Carmen Casaulta

Inselspital, Universitätsspital Bern, Berna, Bern, Switzerland

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Publications (50)175.21 Total impact

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    ABSTRACT: Lung clearance index (LCI), a marker of ventilation inhomogeneity, is elevated early in children with cystic fibrosis (CF). However, in infants with CF, LCI values are found to be normal, although structural lung abnormalities are often detectable. We hypothesized that this discrepancy is due to inadequate algorithms of the available software package. Our aim was to challenge the validity of these software algorithms. We compared multiple breath washout (MBW) results of current software algorithms (automatic modus) to refined algorithms (manual modus) in 17 asymptomatic infants with CF, and 24 matched healthy term-born infants. The main difference between these two analysis methods lies in the calculation of the molar mass differences that the system uses to define the completion of the measurement. In infants with CF the refined manual modus revealed clearly elevated LCI above 9 in 8 out of 35 measurements (23%), all showing LCI values below 8.3 using the automatic modus (paired t-test comparing the means, P < 0.001). Healthy infants showed normal LCI values using both analysis methods (n = 47, paired t-test, P = 0.79). The most relevant reason for false normal LCI values in infants with CF using the automatic modus was the incorrect recognition of the end-of-test too early during the washout. We recommend the use of the manual modus for the analysis of MBW outcomes in infants in order to obtain more accurate results. This will allow appropriate use of infant lung function results for clinical and scientific purposes. Pediatr Pulmonol. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Pediatric Pulmonology 08/2015; DOI:10.1002/ppul.23256 · 2.30 Impact Factor
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    ABSTRACT: We have taken keen interest in the current discussion on the meaning of the lung clearance index (LCI) in patients with primary ciliary dyskinesia (PCD). In patients with cystic fibrosis (CF), LCI from the nitrogen multiple-breath gas washout (N2-MBW) test has become a sensitive marker for detection of ventilation inhomogeneity with a good correlation between LCI and FEV1.1 However, in patients with PCD, two studies failed to find a correlation for the FEV1 and LCI.1 ,2 This difference in functional measures between CF and PCD was recently challenged by Boon et al,3 showing a robust correlation between LCI and FEV … [Full text of this article]
    Thorax 05/2015; DOI:10.1136/thoraxjnl-2015-207206 · 8.56 Impact Factor
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    ABSTRACT: 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.
    European Respiratory Journal 10/2014; 45(2). DOI:10.1183/09031936.00102014 · 7.13 Impact Factor
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    ABSTRACT: 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 < 0.0001. In asthmatic children, PWVcf was inversely associated (r 2 = 0.20, p = 0.004) with forced expiratory volume in 1 s (FEV1). This association remained significant after adjusting for possible confounders including body mass index, blood pressure, steroid use, and FeNO. Conclusion: Arterial stiffness is increased in children with mild-to-moderate asthma. The association between impaired lung function and increased arterial stiffness suggests that severity of disease translates into detrimental effects on the cardiovascular system.
    European Journal of Pediatrics 09/2014; 174(4). DOI:10.1007/s00431-014-2423-2 · 1.98 Impact Factor
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    ABSTRACT: Purpose: 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. Methods: 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. Results: Sixty healthy adults (median with interquartile range [IQR] age of 31 [26–37] years) participated in the study. Higher number of cells (×105 cells/ml) was obtained using brushes (9.8 [5.9–33.5]) compared to swabs (2.4 [1.5–3.9], p < 0.0001) and curettes (5.5 [4.4–6.9], p < 0.01). 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. Conclusions: 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.
    Experimental Lung Research 07/2014; 40(7). DOI:10.3109/01902148.2014.925987 · 1.75 Impact Factor
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    ABSTRACT: 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. Pediatr Pulmonol. © 2013 Wiley Periodicals, Inc.
    Pediatric Pulmonology 04/2014; 49(4). DOI:10.1002/ppul.22841 · 2.30 Impact Factor
