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2.  Influenza A(H1N1)pdm09 and Cystic Fibrosis Lung Disease: A Systematic Meta-Analysis 
PLoS ONE  2014;9(1):e78583.
To systematically assess the literature published on the clinical impact of Influenza A(H1N1)pdm09 on cystic fibrosis (CF) patients.
An online search in PUBMED database was conducted. Original articles on CF patients with Influenza A(H1N1)pdm09 infection were included. We analyzed incidence, symptoms, clinical course and treatment.
Four surveys with a total of 202 CF patients infected by Influenza A(H1N1)pdm09 were included. The meta-analysis showed that hospitalisation rates were higher in CF patients compared to the general population. While general disease symptoms were comparable, the clinical course was more severe and case fatality rate (CFR) was higher in CF patients compared to asthmatics and the general population.
Evidence so far suggests that CF patients infected with Influenza A(H1N1)pdm09 show increased morbidity and a higher CFR compared to patients with other chronic respiratory diseases and healthy controls. Particularly, CF patients with advanced stage disease seem to be more susceptible to severe lung disease. Accordingly, early antiviral and antibiotic treatment strategies are essential in CF patients. Preventive measures, including vaccination as well as hygiene measures during the influenza season, should be reinforced and improved in CF patients.
PMCID: PMC3888399  PMID: 24427261
4.  Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines 
The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood.
We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the TH2 cytokines IL-4, IL-5, and IL-13.
Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen TH2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation.
Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P < .001; biopsy specimen, P < .01); within the STRA group, there was marked between-patient variability in eosinophilia. Submucosal mast cell, neutrophil, and lymphocyte counts were similar in both groups. Reticular basement membrane thickness and airway smooth muscle were increased in patients with STRA compared with those found in control subjects (P < .0001 and P < .001, respectively). There was no increase in BAL fluid IL-4, IL-5, or IL-13 levels in patients with STRA compared with control subjects, and these cytokines were rarely detected in induced sputum. Biopsy IL-5+ and IL-13+ cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid TH2 cytokines had significantly lower lung function than those with undetectable BAL fluid TH2 cytokines.
STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the TH2 mediators that are thought to drive allergic asthma were mostly absent.
PMCID: PMC3381727  PMID: 22385633
Pediatric asthma; eosinophilia; remodeling; severe therapy-resistant asthma; mediators
5.  The Th17 Pathway in Cystic Fibrosis Lung Disease 
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.
Measurements and Main Results
IL-17+ cell counts (median [interquartile range] cells/mm2) 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]) (P<0.01 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 (P < 0.001, R = 0.6) as well as IL-4 (P < 0.001, 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.
PMCID: PMC3381840  PMID: 21474644
Th17 cells; cystic fibrosis; inflammation
6.  The Airway Epithelium: Soldier in the Fight against Respiratory Viruses 
Clinical Microbiology Reviews  2011;24(1):210-229.
Summary: 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.
PMCID: PMC3021210  PMID: 21233513
7.  Airway remodelling in children with cystic fibrosis 
Thorax  2007;62(12):1074-1080.
The relationship between airway structural changes and inflammation is unclear in early cystic fibrosis (CF) lung disease. A study was undertaken to determine changes in airway remodelling in children with CF compared with appropriate disease and healthy controls.
Bronchoalveolar lavage and endobronchial biopsy were performed in a cross‐sectional study of 43 children with CF (aged 0.3–16.8 years), 7 children with primary ciliary dyskinesia (PCD), 26 with chronic respiratory symptoms (CRS) investigated for recurrent infection and/or cough and 7 control children with no lower airway symptoms. Inflammatory cells, cytokines, proteases and matrix constituents were measured in bronchoalveolar lavage fluid (BALF). Reticular basement membrane (RBM) thickness was measured on biopsy specimens using light microscopy.
Increased concentrations of elastin, glycosaminoglycans and collagen were found in BALF from children with CF compared with the CRS group and controls, each correlating positively with age, neutrophil count and proteases (elastase activity and matrix metalloproteinase‐9 (MMP‐9) concentration). There were significant negative correlations between certain of these and pulmonary function (forced expiratory volume in 1 s) in the CF group (elastin: r = −0.45, p<0.05; MMP‐9:TIMP‐1 ratio: r = −0.47, p<0.05). Median RBM thickness was greater in the CF group than in the controls (5.9 μm vs 4.0 μm, p<0.01) and correlated positively with levels of transforming growth factor‐β1 (TGF‐β1; r = 0.53, p = 0.01), although not with other inflammatory markers or pulmonary function.
