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Aims Maximal exercise capacity as measured by peak oxygen consumption (pVO2) in cardiopulmonary exercise testing (CPET) of heart transplant recipients (HTR) is limited to a 50–70% level of healthy age‐matched controls. This study investigated the relationship between body composition and pVO2 during the first decade post‐transplant. Methods and results Body composition was determined by dual‐energy X‐ray absorptiometry (DXA) and pVO2 by CPET in 48 HTR (n = 38 males; mean age 51 ± 12 years). A total of 95 assessments were acquired 1–9 years post‐transplant, and the results of four consecutive periods were compared [Period 1: 1–2 years (n = 25); 2: 3–4 years (n = 23); 3: 5–6 years (n = 23); 4: 7–9 years (n = 24)]. Linear regression analysis analysed the correlation between pVO2 and pairs of appendicular lean mass (ALM) and fat mass (FM). The relation between ALM and daily dose of calcineurin inhibitor (CNI) was explored using partial correlation controlling for age, gender, and height. pVO2 increased from 0.98 (0.34) to 1.35 (0.35) L/min (P 8.8 kg/m2). ALM normalized to body mass index increased from 0.690 (0.188) to 0.848 (0.204) m2 (P = 0.02) between Periods 1 and 4, explaining 45% of the variance of pVO2 (R 2 = 0.455; P

The prognostic role of decongestion-related change of cardiac morphology and in particular right heart function has not been investigated comprehensively in AHF patients. This prospective observational single-centre study included consecutive patients hospitalized for treatment of AHF with reduced, mildly-reduced or preserved left ventricular ejection fraction (LVEF). Comprehensive transthoracic echocardiography at admission and discharge assessed decongestion-related change of cardiac function and morphology. The combined endpoint of 1 year all-cause mortality and cardiovascular rehospitalization explored the prognostic importance of decongestion-related change. The 176 study participants were 83 years old [74-87] and 54% were men. Fifty one (29%) had rLVEF, 65 (37%) mrLVEF, and 60 (34%) pLVEF. The proportion of de novo or worsening chronic HF was not different between LVEF groups. HF aetiology and cardiovascular risk factors were equally distributed across all groups except for a higher BMI in the pLVEF group. Decongestion equally reduced body weight, heart rate, systolic and diastolic blood pressure, tricuspid regurgitation gradient, and inferior vena cava diameter across all groups (P < 0.004 for all). Decongestion-related increase in TAPSE independent of the LVEF was associated with improvement of right-ventricular-pulmonary artery coupling and a lower incidence of the combined outcome in the Cox proportional hazard risk analysis (unadjusted HR 0.50 95% CI 0.33-0.78, P = 0.002; adjusted HR 0.46 95% CI: 0.33-0.78, P = 0.001). Decongestion-related increase in TAPSE and recovery of RV/pulmonary artery coupling was observed across all LVEF groups and associated with a risk reduction for the combined endpoint highlighting the important prognostic role of right heart recovery after an AHF episode.

OBJECTIVE Exercise-induced respiratory symptoms (EIS) are common in childhood and reflect different diseases that can be difficult to diagnose. In children referred to respiratory outpatient clinics for EIS, we compared the diagnosis proposed by the primary care physician with the final diagnosis from the outpatient clinic and described diagnostic tests and treatments. DESIGN Observational study of respiratory outpatients aged 0-16 years nested in the Swiss Paediatric Airway Cohort (SPAC). PATIENTS We included children with EIS as main reason for referral. Information about diagnostic investigations, final diagnosis, and treatment prescribed came from outpatient records. We included 214 children (mean age 12 years, range 2-17, 54% males) referred for EIS. RESULTS The final diagnosis was asthma in 115 (54%), extrathoracic dysfunctional breathing (DB) in 35 (16%), thoracic DB in 22 (10%), asthma plus DB in 23 (11%), insufficient fitness in 10 (5%), chronic cough in 6 (3%), and other diagnoses in 3 (1%). Final diagnosis differed from referral diagnosis in 115 (54%, 95%-CI 46-60%). Spirometry, body plethysmography, and exhaled nitric oxide were performed in almost all, exercise-challenge tests in a third, and laryngoscopy in none. 91% of the children with a final diagnosis of asthma were prescribed inhaled medication and 50% of children with DB were referred to physiotherapy. CONCLUSIONS Diagnosis given at the outpatient clinic often differed from the diagnosis proposed by the referring physician. Diagnostic evaluations, management, and follow-up differed between clinics and diagnostic groups highlighting the need for evidence-based diagnostic guidelines and harmonised procedures for children seen for EIS. This article is protected by copyright. All rights reserved.

Heart transplantation remains the most durable treatment for patients with end-stage heart failure refractory to medical treatment. Central elements of the listing criteria for heart transplantation have remained largely unchanged in the last three decades whereas treatment of heart failure has significantly increased survival and reduced disease-related symptoms. It remains unknown whether the improvement of heart failure therapy changed the profile of heart transplantation candidates or affected post-transplant survival. The study investigated a total of 323 heart transplant recipients of the Lausanne University Hospital with 328 transplant operations between 1987 and 2018. Patients were separated into three groups on the basis of availability of heart failure therapy: period 1 (1987-1998; n = 115) when renin-angiotensin system blockade and diuretic treatment were available; period 2 (1999-2010; n = 106) marked by the addition of beta-blocker and mineralocorticoid receptor antagonist treatment in severe heart failure, and the establishment of cardiac defibrillator and resynchronisation therapy; period 3 (2011-2018; n = 107) characterised by the increasing use of ventricular assist devices for bridge to transplantation. The patient characteristics age (all: 53.4 years), male sex (all: 79%) and body mass index (all: 24.5 kg/m2) did not differ between periods. History of arterial hypertension was less prevalent in period 2 (period 1 vs 2 vs 3: 44 vs 28 vs 43%, p = 0.04) whereas other cardiovascular risk factors were equally distributed. Left ventricular ejection fraction, VO2max, and pulmonary vascular resistance were not different between the three periods. The prevalence of ischaemic cardiomyopathy was higher in periods 1 and 3; dilated non-ischaemic cardiomyopathy was more frequent in period 2. Post-transplant 1-year survival was highest in period 3 (1 vs 2 vs 3: 87.2 ± 3.2% vs 70.8 ± 4.4% vs 93.0 ± 2.6%, p always ≤0.02), and the Kaplan-Meier estimates of survivors of the first year post-transplant were not different between the three periods. In descriptive analysis, early mortality was not associated with acknowledged pretransplant predictors of post-transplant mortality. Availability of different medical heart failure treatments did not result in greatly different pretransplant characteristics of heart transplantation recipients across the three periods. This suggests that the maintained central criteria of listing for heart transplantation still identify end-stage heart failure patients with a similar profile. This finding can explain the unchanged overall mortality on condition of 1-year survival across the three periods, since pretransplant characteristics are relevant for long-term survival after heart transplantation.

Background Asthma treatment should be modified according to symptom control and future risk, but there are scarce data on what drives treatment adjustments in routine tertiary care. Objective We studied factors that drive asthma treatment adjustment in pediatric outpatient clinics. Methods We performed a cross-sectional analysis of the Swiss Paediatric Airway Cohort, a clinical cohort of 0- to 16-year-old children seen by pediatric pulmonologists. We collected information on diagnosis, treatment, lung function, and FeNO from hospital records; and on symptoms, sociodemographic, and environmental factors from a parental questionnaire. We used reported symptoms to classify asthma control and categorized treatment according to the 2020 Global Initiative for Asthma guidelines. We used multivariable logistic regression to study factors associated with treatment adjustment (step-up or down vs no change). Results We included 551 children diagnosed with asthma (mean age, 10 years; 37% female). At the clinical visit, most children were prescribed Global Initiative for Asthma step 3 (35%). Compared with previsit treatment, 252 children remained on the same step (47%), 227 were stepped up (42%), and 58 were stepped down (11%). Female sex (adjusted odds ratio [aOR] = 1.61; 95% confidence interval [CI], 1.05-2.47), poor asthma control (aOR = 3.08; 95% CI, 1.72-5.54), and lower FEV1 Z-score (aOR = 0.70; 95% CI, 0.56-0.86 per one Z-score increase) were independently associated with treatment step-up, and low FeNO (aOR = 2.34; 95% CI, 1.23-4.45) was associated with treatment step-down, with marked heterogeneity between clinics. Conclusions In this tertiary care real-life study, we identified main drivers for asthma treatment adjustment. These findings may help improve both asthma management guidelines and clinical practice.

