCD patients respond differently to inflammatory stimuli, compared to monocytes from healthy children and adults. The receptor for C5a (C5aR) was upregulated in PCD, whereas expression levels of the leukocyte chemoattractant receptors CCR1, CCR2, CCR5, BLT1 and FPR1 on PCD monocytes were similar to those on monocytes from healthy individuals. Also in vitro migration of PCD monocytes towards the ligands of those receptors (CCL2, fMLP, C5a and LTB4) was normal. Compared to healthy children, PCD patients had a higher percentage of the non-classic monocyte subset (CD14+CD16++) in circulation. Finally, PCD monocytes produced higher levels of pro-inflammatory cytokines (IL-1β and TNF-α) and chemokines (CCL3, CCL5, CCL18 and CCL22) in response to LPS, peptidoglycan and/or dsRNA stimulation. These data suggest that monocytes might exacerbate inflammatory reactions in PCD patients and might maintain a positive feedback-loop feeding the inflammatory process.

109 Influence of nebulized antibiotics on ciliary activity in vitro

Introduction The efficacy of several inhaled drugs is well studied in the context of cystic fibrosis (CF). Their use is however extrapolated to other chronic diseases, without clear evidence of benefit. In addition, the effect of inhaled drugs on ciliary activity has rarely been studied. Previously, we validated an in vitro model for testing the effect of nebulized drugs on ciliary beat frequency (CBF) and showed negative influence of Obracin® but not of Tobi®. Objectives To examine the influence of 2 antibiotics on CBF: the approved inhalation drug Cayston® (C) (provided by Gilead) and Glazidim® (G), used off-label for inhalation in patients with specific infections, e.g. Achromobacter. Methods Non-CF nasal epithelial cells were cultured as monolayer. On day 4 to 6, confluent cell monolayers were exposed to nebulization in an aerosol chamber for 10 minutes. C was nebulized with an eFlow nebulizer plus Altera head, G with a Pari boy nebulizer plus Pari LC star head. Isotonic saline (S) was used as paired, neutral control. Images were acquired with a high-speed camera, and CBF was expressed as % of the starting value. CBF until 1 hour after nebulization was compared between the test condition and S using repeated measure mixed effect model statistics. Results Compared to S, C (n = 4) did not influence CBF (p 0.355): CBF was 96% 1 hour after nebulization of C, versus 98% for S. G (n = 3) neither influenced CBF (p 0.346): CBF was 99% 1 hour after nebulization of G, versus 109% for S. Results on days 2 and 3 were similar. Conclusion Nebulization of Cayston® and Glazidim® did not influence ciliary activitity in vitro. This may be relevant to their in vivo efficacy and safety.

WS13.1 Lung clearance index predicts time to pulmonary exacerbation in children with CF

Lung Clearance Index (LCI) is a promising endpoint for use in CF clinical trials. Since correlation with validated clinical endpoints has not yet been established, we investigated the association between baseline LCI and risk of respiratory tract exacerbations (RTE) in children with CF. Methods: During a prospective observational study, baseline LCI (N2 washout), FEV1 and CFQR respiratory domain (CFQRres) were measured. RTE, defined as an increase in respiratory symptoms treated with IV antibiotics, were recorded during one year. Whether basline LCI predicted RTE was assessed with a Poisson regression model and Kaplan–Meier plots. LCI z-scores were calculated from values in 57 healthy children. Results: In 63 children with CF (median age 12.4 years, range 5−19), mean LCI z-score was 5.3 (SD 4.6) and mean FEV1 z-score −0.9 (SD 1.3). CFQRres correlated with LCI (R = −0.43, p< 0.001), but not with FEV1 (R=0.24, p = 0.051). In the 53 patients with a normal FEV1, CFQRres and LCI were still correlated (R = −0.44, p = 0.002). During the 12 months follow up, 25 patients (40%) experienced 47 RTE. LCI and FEV1 were predictors of RTE. Time to first RTE decreased with worsening LCI quartiles (Log Rank test, p< 0.001). Similarly, compared to the quartile with the lowest LCI, yearly RTE rate ratio in increasing LCI quartiles was 2.8 (95%CI 0.6–13.9, p = 0.205), 4.7 (95%CI 1.0–21.4, p = 0.046) and 13.6 (95%CI 3.2–57.0, p< 0.001). In the group with normal FEV1, LCI but not FEV1 z-score was still a predictor of RTE. Conclusion: Baseline LCI predicts the risk of RTE in children with CF, even in the subgroup with normal FEV1. These data further support the use of LCI as surrogate outcome in CF clinical trials.

Hemoptysis after orthopedic surgery in an adolescent boy

In children, post‐obstructive pulmonary edema is a rare condition, caused by a sudden change in upper airway patency. It causes dyspnea, tachypnea, hypoxemia, and at times hemoptysis and respiratory insufficiency. It occurs as a complication in the immediate post‐operative period. Pediatricians should be aware of this clinical entity. Pediatr Pulmonol. 2012; 47:623–625.