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Previous studies showed that the lung clearance index (LCI) determined by multiple-breath washout (MBW) is sensitive to detecting early lung disease in preschool children with cystic fibrosis (CF). In preschool children with primary ciliary dyskinesia (PCD), data on the onset and severity of lung disease and on the sensitivity of the LCI as a noninvasive quantitative outcome measure remain limited.Is MBW feasible and sensitive to detect ventilation inhomogeneity in preschool children with PCD?This was a prospective, cross-sectional, multicenter study and included preschoolers with PCD, preschoolers with CF, and healthy control (HC) participants. LCI was determined using nitrogen MBW and was compared among the three groups.LCI was determined in 27 children with PCD, 34 children with CF, and 30 HC participants (mean age, 4.8 years; range, 2.2-6.9 years). The LCI in preschool children with PCD was increased (median, 9.1; 95% CI, 8.6-10.3) compared with HC participants (median, 7.0; 95% CI, 6.7-7.1; P .0001), but did not differ from preschool children with CF (median, 8.6; 95% CI, 8.4-9.7; P = .71). The feasibility in the PCD group was 93.1% and was similar to that in the CF group (91.9%) and in HC participants (85.7%; P = .55).This study demonstrated early onset of lung disease in preschool children with PCD and indicated that lung disease severity in PCD may be similar to that in CF during preschool years. These data support a need for early diagnostic monitoring and therapy and suggest the LCI as a noninvasive diagnostic tool and as a potential end point in clinical trials testing early interventions in children with PCD.

Introduction: chILD comprises various rare respiratory conditions and partially overlaps with adult ILD. Lung fibrosis is the most common disease entity in adults; however, there are no data on the prevalence, clinical, radiological and histopathological presentation of pulmonary fibrosis in chILD. Aim: To assess the prevalence of fibrosis in lung biopsies from the international management platform, the European chILD registry (NCT02852928), and to correlate paediatric lung fibrosis with radiological findings. Methods: Features of fibrosis in biopsies were defined by the presence of any of the following: description of interstitial fibrosis, fibroblastic foci or honeycombing. A histological diagnosis of chronic pneumonitis of infancy (CPI) was also included. Fibrosis by chest computed tomography (CT) scans was defined by the presence of linear or reticular opacities, honeycombing, traction bronchiectasis or architectural distortion. Results: Lung biopsies were available for 149/825 chILD cases (18%); 46 biopsies (31%) had features of fibrosis and 11 were identified by CPI pattern alone. Mean age at biopsy was 6.4 years (range 0–26). Thirty cases were related to alveolar surfactant region (ABCA3: n=11; SFTPC: n=3), five to systemic disease processes (e.g. connective tissue disease: n=2) and three to immunodeficiency. Individual cases accounted for the other categories. Only 21/46 cases (46%) with biopsy-proven features of fibrosis had fibrosis features by CT. Conclusions: Features of fibrosis were already present in 31% of cases with a diagnostic lung biopsy. Concordance between biopsy- and CT-diagnosed fibrosis was lower than expected and requires further evaluation.

Background: Pulmonary interstitial glycogenosis (PIG) is a rare interstitial lung disease in children. The clinical hallmark is a rapid onset with respiratory distress and hypoxemia shortly after birth in the absence of an infectious cause or a surfactant dysfunction syndrome. The diagnosis can only be made by lung biopsy. The histopathological pattern defining PIG can exist in diffuse or patchy distribution. Only few cases have been reported. Not much is known on clinical features, outcomes, CT imaging and histopathology. Methods: The clinical course, CT-scans and tissue samples of children diagnosed with PIG were collected and systematically re-analysed by clinicians, radiologists and pathologists all specialized in interstitial lung diseases in children. All data were uploaded into the Kidslungregister for follow up. Results: 11 children diagnosed with PIG were included in this study. All presented with respiratory distress shortly after birth. More than half of the children were diagnosed with additional abnormalities, especially congenital heart defects. The CT-scan of the lungs showed mainly groundglass opacities, consolidations and septal thickening. Of interest each tissue sample had signs of reduced alveolarization. The prognosis was favourable in almost all cases. When systemic glucocorticosteroids were given a fast improvement was noticed. Conclusion: PIG is a interstitial lung disease in infants with mostly favourable outcome. As alveolar growth retardation was present in all subjects this can support a theory of an underlying maturation delay. In all infants with congenital heart defects and unexplained respiratory distress an interstitial lung disease due to PIG should be considered.