UNLABELLED Altered arterial stiffness is a recognized risk factor of poor cardiovascular health. Chronic inflammation may increase arterial stiffness. We tested whether arterial stiffness is increased children with asthma, a chronic disease characterized by fluctuating airway and systemic inflammation. Arterial stiffness, expressed as carotid-femoral pulse wave velocity (PWVcf), was measured in 37 mild-to-moderate asthmatic children: 11 girls, median (range) age 11.1 years (6-15). PWVcf in asthma was compared to PWVcf in 65 healthy controls matched for age, height, and gender previously studied in Germany and was correlated with airway inflammation and obstruction. PWVcf was higher in asthmatic children compared to controls: PWVcf median (interquartile range) was 4.7 m/s (4.5-4.9) vs. 4.3 m/s (4.1-4.7), p

This report summarises three cases of Churg-Strauss syndrome (CSS) illustrating the diagnostic challenges associated with the cardiac manifestation of this disease. Here, we illustrate the role of cardiac magnetic resonance (CMR) for diagnosis and follow-up of CSS with a focus on new non-contrast T 2 -weighted imaging sequences for quantification of myocardial scar tissue and quantitative T 2 mapping techniques, which allow the detection of myocardial edema.

Aims Clinical studies suggest beneficial effects of renin–angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicin-induced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity. Methods and results Acute DIC was induced by a single injection of Dox at 15 mg/kg and chronic DIC applied 5 injections of Dox at 4 mg/kg/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K/AKT/mTOR pathway along with normal levels of CTGF. Conclusion Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K/AKT/mTOR axis and normal CTGF levels suggesting potential therapeutic implications.

RationaleAcute viral respiratory tract infections in children with cystic fibrosis (CF) are known causes of disease exacerbation. The role of viral infections during infancy is, however, less known, although early infancy is thought to be a crucial period for CF disease development.We prospectively assessed symptomatic and asymptomatic viral detection in the first year of life in infants with CF and healthy controls.MethodsIn a prospective cohort study, we included 31 infants with CF from the Swiss Cystic Fibrosis Infant Lung Development Cohort and 32 unselected, healthy infants from the Basel Bern Infant Lung Development Cohort and followed them throughout the first year of life. Respiratory symptoms were assessed by weekly telephone interviews. Biweekly nasal swabs were analysed for 10 different viruses and two atypical bacteria with real-time seven duplex PCR (CF=561, controls=712).Measurements and resultsInfants with CF and healthy controls showed similar numbers of swabs positive for virus (mean 42% vs 44%; OR 0.91, 95% CI 0.66 to 1.26, p=0.6). Virus-positive swabs were less often accompanied by respiratory symptoms in infants with CF (17% vs 23%; OR 0.64, 95% CI 0.43 to 0.95, p=0.026). This finding was pronounced for symptomatic human rhinovirus detection (7% vs 11%; OR 0.52, 95% CI 0.31 to 0.9, p=0.02).ConclusionsViral detection is not more frequent in infants with CF and respiratory symptoms during viral detection occur even less often than in healthy controls. It is likely an interplay of different factors such as local epithelial properties and immunological mechanisms that contribute to our findings.

OBJECTIVES The impact of multidisciplinary care on outcome after heart transplantation (HTx) remains unclear. METHODS This retrospective study investigates the impact of multidisciplinary care on the primary end point 1-year all-cause mortality (ACM) and the secondary end point mean acute cellular rejection (ACR) grade within the first postoperative year. RESULTS This study includes a total 140 HTx recipients (median age: 53.5 years; males: 80%; donor/recipient gender mismatch: 38.3%; mean length of in-hospital stay: 34 days; mean donor age: 41 years). Multidisciplinary care was implemented in 2008, 66 HTx recipients had operation in 2000-07 and 74 patients had HTx thereafter (2008-14). Non-ischaemic dilated cardiomyopathy was more prevalent in HTx recipients of 2000-07 (63.6 vs 43.2%; P = 0.024). Pre-transplant mechanical circulatory support was more frequent in 2008-14 (9.1 vs 24.3%; P = 0.030). Groups were not different for pre-transplant cardiovascular risk factors or other comorbidity, invasive haemodynamics or echocardiographic parameters. In-hospital and 1-year ACM were numerically lower in 2008-14 (16.2 vs 22.2%; 18.9% vs 25.8%; P = 0.47/0.47, respectively). In 2000-07, pre-transplant weight and diabetes mellitus predicted in-hospital ACM (odds ratio −0.14, P = 0.02; OR 5.24, P = 0.01, respectively) while post-transplant length of in-hospital stay was related with in-hospital ACM (odds ratio −0.10; P = 0.016) and 1-year ACM (odds ratio −0.07; P = 0.007). In 2000-07, the mean grade of ACR within the first postoperative year was higher (0.65 vs 0.20; P

Background Coronary artery spasm (CAS) is an underdiagnosed disease especially in heart transplant patients, and in those patients the etiology and pathophysiology remain largely unknown, although it has been associated with cardiac allograft vasculopathy or graft rejection. Case presentation We report the case of a heart-transplant patient whose cardiac graft experienced two coronary vasospasms: the first before transplantation, and the other at one-month of a postoperative course complicated by primary graft failure. Conclusion Our case illustrates that a transplanted heart predisposed with coronary vasospasm may suffer from early relapse in the recipient despite of complete post-surgical autonomic denervation. Exacerbated endothelial dysfunction of the donor heart after transplant, with the addition of systemic factors in the recipient may be involved in the genesis of this puzzling phenomenon.

The measurement of an airborne concentration in Amosite fibers above 5035 F/m3 in a school prompted a retrospective quantitative health risk assessment. Dose estimates were built using air measurements, laboratory experiments, previous exposure data, and interviews. A dose response model was adapted for amosite-only exposure and adjusted for the life expectancy and lung cancer incidence in the Swiss population. The average yearly concentrations found were 52&ndash, 320 F/m3. The high concentration previously observed was not representative of the average exposure in the building. Overall, the risk estimates for the different populations of the school were low and in the range of 2 &times, 10&minus, 6 to 3 &times, 5 for mesothelioma and 4 &times, 7 to 8 &times, 6 for lung cancer. The results evidenced however that children have to be considered at higher risk when exposed to asbestos, and that the current reference method and target values are of limited use for amphibole-only exposures. This study confirmed that quantitative health risk assessments and participatory approaches are powerful tools to support public decisions and build constructive communication between exposed people, experts, and policy-makers.

