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Elisabeth Kieninger,
Florian Singer,
Caroline Tapparel,
Marco P Alves,
Philipp Latzin,
Hui-Leng Tan,
Cara Bossley,
Carmen Casaulta,
Andrew Bush,
Jane C Davies,
Laurent Kaiser,
Nicolas Regamey
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ABSTRACT: ABSTRACT 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], p<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-β/-λ, 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.kieinger@insel.ch, florian.singer@insel.ch, marco.alves@dkf.unibe.ch, philipp.latzin@insel.ch, carmen.casaulta@insel.ch, nicolas.regamey@insel.ch2Department of Clinical Research, University of Bern, Bern, Switzerland; elisabeth.kieinger@insel.ch, marco.alves@dkf.unibe.ch, philipp.latzin@insel.ch, nicolas.regamey@insel.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.Tapparel@hcuge.ch, Laurent.Kaiser@sec.hcuge.ch4Department of Pediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom, h.tan@imperial.ac.uk, carajbossley@hotmail.com, a.bush@imperial.ac.uk, j.c.davies@imperial.ac.ukCorresponding author: Nicolas Regamey, MD; Division of Respiratory Medicine, Department of Pediatrics, University Hospital, Inselspital, 3010 Bern, Switzerland Email: nicolas.regamey@insel.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].
Chest 09/2012; · 5.25 Impact Factor
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ABSTRACT: BACKGROUND: Although lung clearance index (LCI) is a sensitive indicator of mild cystic fibrosis (CF) lung disease, it is rarely measured due to lengthy protocols and the commercial unavailability of multiple-breath washout (MBW) setups and tracer gases. We used a newly validated, commercially available nitrogen (N(2) ) MBW setup to assess success rate, duration, and variability of LCI within a 20 min timeframe, during clinical routine. We also evaluated the relationship between LCI and other clinical markers of CF lung disease. METHODS: One hundred thirty six children (83 with CF) between 4 and 16 years were studied in a pediatric CF outpatient setting. One hundred eighteen out of 136 children were naïve to MBW. Within 20 min, each child was trained, N(2) MBW was performed, and LCI was analyzed. We assessed intra- and between-test reproducibility in a subgroup of children. RESULTS: At least one LCI was feasible in 123 (90%) children, with a mean (range) of 3.3 (1.2-6.4) min per test. Two or more measurements were feasible in 56 (41%) children. Comparing LCI in CF versus controls, LCI mean (SD) was 12.0 (3.9) versus 6.1 (0.9), and the intra- and inter-test coefficient of repeatability was 1.00 versus 0.81 and 0.96 versus 0.62, respectively. LCI was correlated with spirometry, blood gases, and Pseudomonas aeruginosa infection. CONCLUSIONS: Using available N(2) MBW equipment, LCI measurements are practical and fast in children. LCI is correlated with markers of CF lung disease. Longer timeframes would be required for triplicate N(2) MBW tests in inexperienced children. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc.
Pediatric Pulmonology 08/2012; · 2.53 Impact Factor
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ABSTRACT: 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 in early life are a risk factor for asthma development later in childhood. Underlying mechanisms, however, 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.
European Respiratory Journal 06/2012; · 5.89 Impact Factor
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ABSTRACT: Standards for online multiple-breath (mb) exhaled nitric oxide (eNO) measurements and studies comparing them with online single-breath (sb) eNO measurements are lacking, although eNOmb requires less cooperation in children at school age or younger.
Online eNOmb and eNOsb were measured in 99 healthy children and (in order to observe higher values) in 21 children with suspected asthma at a median age of 6.1 and 11.7 y, respectively. For eNOmb, we aimed for 20 tidal breathing maneuvers; eNOsb was measured according to standards. The two techniques were compared by standard methods after computing NO output or extrapolating eNOmb to the standard flow of 50 ml/s (eNOmb(50)).
Measurements were acceptable in 82 (eNOmb) and 81 (eNOsb) children. Paired data were available for 65 children. On a log-log scale, eNOmb(50) (geometric mean ± SD 13.1 ± 15.5 parts per billion, ppb) was correlated with eNOsb (12.5 ± 15.8 ppb), with r(2) = 0.87. The mean difference between eNOsb and eNOmb(50) was -0.7 ppb, with limits of agreement (LOAs) of 4.0 and -5.3 ppb.
Despite its correlation with eNOsb, the LOA range hampers eNOmb use in research, where exact values across the whole range are warranted. However, eNOmb might be an alternative tool especially at preschool age, when cooperation during measurements is crucial.
Pediatric Research 02/2012; 71(5):605-11. · 2.70 Impact Factor
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ABSTRACT: Rhinoviruses are important triggers of pulmonary exacerbations and possible contributors to long-term respiratory morbidity in cystic fibrosis (CF), but mechanisms leading to rhinovirus-induced CF exacerbations are poorly understood. It is hypothesised that there is a deficient innate immune response of the airway epithelium towards rhinovirus infection in CF.
Early innate immune responses towards rhinoviruses (RV-16, major-type and RV-1B, minor-type) in CF and non-CF bronchial epithelial cell lines and primary nasal and bronchial epithelial cells from patients with CF (n=13) and healthy controls (n=24) were studied.
Rhinovirus RNA expression and virus release into supernatants was increased more than tenfold in CF cells compared with controls. CF cells expressed up to 1000 times less interferon (IFN) type I (β) and type III (λ) mRNA and produced less than half of IFN-β and IFN-λ protein compared with controls. In contrast, interleukin 8 production was not impaired, indicating a selective deficiency in the innate antiviral defence system. Deficient IFN production was paralleled by lower expression of IFN-stimulated genes including myxovirus resistance A, 2',5'-oligoadenylate synthetase, viperin and nitric oxide synthase 2. Addition of exogenous type I and III IFNs, particularly IFN-β, restored antiviral pathways and virus control in CF cells, underscoring the crucial role of these molecules.