Introduction: Human respiratory syncytial virus (hRSV) is the most common cause of lower respiratory tract disease in infants. Due to the lack of treatment options there is a need for new antiviral drugs. Objective: We aimed to identify small molecules with antiviral activity against hRSV and to investigate the mode-of-action of selected compounds. Methods: A cell-based high-throughput screening system was used to screen a compound library. Time-of-drug-addition, lentiviral hRSV pseudotype assays, infection competition and virus dilution assays were conducted to explore the mode of action of lead compounds. Results: The two lantibiotics Labyrinthopeptin A1 and A2 emerged as potent inhibitors of clinical hRSV strains. IC50 values were in the low micromolar range without cytotoxicity up to a 100-fold higher dosage. The antiviral effect could be shown in carcinoma derived lung cells as wells as in physiologically relevant air-liquid interphase (ALI) cultures involving primary human lung epithelial cells. Application during virus inoculation and therapeutic administration of compounds after hRSV infection reduced virus load in the ALI cultures. Moreover, laboratory and clinical strains of hRSV were inhibited. In addition, lentiviral hRSV pseudotypes with or without resistance mutations against palivizumab or fusion inhibitors in clinical development were susceptible to labyrinthopeptin A1 and A2. Time-of-drug-addition as well as the pseudotype assays indicated that both compounds inhibit cell entry of hRSV. Conclusion: Labyrinthopeptin A1 and A2 exert broad antiviral activity against hRSV subtype A and B strains. Thus, these molecules are candidates for further development as antivirals for treatment of hRSV infections.

Introduction: Children’s interstitial lung disease (chILD) comprises a heterogeneous group of over 200 different entities of diffuse lung diseases with symptom onset in childhood. Only 1-3 of one million children are affected per year. No evidence based treatment guidelines exist. Aim: First analysis of the distribution of chILD disease entities using a classification system also including cases without lung biopsy (Orphanet J Rare Dis 2015 10:122), as well as respiratory medications prescribed. Methods: Patients with chILD reported to the European Management Platform for Childhood Interstitial Lung Diseases between December 2012 and November 2016 were included. Baseline and follow up visits including information on disease course and respiratory treatments used in the whole cohort and specific subcategories were analysed. Results: 366 peer-reviewed patients received a final diagnosis: the most common was chILD related to alveolar surfactant region (category A4, n=194), followed by chILD related to systemic disease (B1, n=60), specific conditions of undefined etiology (A3, n=59) and chILD of the immune intact host (B2, n=46). The most commonly used drugs at baseline were glucocorticosteroids in 175 cases (48%), especially in the subcategories A4 and B1. Azithromycin was used in 24% and hydroxychloroquine in 14%. Conclusion: The knowledge of most frequently diagnosed subcategories of chILD and most commonly used medication in these groups will inform controlled studies in the future, especially for glucocorticosteroids and azithromycin in the subcategories A4 and B1.

Macrophages harbor great plasticity and adapt effectively to specific environmental factors. Here, we analyzed the adaptation of induced pluripotent stem cell (iPSC) derived macrophages to the lung environment. Human iPSC derived macrophages were transplanted intrapulmonary to humanized Pulmonary Alveolar Proteinosis (PAP) mice which display high pulmonary levels of surfactant and human GM-CSF. PAP is a life-threatening lung disease caused by GM-CSF receptor mutations and a differentiation block of alveolar macrophages (AM). Mice were transplanted four times in four consecutive weeks, and iPSC macrophages were re-isolated and analyzed two months after the first treatment. Pulmonary transplantation of iPSC macrophages led to pulmonary engraftment and in situ differentiation of iPSC macrophages which displayed the typical morphology of primary human AM and were red-Oil-O positive illustrating functional surfactant uptake. The surface marker profile of re-isolated macrophages was similar to that of primary human AM and was clearly distinct to that of iPSC macrophages before transplantation. The transcriptome of the iPSC macrophages after re-isolation had clearly changed compared to that of iPSC macrophages before transplantation and was most similar to that of hematopoietic stem cell derived AM like cells or primary human AM. Our data show that human iPSC derived macrophages can adapt to the lung environment in a humanized lung disease model. Future studies include the characterization of specific genes central for the adaptation and proliferation of iPSC macrophages in the lung.

Recently, mutations in CCNO (encoding cyclin O) have been described as a novel genetic cause for primary ciliary dyskinesia (PCD). CCNO mutations are associated with reduced generation of motile cilia in the airways [1]. We here present the case of a two year old Syrian boy presenting with typical symptoms of PCD including recurrent respiratory infections, chronic cough and rhinitis and a history of neonatal RDS. In spite of the clinically suspected diagnosis of PCD, we could not detect any ciliar cells in repeated nasal brushings. Thus, we were unable to confirm PCD by evaluation of the ciliar motility. However, genetic screening of the CCNO gene yielded a homozygote loss of function mutation (c.248_252dup, p.Gly85Cysfs*11). This confirmed the diagnosis of CCNO associated PCD with „reduced generation of multiple motile cilia“. In conclusion, this case illustrates that in case of lack of ciliar cells in nasal brushings, CCNO genetics can confirm the PCD diagnosis. 1 Wallmeier et al. 2014 Nat Genet 46(6):646-51.