OBJECTIVES The objective of this study was to analyse clinical characteristics, survival and adverse events of patients with advanced heart failure supported using the Abbott HeartMate 3 left ventricular assist device (LVAD). METHODS We retrospectively reviewed 42 consecutive HeartMate 3 recipients implanted in our centre between 1 November 2015 and 31 October 2019. RESULTS Our series comprised 39 males, aged 56.7 ± 11.8 years. Eleven (26%) patients had preimplant INTERMACS clinical profiles of 1 or 2. The mean duration support was 14.0 ± 10.6 months (range 0.69–44 months). During follow-up, 4 (10%) patients died while on support, 13 (35%) patients received a heart transplant and 25 patients are still ongoing. Actuarial survival after LVAD implantation was 88.4 ± 5.5% and 84.4 ± 6.6% at 1 and 2 years, respectively. There were no cases of pump thrombosis or technical malfunction. Seven (17%) patients required post-implant temporary right ventricular support. Adverse events included bleeding requiring surgery in 13 (31%) patients, gastrointestinal bleeding in 6 (14%) patients, LVAD-specific infections in 19 (45%) patients and non-disabling ischaemic stroke in 5 (12%) patients. The incidence of ischaemic stroke was significantly higher in patients where the outflow graft was anastomosed to the descending aorta as compared to those where it was anastomosed to the ascending aorta (P CONCLUSIONS We have observed satisfactory survival rates using the HeartMate 3 LVAD for long-term mechanical circulatory support. The absence of technical failure, pump thrombosis, haemolysis or need for pump exchange during our 4-year experience confirms its technical reliability and improved haemocompatibility, but bleeding complications and infections remain a concern.

In search of a non-invasive alternative detection of early-stage cardiac allograft vasculopathy (CAV), in this preliminary study we tested the hypothesis that interstitial fibrosis quantified with cardiac magnetic resonance (CMR) can serve as a biomarker for the detection of CAV. Late-stage CAV was detected with routine X-ray coronary angiography (XRCA), while a coronary intima-media thickness ratio (IMTR) > 1 on optical coherence tomography (OCT) was used to detect early-stage CAV. Interstitial fibrosis was quantified in the endomyocardial biopsy (EMB) and indirectly with CMR as the T 1 relaxation time and extracellular volume (ECV). CMR was performed within 48 h of a single invasive procedure with XRCA, OCT, and EMB procurement in stable HTx recipients (n = 27; age 54 ± 13 years, 5.4 ± 3.7 years post-transplant). XRCA-CAV and IMTR > 1 were present in 15% and 75% of study patients, respectively. The T 1 relaxation times and ECV were increased in patients with XRCA-CAV (p = 0.03 each), while IMTR and EMB interstitial fibrosis were not significantly different (both p > 0.05). ECV (ρ = 0.46, p = 0.02) and IMTR (ρ = 0.58; p = 0.01) correlated with the histological quantity of interstitial fibrosis, while the T 1 relaxation time (p = 0.06) did not. The correlation of the IMTR with the EMB interstitial fibrosis tentatively validates the hypothesis that interstitial fibrosis may serve as an early indicator of CAV. Moreover, the significant association of CMR-based ECV with the magnitude of interstitial fibrosis in the biopsy suggests ECV as a potential biomarker for interstitial fibrosis due to early-stage CAV. The measurement of ECV may therefore have a role for non-invasive detection and follow-up of early-stage CAV.

Background Proline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms. Methods Broncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed. Results Whilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase. Conclusions A striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia., Graphical abstract Unlabelled Image, Highlights • PGP is a collagen-derived pro-neutrophilic mediator. • PGP accumulates in the airways of children with cystic fibrosis. • Imbalance of PGP generation (MMP/PE) vs degradation (LTA4H) enables PGP build-up. • LTA4H is destroyed by neutrophil elastase to prevent PGP degradation. • Infections are key to spiking PGP generation in setting it cannot be degraded.

A 22-year-old male with a typical history of pauci-symptomatic COVID-19 3 weeks earlier, confirmed by positive serology for SARS-CoV-2 (IgG), was admitted to the intensive care unit because of severe myocarditis with refractory cardiogenic shock that required extracorporeal life support. Due to a clinical presentation suggestive of Kawasaki-like disease with coronary aneurysm and severe systemic inflammation, intravenous immunoglobulins were administered in combination with tocilizumab. The initial clinical course was favourable with these treatments. However, the patient subsequently developed a severe mononeuritis multiplex leading to bilateral foot drop, which required intensive immunosuppressive therapy (corticosteroids, cyclophosphamide and rituximab). The clinical presentation meets the criteria for multisystem inflammatory syndrome associated with SARS-CoV-2, but includes very severe organ damages. Early recognition, a multidisciplinary approach and aggressive therapeutic intervention can lead to a favourable outcome.

Primary Ciliary Dyskinesia (PCD) is a rare hereditary, multi-organ disease caused by defects in ciliary structure and function. It results in a wide range of clinical manifestations, most commonly in the upper and lower airways. Central data collection in national and international registries is essential to studying the epidemiology of rare diseases and filling in gaps in knowledge of diseases such as PCD. For this reason, the Swiss Primary Ciliary Dyskinesia Registry (CH-PCD) was founded in 2013 as a collaborative project between epidemiologists and adult and paediatric pulmonologists.The registry records patients of any age, suffering from PCD, who are treated and resident in Switzerland. It collects information from patients identified through physicians, diagnostic facilities, and patient organisations. The registry dataset contains data on diagnostic evaluations, lung function, microbiology and imaging, symptoms, treatments, and hospitalizations.By May 2018, CH-PCD has contacted 566 physicians of different specialties and identified 134 patients with PCD. At present this number represents an overall 1 in 63,000 prevalence of people diagnosed with PCD in Switzerland. Prevalence differs by age and region; it is highest in children and adults younger than 30 years, and in Espace Mittelland. The median age of patients in the registry is 25 years (range 5-73), and 49 patients have a definite PCD diagnosis based on recent international guidelines. Data from CH-PCD are contributed to international collaborative studies and the registry facilitates patient identification for nested studies.CH-PCD has proven to be a valuable research tool that already has highlighted weaknesses in PCD clinical practice in Switzerland. Development of centralised diagnostic and management centres and adherence to international guidelines are needed to improve diagnosis and management—particularly for adult PCD patients.

Vitamin D has immunomodulatory properties in the defence against pathogens. Its insufficiency is a widespread feature of cystic fibrosis (CF) patients, which are repeatedly suffering from rhinovirus (RV)-induced pulmonary exacerbations.To investigate whether vitamin D has antiviral activity, primary bronchial epithelial cells from CF children were pre-treated with vitamin D and infected with RV16. Antiviral and anti-inflammatory activity of vitamin D was assessed. RV and LL-37 levels were measured in bronchoalveolar lavage (BAL) of CF children infected with RV.Vitamin D reduced RV16 load in a dose-dependent manner in CF cells (10−7 M, pRV replication in primary CF bronchial cells was reduced by vitamin D through the induction of LL-37. Clinical studies are needed to determine the importance of an adequate control of vitamin D for prevention of virus-induced pulmonary CF exacerbations.