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    ABSTRACT: Small airways disease is a hallmark in adults with persistent asthma but little is known on small airways function in children with mild asthma and normal spirometry. We assessed ventilation heterogeneity, a marker of small airways function, using an easy tidal breath single-breath washout (SBW) technique in school-aged children with mild asthma and normal FEV1 and healthy age-matched controls. Primary outcome was the double-tracer gas phase III slope (SDTG), an index of ventilation heterogeneity in acinar airways derived from the tidal double-tracer gas SBW test. The second outcome was the nitrogen phase III slope (SN2), an index of global ventilation heterogeneity derived from the tidal nitrogen SBW test using pure oxygen. Triplicate SBW and spirometry tests were performed in healthy (n = 35) and asthmatic children (n = 31) at baseline and in asthmatic children after bronchodilation. Acinar (SDTG) but not global (SN2) ventilation heterogeneity was significantly increased in asthma despite normal FEV1. SDTG was abnormal (≤-2 z-scores) in 11/31 asthmatic children, FEF25-75 in 3/31 and FEV1 in 0/31. After bronchodilaton, SDTG, SN2, and FEF25-75 and FEV1 significantly changed: Average (95% CI) change given as percentage from baseline was 36 (15-56)%, 38 (18-58)%, 17 (9-25)% and 6 (3-9)%, respectively. Abnormal acinar ventilation heterogeneity in one third of children suggests that small airways disease may be present despite rare and mild asthma symptoms and normal spirometry. The easy tidal SBW technique has considerable potential as a clinical and research outcome in children with asthma.
    Chest 10/2013; 145(3). DOI:10.1378/chest.13-0784 · 7.13 Impact Factor
  • Thorax 08/2013; 69(2). DOI:10.1136/thoraxjnl-2013-204283 · 8.56 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 08/2013; 48(8). DOI:10.1002/ppul.22651 · 2.30 Impact Factor
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    ABSTRACT: We studied the ability of 4 single-breath gas washout (SBW) tests to measure immediate effects of airway clearance in children with CF. 25 children aged 4-16years with CF performed pulmonary function tests to assess short-term variability at baseline and response to routine airway clearance. Tidal helium and sulfur hexafluoride (double-tracer gas: DTG) SBW, tidal capnography, tidal and vital capacity nitrogen (N2) SBW and spirometry were applied. We analyzed the gasses' phase III slope (SnIII - normalized for tidal volume) and FEV1 from spirometry. SnIII from tidal DTG-SBW, SnIII from vital capacity N2-SBW, and FEV1 improved significantly after airway clearance. From these tests, individual change of SnIII from tidal DTG-SBW and FEV1 exceeded short-term variability in 10 and 6 children. With the tidal DTG-SBW, an easy and promising test for peripheral gas mixing efficiency, immediate pulmonary function response to airway clearance can be assessed in CF children.
    Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 06/2013; 12(6). DOI:10.1016/j.jcf.2013.05.010 · 3.82 Impact Factor
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    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. Here, we assess in vivo the association of RV prevalence and load with antiviral defense mechanisms, airway inflammation, and lung function parameters in children with CF compared with a control group and children with other chronic respiratory diseases. METHODS: RV presence and load were measured by real-time reverse transcription-polymerase chain reaction in BAL samples and were related to antiviral 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), or asthma (n = 29) and from a control group (n = 35) at a median (interquartile range [IQR]) age of 8.2 (4.0-11.7) years. RV was detected in 73 samples (24.4%). RV prevalence was similar among groups. RV load (median [IQR] x 10(3) copies/mL) was higher in children with CF (143.0 [13.1-1530.0]), especially during pulmonary exacerbations, compared with children with asthma (3.0 [1.3-25.8], P = .006) and the control group (0.5 [0.3-0.5], P < .001), but similar to patients with non-CF bronchiectasis (122.1 [2.7-4423.5], P = not significant). In children with CF, RV load was negatively associated with interferon (IFN)- b and IFN- l , IL-1ra levels, and FEV 1 , and positively with levels of the cytokines CXCL8 and CXCL10. CONCLUSIONS: RV load in CF BAL is high, especially during exacerbated lung disease. Impaired production of antiviral 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.
    Chest 09/2012; 143(3). DOI:10.1378/chest.12-0954 · 7.13 Impact Factor