This study provides evidence for two forms of airway remodelling in children with CF: (1) matrix breakdown, related to inflammation, proteolysis and impaired pulmonary function, and (2) RBM thickening, related to TGF‐β1 concentration but independent of other markers of inflammation.
PMCID: PMC2094274  PMID: 17526676
8.  New Molecular Detection Tools Adapted to Emerging Rhinoviruses and Enteroviruses▿  
Journal of Clinical Microbiology  2009;47(6):1742-1749.
Human rhinoviruses (HRV), and to a lesser extent human enteroviruses (HEV), are important respiratory pathogens. Like other RNA viruses, these picornaviruses have an intrinsic propensity to variability. This results in a large number of different serotypes as well as the incessant discovery of new genotypes. This large and growing diversity not only complicates the design of real-time PCR assays but also renders immunofluorescence unfeasible for broad HRV and HEV detection or quantification in cells. In this study, we used the 5′ untranslated region, the most conserved part of the genome, as a target for the development of both a real-time PCR assay (Panenterhino/Ge/08) and a peptide nucleic acid-based hybridization oligoprobe (Panenterhino/Ge/08 PNA probe) designed to detect all HRV and HEV species members according to publicly available sequences. The reverse transcription-PCR assay has been validated, using not only plasmid and viral stocks but also quantified RNA transcripts and around 1,000 clinical specimens. These new generic detection PCR assays overcame the variability of circulating strains and lowered the risk of missing emerging and divergent HRV and HEV. An additional real-time PCR assay (Entero/Ge/08) was also designed specifically to provide sensitive and targeted detection of HEV in cerebrospinal fluid. In addition to the generic probe, we developed specific probes for the detection of HRV-A and HRV-B in cells. This investigation provides a comprehensive toolbox for accurate molecular identification of the different HEV and HRV circulating in humans.
PMCID: PMC2691104  PMID: 19339471
9.  New Respiratory Enterovirus and Recombinant Rhinoviruses among Circulating Picornaviruses  
Emerging Infectious Diseases  2009;15(5):719-726.
Increased genomic diversity of these viruses is demonstrated.
Rhinoviruses and enteroviruses are leading causes of respiratory infections. To evaluate genotypic diversity and identify forces shaping picornavirus evolution, we screened persons with respiratory illnesses by using rhinovirus-specific or generic real-time PCR assays. We then sequenced the 5′ untranslated region, capsid protein VP1, and protease precursor 3CD regions of virus-positive samples. Subsequent phylogenetic analysis identified the large genotypic diversity of rhinoviruses circulating in humans. We identified and completed the genome sequence of a new enterovirus genotype associated with respiratory symptoms and acute otitis media, confirming the close relationship between rhinoviruses and enteroviruses and the need to detect both viruses in respiratory specimens. Finally, we identified recombinants among circulating rhinoviruses and mapped their recombination sites, thereby demonstrating that rhinoviruses can recombine in their natural host. This study clarifies the diversity and explains the reasons for evolution of these viruses.
PMCID: PMC2687021  PMID: 19402957
Respiratory infections; molecular epidemiology; picornavirus; rhinovirus; enterovirus; recombination; capsid protein; nonstructural protein; genotype; research
10.  Generic Detection of Coronaviruses and Differentiation at the Prototype Strain Level by Reverse Transcription-PCR and Nonfluorescent Low-Density Microarray▿ †  
Journal of Clinical Microbiology  2007;45(3):1049-1052.
A nonfluorescent low-cost, low-density oligonucleotide array was designed for detecting the whole coronavirus genus after reverse transcription (RT)-PCR. The limit of detection was 15.7 copies/reaction. The clinical detection limit in patients with severe acute respiratory syndrome was 100 copies/sample. In 39 children suffering from coronavirus 229E, NL63, OC43, or HKU1, the sensitivity was equal to that of individual real-time RT-PCRs.
PMCID: PMC1829107  PMID: 17229859
11.  High Human Herpesvirus 8 Seroprevalence in the Homosexual Population in Switzerland 
Journal of Clinical Microbiology  1998;36(6):1784-1786.
The seroprevalence of human herpesvirus 8 (HHV-8) in the Swiss population was investigated. By enzyme-linked immunosorbent assay, sera reactive to the recombinant HHV-8 antigen orf 65.2 were found in 24% of human immunodeficiency virus (HIV)-positive patients without and in 92% of HIV-positive patients with Kaposi’s sarcoma. Surprisingly, 20% of homosexual HIV-negative men, versus only 7% of heterosexual HIV-negative individuals and 5% of blood donors, had antibodies to HHV-8.
PMCID: PMC104922  PMID: 9620422

Results 1-11 (11)