BACKGROUND: Rhinovirus (RV) induced pulmonary exacerbations are common in cystic fibrosis (CF) and have been associated with impaired virus clearance by the CF airway epithelium in vitro. OBJECTIVE: To assess in vivo the association of RV prevalence and load with anti viral defense mechanisms airway inflammation and lung function parameters in children with CF as compared to children with other chronic respiratory diseases and controls. METHODS: RV presence and load was measured by real time RT PCR in bronchoalveolar lavage (BAL) samples and related to anti viral and inflammatory mediators measured in BAL and to clinical parameters. RESULTS: BAL samples were obtained from children with CF (n=195) non CF bronchiectasis (n=40) asthma (n=29) and controls (n=35) at a median (IQR) age of 8.2 (4.0 11.7) years. RV was detected in 73 samples (24.4). RV prevalence was similar between groups. RV load (median [IQR] x103 copies/mL) was higher in CF (143.0 [13.1 1530.0]) especially during pulmonary exacerbations compared to asthmatics (3.0 [1.3 25.8] p=0.006) and controls (0.5 [0.3 0.5] plt;0.001) but similar to non CF bronchiectasis (122.1 [2.7 4423.5] p=NS). In children with CF RV load was negatively associated with IFN ß/ ? IL r1a levels and FEV1 and positively with CXCL8 and CXCL10 levels. CONCLUSION: RV load in CF BAL is high especially during exacerbated lung disease. Impaired production of anti viral mediators may lead to the high RV burden in the lower airways of children with CF. Whether high RV load is a cause or a consequence of inflammation needs further investigation in longitudinal studies.1Division of Pediatric Respiratory Medicine Department of Pediatrics University Hospital Bern Switzerland; elisabeth.kieingerinsel.ch florian.singerinsel.ch marco.alvesdkf.unibe.ch philipp.latzininsel.ch carmen.casaultainsel.ch nicolas.regameyinsel.ch2Department of Clinical Research University of Bern Bern Switzerland; elisabeth.kieingerinsel.ch marco.alvesdkf.unibe.ch philipp.latzininsel.ch nicolas.regameyinsel.ch3Laboratory of Virology Division of Infectious Diseases and Division of Laboratory Medicine University of Geneva Hospitals and Faculty of Medicine University of Geneva Switzerland; Caroline.Tapparelhcuge.ch Laurent.Kaisersec.hcuge.ch4Department of Pediatric Respiratory Medicine Royal Brompton Hospital London United Kingdom h.tanimperial.ac.uk carajbossleyhotmail.com a.bushimperial.ac.uk j.c.daviesimperial.ac.ukCorresponding author: Nicolas Regamey MD; Division of Respiratory Medicine Department of Pediatrics University Hospital Inselspital 3010 Bern Switzerland Email: nicolas.regameyinsel.chFunding Sources: Supported by the Swiss National Science Foundation [PP00P3_123453/1 to N.R] the Fondazione Ettore e Valeria Rossi [long time fellowship to E.K.] and the Austrian German and Swiss Pediatric Respiratory Society [short time fellowship to E.K].

Background In vitro systems of primary cystic fibrosis (CF) airway epithelial cells are an important tool to study molecular and functional features of the native respiratory epithelium. However, undifferentiated CF airway cell cultures grown under submerged conditions do not appropriately represent the physiological situation. A more advanced CF cell culture system based on airway epithelial cells grown at the air-liquid interface (ALI) recapitulates most of the in vivo-like properties but requires the use of invasive sampling methods. In this study, we describe a detailed characterization of fully differentiated primary CF airway epithelial cells obtained by non-invasive nasal brushing of pediatric patients. Methods Differentiated cell cultures were evaluated with immunolabelling of markers for ciliated, mucus-secreting and basal cells, and tight junction and CFTR proteins. Epithelial morphology and ultrastructure was examined by histology and transmission electron microscopy. Ciliary beat frequency was investigated by a video-microscopy approach and trans-epithelial electrical resistance was assessed with an epithelial Volt-Ohm meter system. Finally, epithelial permeability was analysed by using a cell layer integrity test and baseline cytokine levels where measured by an enzyme-linked immunosorbent assay. Results Pediatric CF nasal cultures grown at the ALI showed a differentiation into a pseudostratified epithelium with a mucociliary phenotype. Also, immunofluorescence analysis revealed the presence of ciliated, mucus-secreting and basal cells and tight junctions. CFTR protein expression was observed in CF (F508del/F508del) and healthy cultures and baseline interleukin (IL)-8 and IL-6 release were similar in control and CF ALI cultures. The ciliary beat frequency was 9.67 Hz and the differentiated pediatric CF epithelium was found to be functionally tight. Conclusion In summary, primary pediatric CF nasal epithelial cell cultures grown at the ALI showed full differentiation into ciliated, mucus-producing and basal cells, which adequately reflect the in vivo properties of the human respiratory epithelium. Electronic supplementary material The online version of this article (10.1186/s12931-017-0706-7) contains supplementary material, which is available to authorized users.

Virus-associated pulmonary exacerbations, often associated with rhinoviruses (RVs), contribute to cystic fibrosis (CF) morbidity. Currently, there are only a few therapeutic options to treat virus-induced CF pulmonary exacerbations. The macrolide antibiotic azithromycin has antiviral properties in human bronchial epithelial cells. We investigated the potential of azithromycin to induce antiviral mechanisms in CF bronchial epithelial cells.Primary bronchial epithelial cells from CF and control children were infected with RV after azithromycin pre-treatment. Viral RNA, interferon (IFN), IFN-stimulated gene and pattern recognition receptor expression were measured by real-time quantitative PCR. Live virus shedding was assessed by assaying the 50% tissue culture infective dose. Pro-inflammatory cytokine and IFN-β production were evaluated by ELISA. Cell death was investigated by flow cytometry.RV replication was increased in CF compared with control cells. Azithromycin reduced RV replication seven-fold in CF cells without inducing cell death. Furthermore, azithromycin increased RV-induced pattern recognition receptor, IFN and IFN-stimulated gene mRNA levels. While stimulating antiviral responses, azithromycin did not prevent virus-induced pro-inflammatory responses.Azithromycin pre-treatment reduces RV replication in CF bronchial epithelial cells, possibly through the amplification of the antiviral response mediated by the IFN pathway. Clinical studies are needed to elucidate the potential of azithromycin in the management and prevention of RV-induced CF pulmonary exacerbations.

Primary nasal epithelial cells are used for diagnostic purposes in clinical routine and have been shown to be good surrogate models for bronchial epithelial cells in studies of airway inflammation and remodeling. We aimed at comparing different instruments allowing isolation of nasal epithelial cells.Primary airway epithelial cell cultures were established using cells acquired from the inferior surface of the middle turbinate of both nostrils. Three different instruments to isolate nasal cells were used: homemade cytology brush, nasal swab, and curette. Cell count, viability, time until a confluent cell layer was reached, and success rate in establishing cell cultures were evaluated. A standard numeric pain intensity scale was used to assess the acceptability of each instrument.Sixty healthy adults (median with interquartile range [IQR] age of 31 [26-37] years) participated in the study. Higher number of cells (×10(5) cells/ml) was obtained using brushes (9.8 [5.9-33.5]) compared to swabs (2.4 [1.5-3.9], p0.0001) and curettes (5.5 [4.4-6.9], p0.01). Cell viability was similar between groups. Cells obtained by brushes had the fastest growth rate, and the success rate in establishing primary cell cultures was highest with brushes (90% vs. 65% for swabs and 70% for curettes). Pain was highest with curettes (VAS score 4.0 [3.0-5.0] out of 10). The epithelial phenotype of the cultures was confirmed through cytokeratin and E-cadherin staining.All three types of instruments allow collection and growth of human nasal epithelial cells with good acceptability to study participants. The most efficient instrument is the nasal brush.

Human rhinoviruses (HRV) are the most common respiratory viruses identified in humans with respiratory infections. HRV-induced wheezing during early life is strongly associated with the later development of asthma. However, detailed information is lacking on prevalence of HRV types and their association with respiratory symptoms. We therefore investigated the prevalence of HRV types in nasal swabs of 20 unselected healthy infants and its association with respiratory symptoms on a weekly basis during the first year of life. HRV was detected in 261 out of 825 of all nasal swabs (32%). HRV species A (HRV-A) and -C were equally frequent (39%), followed by HRV-B (12%). 76 different HRV types were detected with A78, A16 and B6 being the most frequent ones. HRV species A and C tended to induce more respiratory symptoms than HRV-B. The presence of different HRV species and types in the airways and the association between HRV types and respiratory symptoms during infancy is highly heterogeneous and dynamic without any immediately recognizable pattern.

Deficient type I interferon-β and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.