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    ABSTRACT: Our understanding of regional filling of the lung and regional ventilation distribution is based on studies using stepwise inhalation of radiolabelled tracer gases, magnetic resonance imaging and positron emission tomography. We aimed to investigate whether these differences in ventilation distribution at different end-expiratory levels (EELs) and tidal volumes (V (T)s) held also true during tidal breathing. Electrical impedance tomography (EIT) measurements were performed in ten healthy adults in the right lateral position. Five different EELs with four different V (T)s at each EEL were tested in random order, resulting in 19 combinations. There were no measurements for the combination of the highest EEL/highest V (T). EEL and V (T) were controlled by visual feedback based on airflow. The fraction of ventilation directed to different slices of the lung (VENT(RL1)-VENT(RL8)) and the rate of the regional filling of each slice versus the total lung were analysed. With increasing EEL but normal tidal volume, ventilation was preferentially distributed to the dependent lung and the filling of the right and left lung was more homogeneous. With increasing V (T) and maintained normal EEL (FRC), ventilation was preferentially distributed to the dependent lung and regional filling became more inhomogeneous (p < 0.05). We could demonstrate that regional and temporal ventilation distribution during tidal breathing was highly influenced by EEL and V (T).
    Arbeitsphysiologie 08/2012; 113(3). DOI:10.1007/s00421-012-2469-7 · 2.30 Impact Factor
  • European Respiratory Journal 06/2012; 39(6):1536-7. DOI:10.1183/09031936.00212511 · 7.13 Impact Factor
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    ABSTRACT: In cystic fibrosis (CF) lung disease, tests for ventilation inhomogeneity are sensitive but not established for clinical routine. We assessed feasibility of a new double-tracer gas single-breath washout (SBW) in school-aged children with CF and controls, and compared SBW between groups and with nitrogen multiple-breath washout (MBNW).Three SBW and MBNW were done in 118 children (66 with CF) using a side-stream ultrasonic flowmeter setup. The double-tracer gas containing 5% sulfur hexafluoride and 26.3% helium was applied during one tidal breath. Outcomes were SBW phase III slope (SIIIDTG), MBNW derived lung clearance index (LCI), and indices of acinar (Sacin) and conductive (Scond) ventilation inhomogeneity.SBW took significantly less time to perform than MBNW. SBW and MBNW were feasible in 109 (92.4%) and 98 (83.0%) children, respectively. SIIIDTG differed between children with CF and controls, mean (SD) was -456.7 (492.8) and -88.4 (129.1) mg·mol.L(-1), respectively. Abnormal SIIIDTG was present in 36 (59%) of CF children. SIIIDTG was associated with LCI (r= -0.58), Sacin (r= -0.58), but not with Scond.In CF, steeply sloping SIIIDTG potentially reflects ventilation inhomogeneity near the acinus entrance. This tidal SBW is a promising test to assess ventilation inhomogeneity in an easy and fast way.
    European Respiratory Journal 05/2012; 41(2). DOI:10.1183/09031936.00044312 · 7.13 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. DOI:10.1038/pr.2012.13 · 2.84 Impact Factor
  • The Thoracic and Cardiovascular Surgeon 02/2012; 60(S 01). DOI:10.1055/s-0031-1297691 · 1.08 Impact Factor
  • Chest 10/2011; 140(4):1086-9. DOI:10.1378/chest.10-2607 · 7.13 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. DOI:10.1016/j.jcf.2011.07.006 · 3.82 Impact Factor
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    ABSTRACT: Respiratory virus infections play an important role in cystic fibrosis (CF) exacerbations, but underlying pathophysiological mechanisms are poorly understood. We aimed to assess whether an exaggerated inflammatory response of the airway epithelium on virus infection could explain the increased susceptibility of CF patients towards respiratory viruses. We used primary bronchial and nasal epithelial cells obtained from 24 healthy control subjects and 18 CF patients. IL-6, IL-8/CXCL8, IP-10/CXCL10, MCP-1/CCL2, RANTES/CCL5 and GRO-α/CXCL1 levels in supernatants and mRNA expression in cell lysates were measured before and after infection with rhinoviruses (RV-16 and RV-1B) and RSV. Cytotoxicity was assessed by lactate dehydrogenate assay and flow cytometry. All viruses induced strong cytokine release in both control and CF cells. The inflammatory response on virus infection was heterogeneous and depended on cell type and virus used, but was not increased in CF compared with control cells. On the contrary, there was a marked trend towards lower cytokine production associated with increased cell death in CF cells. An exaggerated inflammatory response to virus infection in bronchial epithelial cells does not explain the increased respiratory morbidity after virus infection in CF patients.
    European Respiratory Journal 06/2011; 39(2):297-304. DOI:10.1183/09031936.00054511 · 7.13 Impact Factor
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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 06/2011; 6(9):e24399. DOI:10.1371/journal.pone.0024399 · 3.23 Impact Factor

Publication Stats

392 Citations
175.21 Total Impact Points


  • 2002–2015
    • Inselspital, Universitätsspital Bern
      • • Department of Paediatrics
      • • Department of Pneumology
      Berna, Bern, Switzerland
  • 2002–2014
    • University Children's Hospital Basel
      Bâle, Basel-City, Switzerland
  • 2009
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland