Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis

Morbi-mortality in cystic fibrosis (CF) is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy

Spirometry in the asthmatic child: is FEF25-75 a more sensitive test than FEV1/FVC?

The use of spirometry in the assessment of children with asthma is taking on new importance with the realization that considerable airway obstruction may exist in the absence of clinically detectable abnormalities. There has been controversy over the value and relative sensitivity of various spirometry indices. This study evaluated the forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), forced expired volume in 1 second (FEV1), and the ratio between the FEV1 and the forced vital capacity (FVC) in 100 asthmatic children aged 6-17 years, 29 of whom were wheezing at the time of the evaluation. All children with clinical wheezing had a FEV25-75 < 2 standard deviations (SD) below the mean (-2 SD), whereas 8 had a normal FEV1. The majority of the wheezing children had abnormalities of all 3 indices, whether expressed as < or = -2 SD or, in the case of the FEV1/FVC, arbitrarily taken as < 80%. Sixty-seven children of the entire study group had at least 1 abnormal spirometric index, but 38 of these had no clinical abnormalities. Twelve children had a reduced FEF25-75 as the only abnormality. These results suggest that FEF25-75 is a sensitive index of airway obstruction

Comparison of spirometric reference values

Lung-function reference values play a vital role in the management of respiratory disorders. There are many proposed reference equations for pediatric spirometry. Recently, spirometric reference equations were proposed, using data from people aged 8-80 years living in the US compiled by the third National Health and Nutrition Examination Survey. Our objective was to compare the predictive value of wider age-range reference equations to established pediatric reference equations for the pediatric population. Spirometry, height, and weight were obtained from 70 normal children aged 6-18 years. The difference between measured and predicted values as suggested by different reference equations was compared. Predicted values from general equations significantly differed from those generated from pediatric equations and from measured values in this population. The difference between measured and predicted values from the wider age-range equations varied between 7-16% for forced expired volume in 1 sec (FEV1) and forced vital capacity (FVC). The difference between measured and predicted values for the pediatric equations varied between 1-4%. Although wider age-range equations provide continuity through age ranges, their predictive accuracy may be low in the pediatric age group, especially for the youngest, smallest children. Extrapolating reference equations beyond the age range of subjects used to generate then is not recommended. (C) 2004 Wiley-Liss, Inc

A specific database for providing local and national level of integration of clinical data in cystic fibrosis

It has recently been stated that a database is an essential tool in the management of CF. The purpose of this work is to create a specific database allowing optimal performance of storage, search and retrieval functions on patients with CF. A specific database was developed using a Windev licence, for application via Microsoft supported platforms or Intranet system. The database allows real-time point of care data management of medical, investigational and administrative data. It is currently being used in the 6 Belgian reference centres. It represents a useful tool for gathering information on routine clinical and lab data, bacteriology, treatments, complications and specific outcomes for clinical and research purposes. The ongoing evolution of the database includes enhancements toward research data orientation including comparison of patient data between different centres and completeness of the National CF registry questionnaire. A complimentary copy of the software can be provided to multidisciplinary accredited CF centres worldwide upon request

Pseudomonas aeruginosa in the home environment of newly infected cystic fibrosis patients

The source of acquisition of Pseudomonas aeruginosa in cystic fibrosis (CF) patients remains unknown. Patient-to-patient transmission has been well documented but the role of the environment as a source of initial infection is as yet unclear. In the present study, the origin of the first P. aeruginosa isolate in CF patients was investigated by comparing the P. aeruginosa genotype(s) from newly infected patients with genotypes of P. aeruginosa isolates from the home environment and from other patients from the same CF centre. A total of 50 newly infected patients were studied. P. aeruginosa could be cultured from 5.9% of the environmental samples, corresponding to 18 patients. For nine of these, the genotype of the environmental P. aeruginosa isolate was identical to the patient's isolate. In total, 72% of the environmental P. aeruginosa isolates were encountered in the bathroom. Patient-to-patient transmission within the CF centre could not be ruled out for three patients. In summary, a low prevalence of Pseudomonas aeruginosa was found in the home environment of the newly infected cystic fibrosis patients. The bathroom should be targeted in any preventive cleaning procedures. An environmental source of the new infection could not be ruled out in nine patients

Pseudomonas aeruginosa: Résistance et options thérapeutiques à l'aube du deuxième millénaire

Pseudomonas aeruginosa is a major cause of nosocomial infections. Due to its genetic plasticity, it can adapt to a wide variety of environments, causing infections in almost all body sites (with however a predilection for the respiratory tract, especially in cystic fibrosis patients). It also shows a remarkable capacity to resist to antibiotics, either intrinsically (through constitutive expression of β-lactamases and efflux pumps, or low permeability of the outer membrane), or upon exposure to antibiotics through acquisition of resistance genes (coding fo antibiotic-degrading enzymes inactivating or target modifications), overexpression of efflux pumps, decreased expression of porins, or target mutations. Worryingly also, these mechanisms are often present simultaneously, conferring multiresistant phenotypes. Susceptibility testing is therefore crucial in clinical practice. Empiric treatment is usually initiated using a bitherapy, selected based on local epidemiology (β-lactam plus aminoglycoside or fluoroquinolone). However, it should be streamlined as soon as possible, based on susceptibility data and patient's evolution. Alternative drugs (colistin, e.g.) have proven useful for multiresistant strains. Innovative therapeutic options for the future remain scarce, while attempts to develop vaccines have been so far unsuccessful. Among broad-spectrum antibiotics in development, ceftobiprole, sitafloxacin and doripenem show interesting in vitro activity. The two first molecules, however, are evaluated in the clinics towards Gram-positive only. Pump inhibitors are under study but proved much more difficult to develop than originally anticipated. Therefore, selecting appropriate antibiotics and optimizing their use based on pharmacodynamic concepts remains the only way to cope with pseudomonal infections

Epidemiology of Burkholderia cepacia complex colonisation in cystic fibrosis patients

In Belgian cystic fibrosis (CF) clinics, sputum samples are evaluated on selective MAST medium routinely every 3 months. In this study, in 1993 and 1999, isolates were further examined by recA restriction fragment length polymorphism analysis and pulsed-field gel electrophoresis of genomic DNA restricted with SpeI. In 1993, 12 patients were colonised with Burkholderia cepacia complex (Bcc): B. cenocepacia (n=6), B. multivorans (n=3), B. stabilis (n=3). Four patients were colonised with the same B. cenocepacia strain; two with the same B. stabilis strain. After 5 yrs, three B. cenocepacia- and one B. multivorans-colonised patients had died. In 1999, Bcc was isolated in 12 patients: B. multivorans (n=9), B. stabilis (n=1) and B. cenocepacia (n=2). Three patients were colonised by the same B. multivorans strain. Compared to matched controls, the 5 yr outcome was poor; four B. cepacia patients died and none of the control patients died. Lung-function evolution was poor. In conclusion, the rate of colonisation in Belgian cystic fibrosis patients is stable and low. Burkholderia cenocepacia was most prevalent in 1993; Burkholderia multivorans in 1999. The cross-infection rate is low. Three patients had transient colonisation. The impact of Burkholderia cepacia complex on morbidity in the Belgian cystic fibrosis population is high and not limited to Burkholderia cenocepacia