Knowledge about the clinical spectrum of lung disease caused by variations in the ATP binding cassette subfamily A member 3 (ABCA3) gene is limited. Here we describe genotype-phenotype correlations in a European cohort.We retrospectively analysed baseline and outcome characteristics of 40 patients with two disease-causing ABCA3 mutations collected between 2001 and 2015.Of 22 homozygous (15 male) and 18 compound heterozygous patients (3 male), 37 presented with neonatal respiratory distress syndrome as term babies. At follow-up, two major phenotypes are documented: patients with (1) early lethal mutations subdivided into (1a) dying within the first 6 months or (1b) before the age of 5 years, and (2) patients with prolonged survival into childhood, adolescence or adulthood. Patients with null/null mutations predicting complete ABCA3 deficiency died within the 1st weeks to months of life, while those with null/other or other/other mutations had a more variable presentation and outcome. Treatment with exogenous surfactant, systemic steroids, hydroxychloroquine and whole lung lavages had apparent but many times transient effects in individual subjects.Overall long-term (5 years) survival of subjects with two disease-causing ABCA3 mutations was20%. Response to therapies needs to be ascertained in randomised controlled trials.

Summary Background Respiratory tract infections and subsequent airway inflammation occur early in the life of infants with cystic fibrosis. However, detailed information about the microbial composition of the respiratory tract in infants with this disorder is scarce. We aimed to undertake longitudinal in-depth characterisation of the upper respiratory tract microbiota in infants with cystic fibrosis during the first year of life. Methods We did this prospective cohort study at seven cystic fibrosis centres in Switzerland. Between Feb 1, 2011, and May 31, 2014, we enrolled 30 infants with a diagnosis of cystic fibrosis. Microbiota characterisation was done with 16S rRNA gene pyrosequencing and oligotyping of nasal swabs collected every 2 weeks from the infants with cystic fibrosis. We compared these data with data for an age-matched cohort of 47 healthy infants. We additionally investigated the effect of antibiotic treatment on the microbiota of infants with cystic fibrosis. Statistical methods included regression analyses with a multivariable multilevel linear model with random effects to correct for clustering on the individual level. Findings We analysed 461 nasal swabs taken from the infants with cystic fibrosis; the cohort of healthy infants comprised 872 samples. The microbiota of infants with cystic fibrosis differed compositionally from that of healthy infants (p=0·001). This difference was also found in exclusively antibiotic-naive samples (p=0·001). The disordering was mainly, but not solely, due to an overall increase in the mean relative abundance of Staphylococcaceae in infants with cystic fibrosis compared with healthy infants (multivariable linear regression model stratified by age and adjusted for season; second month: coefficient 16·2 [95% CI 0·6–31·9]; p=0·04; third month: 17·9 [3·3–32·5]; p=0·02; fourth month: 21·1 [7·8–34·3]; p=0·002). Oligotyping analysis enabled differentiation between Staphylococcus aureus and coagulase-negative Staphylococci. Whereas the analysis showed a decrease in S aureus at and after antibiotic treatment, coagulase-negative Staphylococci increased. Interpretation Our study describes compositional differences in the microbiota of infants with cystic fibrosis compared with healthy controls, and disordering of the microbiota on antibiotic administration. Besides S aureus , coagulase-negative Staphylococci also contributed to the disordering identified in these infants. These findings are clinically important in view of the crucial role that bacterial pathogens have in the disease progression of cystic fibrosis in early life. Our findings could be used to inform future studies of the effect of antibiotic treatment on the microbiota in infants with cystic fibrosis, and could assist in the prevention of early disease progression in infants with this disorder. Funding Swiss National Science Foundation, Fondation Botnar, the Swiss Society for Cystic Fibrosis, and the Swiss Lung Association Bern.

Rhinovirus (RV) infections occur early and recurrently in life, imposing a significant burden of disease on infants and young children. They are the most frequent causative agents of both upper and lower respiratory tract infections in this age group and are associated with a broad variety of clinical outcomes, ranging from asymptomatic infections to severe respiratory disease requiring hospitalisation. In addition to their impact on short-term morbidity, RVs are also debated as important pathogens in the development of recurrent wheeze and/or asthma. Several studies in infants at high-risk for atopy and asthma and in hospitalised children have demonstrated that recurrent wheezing illnesses induced by RVs early in life are a risk factor for the development of asthma later in childhood. However, underlying mechanisms are poorly understood. The question whether RVs are directly involved in the development of childhood wheeze and asthma, or whether symptomatic RV infections only represent a proxy for infants prone to develop obstructive lung diseases, is still open. In this review we provide an overview on the role of RVs as important disease-causing agents from infancy to early childhood and discuss their contribution to the subsequent development of childhood wheeze and/or asthma.

Background Two distinct, stable inflammatory phenotypes have been described in adults with asthma: eosinophilic and non-eosinophilic. Treatment strategies based on these phenotypes have been successful. This study evaluated sputum cytology in children with asthma to classify sputum inflammatory phenotypes and to assess their stability over time. Methods Sputum induction was performed in 51 children with severe asthma and 28 with mild to moderate asthma. Samples were classified as eosinophilic (>2.5% eosinophils), neutrophilic (>54% neutrophils); mixed granulocytic (>2.5% eosinophils, >54% neutrophils); or paucigranulocytic (≤2.5% eosinophils, ≤54% neutrophils). Sputum induction was repeated every 3 months in children with severe asthma (n=42) over a 1-year period and twice in mild to moderate asthma (n=17) over 3–6 months. Results 62 children (78%) had raised levels of inflammatory cells in at least one sputum sample. In the longitudinal analysis 37 of 59 children (63%) demonstrated two or more phenotypes. Variability in sputum inflammatory phenotype was observed in both the severe and the mild to moderate asthma groups. Change in phenotype was not related to change in inhaled corticosteroid (ICS) dose or asthma control, nor was it reflected in a change in exhaled nitric oxide (FE NO ). 24 children (41%) fulfilled the criteria for non-eosinophilic asthma on one occasion and eosinophilic on another. There were no differences in severity, asthma control, atopy, ICS dose or forced expiratory volume in 1 s between those who were always non-eosinophilic and those always eosinophilic. Conclusion Raised levels of inflammatory cells were frequently found in children with asthma of all severities. Sputum inflammatory phenotype was not stable in children with asthma.

Studies in cystic fibrosis (CF) generally focus on inflammation present in the airway lumen. Little is known about inflammation occurring in the airway wall, the site ultimately destroyed in end-stage disease.To test the hypothesis that inflammatory patterns in the lumen do not reflect those in the airway wall of children with CF.Bronchoalveolar lavage (BAL) fluid and endobronchial biopsies were obtained from 46 children with CF and 16 disease-free controls. BAL cell differential was assessed using May-Gruenwald-stained cytospins. Area profile counts of bronchial tissue immunopositive inflammatory cells were determined.BAL fluid from children with CF had a predominance of neutrophils compared with controls (median 810×10(3)/ml vs 1×10(3)/ml, p0.0001). In contrast, subepithelial bronchial tissue from children with CF was characterised by a predominance of lymphocytes (median 961 vs 717 cells/mm(2), p=0.014), of which 82% were (CD3) T lymphocytes. In chest exacerbations, BAL fluid from children with CF had more inflammatory cells of all types compared with those with stable disease whereas, in biopsies, only the numbers of lymphocytes and macrophages, but not of neutrophils, were higher. A positive culture of Pseudomonas aeruginosa was associated with higher numbers of T lymphocytes in subepithelial bronchial tissue (median 1174 vs 714 cells/mm(2), p=0.029), but no changes were seen in BAL fluid. Cell counts in BAL fluid and biopsies were positively correlated with age but were unrelated to each other.The inflammatory response in the CF airway is compartmentalised. In contrast to the neutrophil-dominated inflammation present in the airway lumen, the bronchial mucosa is characterised by the recruitment and accumulation of lymphocytes.