This study describes a novel mechanism to explain the increased susceptibility of patients with CF to rhinovirus infections. A profound impairment of the antiviral early innate response in CF airway epithelial cells was identified, suggesting a potential use of IFNs in the treatment of rhinovirus-induced CF exacerbations.
Thorax 01/2012; 67(6):517-25. · 6.84 Impact Factor
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ABSTRACT: 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.
Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 08/2011; 10(6):487-90. · 3.19 Impact Factor
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ABSTRACT: Ambient air pollution can alter cytokine concentrations as shown in vitro and following short-term exposure to high air pollution levels in vivo. Exposure to pollution during late pregnancy has been shown to affect fetal lymphocytic immunophenotypes. However, effects of prenatal exposure to moderate levels of air pollutants on cytokine regulation in cord blood of healthy infants are unknown.
In a birth cohort of 265 healthy term-born neonates, we assessed maternal exposure to particles with an aerodynamic diameter of 10 µm or less (PM₁₀), as well as to indoor air pollution during the last trimester, specifically the last 21, 14, 7, 3 and 1 days of pregnancy. As a proxy for traffic-related air pollution, we determined the distance of mothers' homes to major roads. We measured cytokine and chemokine levels (MCP-1, IL-6, IL-10, IL-1ß, TNF-α and GM-CSF) in cord blood serum using LUMINEX technology. Their association with pollution levels was assessed using regression analysis, adjusted for possible confounders.
Mean (95%-CI) PM₁₀ exposure for the last 7 days of pregnancy was 18.3 (10.3-38.4 µg/m³). PM₁₀ exposure during the last 3 days of pregnancy was significantly associated with reduced IL-10 and during the last 3 months of pregnancy with increased IL-1ß levels in cord blood after adjustment for relevant confounders. Maternal smoking was associated with reduced IL-6 levels. For the other cytokines no association was found.
Our results suggest that even naturally occurring prenatal exposure to moderate amounts of indoor and outdoor air pollution may lead to changes in cord blood cytokine levels in a population based cohort.
PLoS ONE 01/2011; 6(8):e23130. · 4.09 Impact Factor
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ABSTRACT: The airway epithelium acts as a frontline defense against respiratory viruses, not only as a physical barrier and through the mucociliary apparatus but also through its immunological functions. It initiates multiple innate and adaptive immune mechanisms which are crucial for efficient antiviral responses. The interaction between respiratory viruses and airway epithelial cells results in production of antiviral substances, including type I and III interferons, lactoferrin, β-defensins, and nitric oxide, and also in production of cytokines and chemokines, which recruit inflammatory cells and influence adaptive immunity. These defense mechanisms usually result in rapid virus clearance. However, respiratory viruses elaborate strategies to evade antiviral mechanisms and immune responses. They may disrupt epithelial integrity through cytotoxic effects, increasing paracellular permeability and damaging epithelial repair mechanisms. In addition, they can interfere with immune responses by blocking interferon pathways and by subverting protective inflammatory responses toward detrimental ones. Finally, by inducing overt mucus secretion and mucostasis and by paving the way for bacterial infections, they favor lung damage and further impair host antiviral mechanisms.
Clinical microbiology reviews 01/2011; 24(1):210-29. · 14.69 Impact Factor
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Andreas Hector,
Michael S D Kormann,
Ines Mack,
Philipp Latzin,
Carmen Casaulta, Elisabeth Kieninger,
Zhe Zhou,
Ali Ö Yildirim,
Alexander Bohla,
Nikolaus Rieber,
Matthias Kappler,
Barbara Koller,
Ernst Eber,
Olaf Eickmeier,
Stefan Zielen,
Oliver Eickelberg,
Matthias Griese,
Marcus A Mall,
Dominik Hartl
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ABSTRACT: The chitinase-like protein YKL-40 was found to be increased in patients with severe asthma and chronic obstructive pulmonary disease (COPD), two disease conditions featuring neutrophilic infiltrates. Based on these studies and a previous report indicating that neutrophils secrete YKL-40, we hypothesized that YKL-40 plays a key role in cystic fibrosis (CF) lung disease, a prototypic neutrophilic disease. The aim of this study was (i) to analyze YKL-40 levels in human and murine CF lung disease and (ii) to investigate whether YKL-40 single-nucleotide polymorphisms (SNPs) modulate CF lung disease severity. YKL-40 protein levels were quantified in serum and sputum supernatants from CF patients and control individuals. Levels of the murine homologue BRP-39 were analyzed in airway fluids from CF-like βENaC-Tg mice. YKL-40SNPs were analyzed in CF patients. YKL-40 levels were increased in sputum supernatants and in serum from CF patients compared to healthy control individuals. Within CF patients, YKL-40 levels were higher in sputum than in serum. BRP-39 levels were increased in airways fluids from βENaC-Tg mice compared to wild-type littermates. In both CF patients and βENaC-Tg mice, YKL-40/BRP-39 airway levels correlated with the severity of pulmonary obstruction. Two YKL-40 SNPs (rs871799 and rs880633) were found to modulate age-adjusted lung function in CF patients. YKL-40/BRP-39 levelsare increased in human and murine CF airway fluids, correlate with pulmonary function and modulate CF lung disease severity genetically. These findings suggest YKL-40 as a potential biomarker in CF lung disease.
PLoS ONE 01/2011; 6(9):e24399. · 4.09 Impact Factor
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Respiration 12/2009; 79(3):189-90. · 2.26 Impact Factor