The "low volume hypothesis," stating that imbalanced ion movement across the cystic fibrosis (CF) airway epithelium leads to a reduction in periciliary fluid (PCL) and consequently impaired mucociliary clearance, has been the prevailing theory explaining CF pathophysiology, and has been supported by animal models and ex vivo cell culture systems. However, studies in freshly obtained human tissue have not yet been performed. Methods to quantify PCL height in freshly obtained airway biopsies may be useful to assess efficacy of new treatments aimed at restoring PCL height. Here, we established methods to quantify PCL height in freshly obtained CF and non-CF human lower airway biopsies. More than 90% of biopsies contained ciliated epithelium, and PCL height measurements were feasible in approximately 50% of these. Although the mean PCL height was reduced in CF tissue (non-CF, 5.60 ± 0.28 μm; CF, 4.52 ± 0.47 μm), this did not reach statistical significance (P = 0.06). To strengthen the data, we performed similar studies in wild-type and CF knockout mice, and confirmed the results (non-CF, 4.70 ± 0.13; CF, 4.10 ± 0.09 μm; P0.05). PCL height measurements in freshly obtained human airway biopsies are feasible, and PCL height appears reduced in subjects with CF, thereby further supporting the "low volume hypothesis." However, power calculations indicate that this assay can only be considered as a biomarker in large, late-phase clinical trials, because sample sizes required to achieve sufficient power are comparatively large.

Respiratory infections cause considerable morbidity during infancy. The impact of innate immunity mechanisms, such as mannose‐binding lectin (MBL), on respiratory symptoms remains unclear. The aims of this study were to investigate whether cord blood MBL levels are associated with respiratory symptoms during infancy and to determine the relative contribution of MBL when compared with known risk factors. This is a prospective birth cohort study including 185 healthy term infants. MBL was measured in cord blood and categorized into tertiles. Frequency and severity of respiratory symptoms were assessed weekly until age one. Association with MBL levels was analysed using multivariable random effects Poisson regression. We observed a trend towards an increased incidence rate of severe respiratory symptoms in infants in the low MBL tertile when compared with infants in the middle MBL tertile [incidence rate ratio (IRR) = 1.59; 95% confidence interval (CI): 0.95–2.66; p = 0.076]. Surprisingly, infants in the high MBL tertile suffered significantly more from severe and total respiratory symptoms than infants in the middle MBL tertile (IRR = 1.97; 95% CI: 1.20–3.25; p = 0.008). This association was pronounced in infants of parents with asthma (IRR = 3.64; 95% CI: 1.47–9.02; p = 0.005). The relative risk associated with high MBL was similar to the risk associated with well‐known risk factors such as maternal smoking or childcare. In conclusion the association between low MBL levels and increased susceptibility to common respiratory infections during infancy was weaker than that previously reported. Instead, high cord blood MBL levels may represent a so far unrecognized risk factor for respiratory morbidity in infants of asthmatic parents.

Structural alterations to airway smooth muscle (ASM) are a feature of asthma and cystic fibrosis (CF) in adults.We investigated whether increase in ASM mass is already present in children with chronic inflammatory lung disease.Fiberoptic bronchoscopy was performed in 78 children (median age [IQR], 11.3 [8.5-13.8] yr): 24 with asthma, 27 with CF, 16 with non-CF bronchiectasis (BX), and 11 control children without lower respiratory tract disease. Endobronchial biopsy ASM content and myocyte number and size were quantified using stereology.The median (IQR) volume fraction of subepithelial tissue occupied by ASM was increased in the children with asthma (0.27 [0.12-0.49]; P0.0001), CF (0.12 [0.06-0.21]; P0.01), and BX (0.16 [0.04-0.21]; P0.01) compared with control subjects (0.04 [0.02-0.05]). ASM content was related to bronchodilator responsiveness in the asthmatic group (r = 0.66, P0.01). Median (IQR) myocyte number (cells per mm(2) of reticular basement membrane) was 8,204 (5,270-11,749; P0.05) in children with asthma, 4,504 (2,838-8,962; not significant) in children with CF, 4,971 (3,476-10,057; not significant) in children with BX, and 1,944 (1,596-6,318) in control subjects. Mean (SD) myocyte size (mum(3)) was 3,344 (801; P0.01) in children with asthma, 3,264 (809; P0.01) in children with CF, 3,177 (873; P0.05) in children with BX, and 1,927 (386) in control subjects. In all disease groups, the volume fraction of ASM in subepithelial tissue was related to myocyte number (asthma: r = 0.84, P0.001; CF: r = 0.81, P0.01; BX: r = 0.95, P0.001), but not to myocyte size.Increases in ASM (both number and size) occur in children with chronic inflammatory lung diseases that include CF, asthma, and BX.

Background Studies on airway remodeling in children with cystic fibrosis (CF) may be hampered by difficulty in obtaining evaluable endobronchial biopsy specimens because of large amounts of mucus and inflammation in the CF airway. We prospectively assessed how the quality of biopsy specimens obtained from children with CF compare with those from children with other airway diseases. Methods Fiberoptic bronchoscopy with endobronchial biopsy was performed in 67 CF children (age range, 0.2 to 16.8 years), 34 children with wheeze/asthma (W/A), and 64 control children with chronic respiratory symptoms. Up to three biopsy specimens were taken and stained with hematoxylin and eosin. Biopsy specimen size and structural composition were quantified using stereology. Results At least one evaluable biopsy specimen was obtained in 72% of CF children, in 79% of children with W/A, and in 72% of control subjects (difference was not significant). The use of large biopsy forceps (2.0 mm) rather than small biopsy forceps (1.0 mm) [odds ratio (OR), 5.8; 95% confidence interval (CI), 1.1 to 29.8; p = 0.037] and the number of biopsy specimens taken (odds ratio, 2.6; 95% confidence interval, 1.3 to 5.2; p = 0.006) significantly contributed to the success rate. Biopsy size and composition were similar between groups, except that CF children and those patients with W/A had a higher percentage of the biopsy specimen composed of muscle than did control subjects (median 6.2% and 9.7% vs 0.9%, respectively; p = 0.002). Conclusions Biopsy size and quality are adequate for the study of airway remodeling in CF children as young as 2 months of age. Researchers should use large forceps when possible and take at least two biopsy specimens per patient. An increased airway smooth muscle content of the airway mucosa may contribute to the pathophysiology of CF lung disease.

BACKGROUND AND OBJECTIVE Rhinoviruses (RV) replicate in both upper and lower airway epithelial cells. We evaluated the possibility of using nasal epithelial cells (NEC) as surrogate of bronchial epithelial cells (BEC) for RV pathogenesis cell culture studies. METHODS We used primary paired NEC and BEC cultures established from healthy subjects and compared the replication of RV belonging to the major (RV16) and minor (RV1B) group, and the cellular antiviral and proinflammatory cytokine responses towards these viruses. We related antiviral and pro-inflammatory responses of NEC isolated from CF and COPD patients with those of BEC. RESULTS RV16 replication and major group surface receptor (ICAM-1) expression were higher in healthy NEC compared with BEC (P

Respiratory symptoms are common in infancy. Nevertheless, few prospective birth cohort studies have studied the epidemiology of respiratory symptoms in normal infants. The aim of this study was to prospectively obtain reliable data on incidence, severity, and determinants of common respiratory symptoms (including cough and wheeze) in normal infants and to determine factors associated with these symptoms. In a prospective population-based birth cohort, we assessed respiratory symptoms during the first year of life by weekly phone calls to the mothers. Poisson regression was used to examine the association between symptoms and various risk factors. In the first year of life, respiratory symptoms occurred in 181/195 infants (93%), more severe symptoms in 89 (46%). The average infant had respiratory symptoms for 4 weeks and 90% had symptoms for less than 12 weeks (range 0 to 23). Male sex, higher birth weight, maternal asthma, having older siblings and nursery care were associated with more, maternal hay fever with fewer respiratory symptoms. The association with prenatal maternal smoking decreased with time since birth. This study provides reliable data on the frequency of cough and wheeze during the first year of life in healthy infants; this may help in the interpretation of published hospital and community-based studies. The apparently reduced risk in children of mothers with hayfever but no asthma, and the decreasing effect of prenatal smoke exposure over time illustrate the complexity of respiratory pathology in the first year of life.

Cystic Fibrosis is the most common autosomal-recessive hereditary disease among white Europeans. The average survival of CF patients has increased to above 40 years and transition from paediatric to adult care has therefore become a significant issue.With this study, experiences of adolescents with CF and their parents with the transition from the paediatric to the adult care were explored.At a Swiss university CF centre, six adolescents and their mothers were recruited. Twelve narrative interviews were conducted on how the phase of transition was experienced. The transcribed interviews were analysed according to the method of hermeneutic phenomenology.Positive and negative experiences with long term routine care in the paediatric service, general themes of adolescence and the quality of the relationship with paediatric doctors influenced the families' experience during transition significantly. For mothers, insensitive information on the CF diagnosis might have influenced the transition experience. The adolescents welcomed an individualized and age appropriate care. Continuity in care, the announcement of, and involvement in the planning of the transfer were of great importance. The families particularly appreciated the timed adaptations of the transfer to individual needs.Flexibility and a strong collaboration between paediatric and adult CF teams are most relevant in the care of families.Hintergrund: Cystische Fibrose (CF) ist die häufigste autosomal-rezessiv vererbte Erkrankung in der europäischen Bevölkerung. Die mittlere Überlebenszeit von CF-Betroffenen steigt und liegt heute bei über 40 Jahren. Deshalb ist die Betreuung in der Adoleszenz während des Übergangs von der Pädiatrie in die Erwachsenenmedizin, in der Fachsprache Transition genannt, ein wichtiges Thema. Ziel: Mit dieser Studie wurde exploriert, wie Jugendliche mit CF und ihre Eltern die Transition erlebten. Methode: Die Studie wurde an einem universitären CF Zentrum durchgeführt. Sechs Jugendliche und ihre Mütter erzählten in zwölf Interviews, wie sie die Phase der Transition erlebten. Die Auswertung der transkribierten Interviews erfolgte nach der Methode der hermeneutischen Phänomenologie. Ergebnisse: Positive und negative Erfahrungen während der langjährigen Behandlung in der Kinderklinik, die Adoleszenz als Lebensphase und die Zusammenarbeit mit den Ärzten während der Transition beeinflussten das Erleben der Betroffenen. Für die Mütter könnte eine unsensible Eröffnung der CF Diagnose Auswirkungen auf die Transition gehabt haben. Die Jugendlichen begrüßten eine individualisierte, ihrer Entwicklung angepasste Begleitung. Kontinuität in der ärztlichen Betreuung, die Ankündigung des Übertritts und der Einbezug in dessen Planung erleichterten die Transition. Besonders geschätzt wurde die zeitliche Anpassung an individuelle Bedürfnisse. Schlussfolgerung: Flexibilität und die enge Zusammenarbeit zwischen dem pädiatrischen und adulten CF-Team sind zentral für die Betreuung der Familien.

The clinical course of rhinovirus (RV)-associated wheezing illnesses is difficult to predict. We measured lactate dehydrogenase concentrations, RV load, antiviral and proinflammatory cytokines in nasal washes obtained from 126 preschool children with RV wheezy bronchitis. lactate dehydrogenase values were inversely associated with subsequent need for oxygen therapy. lactate dehydrogenase may be a useful biomarker predicting disease severity in RV wheezy bronchitis.

The relationship between viral infection with Kaposi sarcoma-associated herpesvirus (KSHV) and the onset of Kaposi sarcoma (KS) in AIDS patients is incompletely understood. This study investigates the use of three serological assays to predict the development of KS in HIV-positive patients. Serially collected serum samples from 36 patients with KS and matched controls in the Swiss HIV Cohort Study (SHCS) were analyzed in a case control study. Three serologic assays to detect antibodies against KSHV (nuclear and membrane antigen immunofluorescence assay, N-IFA, M-IFA and ORF 65.2 ELISA) were used to determine the predictive value of KSHV-seropositivity. Serial samples from the cases were also analyzed to determine longitudinal patterns of seroreactivity and identify cases of seroconversion. Assay sensitivity for detection of KSHV antibodies was highest for M-IFA (83%), followed by N-IFA (74%) and 65.2 ELISA (52%). At the time of initial serum sampling (median 4.7 years before KS), only the N-IFA distinguished case and control sera (61% vs. 32%) and no assay was clearly predictive of subsequent onset of clinical KS. Moreover, an unexpectedly high rate of reversions to seronegativity were observed by N-IFA (27/33) as well as by 65.2 ELISA (11/26) in the longitudinal analysis. Analysis of the ORF65.2 ELISA index indicated that these reversions before the clinical onset of KS were associated with antibody levels that frequently hovered around the level of detectability. A marked increase in ORF 65.2 antibody titer occurred in a third of the patients at the time of KS diagnosis. Only two seroconversions were documented. KSHV infection within the SHCS is likely to have preceded HIV infection. KSHV infection alone is not highly predictive of KS development in this cohort of HIV-infected homosexual men as compared with matched controls. Three KSHV serologic assays, though sensitive at the time of clinical KS are inconsistently positive before the development of AIDS-related KS.

We report the case of a 70-year-old hypertensive man with a solitary kidney and chronic renal insufficiency who developed two episodes of transient anuria after losartan administration. He was hospitalized for a myocardial infarction with pulmonary edema, treated with high-dose diuretics. Due to severe systolic dysfunction losartan was prescribed. Surprisingly, the first dose of 50 mg of losartan resulted in a sudden anuria, which lasted eight hours despite high-dose furosemide and amine infusion. One week later, by mistake, losartan was prescribed again and after the second dose of 50 mg, the patient developed a second episode of transient anuria lasting 10 hours. During these two episodes, his blood pressure diminished but no severe hypotension was noted. Ultimately, an arteriography showed a 70-80% renal artery stenosis. In this patient, renal artery stenosis combined with heart failure and diuretic therapy certainly resulted in a strong activation of the renin-angiotensin system (RAS). Under such conditions, angiotensin II receptor blockade by losartan probably induced a critical fall in glomerular filtration pressure. This case report highlights the fact that the angiotensin II receptor antagonist losartan can cause serious unexpected complications in patients with renovascular disease and should be used with extreme caution in this setting.

To the Editor: Measurement of fraction of exhaled nitric oxide (FeNO) is an established tool for the assessment of airway inflammation in asthma. Despite increasing evidence of a poor relationship between the two (1), FeNO continues to be widely regarded as a surrogate marker of sputum eosinophilia (2–4). Furthermore, recent American Thoracic Society (ATS) guidelines have suggested clinically significant cut points for low and high FeNO levels that can be used to indicate the presence or absence of sputum eosinophilia (5). It is known that levels of FeNO may be elevated even in the absence of eosinophilic inflammation and are strongly associated with atopy (6, 7). Furthermore, adult studies have also reported some patients with low FeNO levels despite high sputum eosinophils (8). These discordant relationships make interpretation of FeNO levels, in the individual, more difficult. In view of these published guidelines, we retrospectively analyzed data from two previous studies (9, 10) to assess the validity of these cut points in our population and whether in an individual the relationship between sputum eosinophils and FeNO would be consistent over time and thus aid the interpretation of FeNO results by identifying those in whom FeNO consistently reflects the presence or absence of sputum eosinophilia. Some of these results have been previously reported in the form of an abstract (11). We analyzed paired sputum eosinophil and FeNO levels in children with a range of asthma severity up to four times per child in a 1-year period. A total of 79 school-aged children were recruited. Fifty-one had severe asthma and were recruited for a previously reported randomized controlled trial comparing a management strategy aimed at controlling sputum eosinophils with a conventional symptom-based strategy ({"type":"clinical-trial","attrs":{"text":"NCT00262340","term_id":"NCT00262340"}}NCT00262340) (9). Twenty-eight had mild to moderate asthma. They were prospectively recruited for a previously described observational study of inflammatory phenotypes (10). Their demographics are shown in Table 1. A total of 197 sputum and FeNO pairs were obtained. TABLE 1. DEMOGRAPHICS OF THE SEVERE ASTHMA AND MILD TO MODERATE ASTHMA COHORTS FeNO was measured at a flow rate of 50 ml/s according to published European Respiratory Society/ATS guidelines (12). Spirometry, sputum induction, and processing were performed as previously described (13–15). Atopy was defined as one or more positive skin-prick tests (wheal ≥ 3 mm) or serum-specific IgE > 0.34 kU/L to a standard panel of six aeroallergens. Concordance and discordance between sputum eosinophils and FeNO were defined using the FeNO cut points recommended by the recent ATS guidelines to define high and low FeNO levels (5). Concordance: high eosinophils and high FeNO (eos+FeNO+), eosinophils > 2.5%, FeNO ≥ 20 ppb; low eosinophils and low FeNO (eos−FeNO−), eosinophils ≤ 2.5%, FeNO ≤ 35 ppb. Discordance: high eosinophils and low FeNO (eos+FeNO−), eosinophils > 2.5%, FeNO 35 ppb. FeNO values between 20 and 35 ppb were always considered concordant whatever the eosinophil value. The relationship between sputum eosinophils and FeNO was calculated using one pair per subject (the first available). There was a significant positive correlation between sputum eosinophils and FeNO (r = 0.49, P 2.5% and ≤2.5% (Figure E1 in the online supplement). FeNO levels of >35 ppb gave a sensitivity of 58%, specificity of 73%, positive predictive value of 67%, and negative predictive value of 65% for identifying a sputum eosinophil count of >2.5%. FeNO levels of

Nitrogen multiple-breath washout (N2 MBW) using 100% oxygen (O2) has regained interest to assess efficiency of tracer gas clearance in, for example, children with Cystic Fibrosis (CF). However, the influence of hyperoxia on the infants' respiratory control is unclear. We assessed safety and impact on breathing pattern from hyperoxia, and if exposure to 40% O2 first induces tolerance to subsequent 100% O2 for N2 MBW.We prospectively enrolled 39 infants aged 3-57 weeks: 15 infants with CF (8 sedated for testing) and 24 healthy controls. Infants were consecutively allocated to the protocols comprising of 100% O2 or 40/100% O2 administered for 30 breaths. Lung function was measured using an ultrasonic flowmeter setup. Primary outcome was tidal volume (VT).None of the infants experienced apnea, desaturation, or bradycardia. Both protocols initially induced hypoventilation. VT temporarily declined in 33/39 infants across 10-25 breaths. Hypoventilation occurred independent of age, disease, and sedation. In the new 40/100% O2 protocol, VT returned to baseline during 40% O2 and remained stable during 100% O2 exposure. End-tidal carbon dioxide monitored online did not change.The classical N2 MBW protocol with 100% O2 may change breathing patterns of the infants. The new protocol with 40% O2 induces hyperoxia-tolerance and does not lead to changes in breathing patterns during later N2 washout using 100% O2. Both protocols are safe, the new protocol seems an attractive option for N2 MBW in infants.

Multiple breath washout (MBW) measurements have recently been shown to be sensitive for detection of early cystic fibrosis (CF) lung disease, with the lung clearance index (LCI) being the most common measure for ventilation inhomogeneity. The aim of this observational study was to describe the longitudinal course of LCI from time of clinical diagnosis during infancy to school-age in eleven children with CF.Elevated LCI during infancy was present in seven subjects, especially in those with later clinical diagnosis. Tracking of LCI at follow-up was evident only in the four most severe cases.We provide the first longitudinal data describing the long-term course of LCI in a small group of infants with CF. Our findings support the clinical usefulness of MBW measurements to detect and monitor early lung disease in children with CF already present shortly after clinical diagnosis.

Cystic fibrosis (CF) is characterized by bronchoalveolar neutrophilia and submucosal lymphocytosis. We hypothesized that Th17 lymphocytes are part of this submucosal infiltrate.Quantification and phenotyping of the lymphocytic infiltrate in the bronchial submucosa of patients with CF (n = 53, of which 20 were newly diagnosed), non-CF bronchiectasis (n = 17), and healthy control subjects (n = 13).We measured IL-17 levels in bronchoalveolar lavage and CD4(+), CD8(+), and IL-17(+) cell counts in endobronchial biopsies. Correlations were made with infection status and other inflammatory markers. Potential cellular sources of IL-17 were determined by double staining.IL-17(+) cell counts (median [interquartile range] cells/mm(2)) were significantly higher in patients with established CF (205 [115-551]) and non-CF bronchiectasis (245 [183-436]) than in control subjects (53 [12-82]) (P0.01 for both). Patients with newly diagnosed CF had intermediate counts (171 [91-252]). IL-17-positive CD4(+) T cells, γδT cells, natural killer T cells, and neutrophils were identified. Bronchoalveolar lavage IL-17 levels (pg/ml) were highest in established CF (14.6 [2.2-38.4]), low in newly diagnosed CF and control subjects (1.7 [1.7-1.74]; 1.7 [1.7-3]), and intermediate in non-CF bronchiectasis (9.1 [1.7-34] pg/ml) (Kruskal-Wallis P = 0.001). There was a significant correlation between IL-17 and neutrophil counts (P0.001, R = 0.6) as well as IL-4 (P0.001, R = 0.84).Th17 lymphocytes are present in the airway submucosa in CF, even in a young, newly diagnosed group. Other IL-17(+) cells include neutrophils, γδ T cells, and natural killer T cells.

This article reports the case of a 31 years old man who suffered from an acute pulmonary oedema after laryngospasma following extubation. This pathology, better known by anesthesiologists than internists, results primarly from a rapid rise in negative intrapleural pressure. It is not associated with previous cardio-pulmonary illness and has a begnin course with resolution within 48 hours with oxygen and positive end expiratory pressure support.

The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) is a challenge. Thymus- and activation-regulated chemokine (TARC) has recently been reported to play a role in ABPA. The aim of this study was to compare the diagnostic value of TARC with that of known serological markers for diagnosis of ABPA in CF patients. The present study longitudinally followed 48 CF patients, of whom 12 had a diagnosis of ABPA according to Nelson's criteria, for 1-8 yrs with repeated measurements of serum total immunoglobulin (Ig)E, specific Aspergillus fumigatus IgE and IgG, specific IgE against recombinant A. fumigatus allergens (rAsp f) 1, 3, 4 and 6, and TARC. Median (interquartile range) TARC levels were 589 (465-673) pg x mL(-1) in ABPA patients and 232 (189-289) pg x mL(-1) in non-ABPA patients. Receiver operating characteristic curves revealed that TARC was superior to the other markers for diagnosis of ABPA. Diagnostic accuracy was greater for TARC (93%) than for total IgE (74%), or rAsp f 4 (75%) or f 6 (79%). The present study indicates that thymus- and activation-regulated chemokine may be useful in the diagnosis of allergic bronchopulmonary aspergillosis in cystic fibrosis patients. However, larger studies are needed before thymus- and activation-regulated chemokine can routinely be used in diagnostic algorithms.