V. Vavrova

Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials.

Pulmonary exacerbations represent a key outcome variable in clinical trials of cystic fibrosis (CF). As there is variation in the trigger for use of intravenous antibiotics compared to the use of oral antibiotics or new nebulised therapy for treatment of exacerbations, the consensus view is that use of intravenous antibiotics cannot be regarded as the key defining character for an exacerbation on its own. The consensus view is that the clinical need for additional treatment as indicated by a recent change in clinical parameters provides the best definition of an exacerbation. Which parameters to include as well as the problems associated with the use of scoring systems and symptom clusters are being discussed.

Chronic Pseudomonas aeruginosa infection definition: EuroCareCF Working Group report

Chronic pulmonary infection with P. aeruginosa develops in most patients with cystic fibrosis (CF); by adulthood 80% of patients are infected and chronic P. aeruginosa infection is the primary cause of increased morbidity and mortality in CF. Chronic infection is preceded by an intermittent stage of infection. The initial stage is characteristically followed by the gradual emergence of mucoid variants of the colonizing strains and a rise in anti-Pseudomonas antibodies. In addition to optimizing existing therapeutic strategies, effective new agents need to be identified. Studies in patients with CF are particularly challenging: the progressive nature of the disease and the wide variation in severity influence considerably the outcome of drug testing. A validated, universally accepted, and clinically useful classification of patients infected with P. aeruginosa, particularly those chronically infected, is needed that can be used as both a criterion for patient selection for clinical trials and as a study endpoint.

Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype

ystic fibrosis is a common lethal autosomal recessive disease affecting whites with an incidence of about 1 in 2500. The median lifespan is approximately 30 years. Chronic obstruction and infection of the respiratory tract, pancreatic insufficiency, elevated sweat electrolyte concentration, and male infertility characterise this disease. Clinical manifestations are attributed to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, 1 which encodes an epithelial chloride channel. 2 Certain phenotypes of cystic fibrosis, such as pancreatic insufficiency, are highly associated with the CFTR genotype. Pulmonary symptoms are highly variable, even among patients from the same family. 3 Other genetic factors, as well as environmental factors, thus affect the cystic fibrosis disease phenotype. In association studies, evidence has been found that mannose binding lectin (MBL) protein affects cystic fibrosis disease. 45 MBL protein is an important mediator component of the innate immune defense system, which functions as an opsonin and complement activator. It is part of a family of proteins called collectins, because they contain collagen-like regions and lectin domains. Through the lectin domain, they bind to carbohydrate structures presented by a wide range of pathogenic bacteria, viruses, fungi, and parasites. Mannose binding lectin protein is synthesised in the liver by hepatocytes and secreted in the blood, and circulates as dimers or hexamers composed of subunits containing three identical polypeptides. 67

Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype

Background: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor α (TNFα), a member of the immune system. Methods: Three polymorphic loci in the promoter (−851c/t, −308g/a, −238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFα gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients’ medical records. Results: An association was found between the TNFα +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV1) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV1 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the −851c/t polymorphic locus. In the group of patients with more severe FEV1% predicted, a higher proportion of patients were homozygous for the −851c allele than in the other group of patients (p = 0.04, likelihood ratio χ2, odds ratio = 2.4). Conlusion: TNFα polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.

Insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in cystic fibrosis: a positive effect of antibiotic therapy and hyperalimentation

Patients with cystic fibrosis (CF) are underweight and growth retarded. This study tested the link between serum insulin‐like growth factor‐I (IGF‐I) and insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) levels and body height, nutritional status, pulmonary function tests and activity of inflammation in 92 subjects with CF (age 2.1–18.8 y). It also analysed the effect of short‐term antibiotic treatment and hyperalimentation on IGF‐I and IGFBP‐3 levels in 33 subjects (age 3.6–33.7 y) on 41 occasions. Both IGF‐I (‐1.19 ±0.17 SD) and IGFBP‐3 levels (‐0.66 ±0.12 SD; both p 0.0001 vs 0) were decreased in cross‐sectional measurements. Their standardized values were inversely proportional to age (IGF‐I: r= ‐0.23, p= 0.03; IGFBP‐3: r= ‐0.29, p= 0.005) and positively correlated with SDS of height (IGF‐I: r= 0.40, p 0.0001; IGFBP‐3: r= 0.36, p= 0.0005) and of mid‐arm circumference (IGF‐I: r= 0.39, p= 0.0001; IGFBP‐3: r= 0.38, p= 0.0002), and with pulmonary function tests. After a short‐term course of intensive antibiotic therapy and hyperalimentation, IGF‐I normalized (from ‐0.66 ± 0.20 to 0.00 ± 0.25 SD; pľ 0 0001) and IGFBP‐3 increased (from ‐0.78 ± 0.15 to ‐0.53 ± 0.16 SD; p= 0.002). IGFBP‐3 correlated inversely with erythrocyte sedimentation rate (r= ‐0.40, p= 0.01).

Low-dose insulin therapy in patients with cystic fibrosis and early-stage insulinopenia prevents deterioration of lung function: a 3-year prospective study.

Abstract Cystic fibrosis related diabetes (CFRD) is an insulinopenic condition. We aimed to detect insulinopenia early and to evaluate the impact of low dose insulin on nutritional status and forced expiratory volume in first second (FEV1). Out of 142 cystic fibrosis patients (CFpts) older than 10 years, 28 with abnormal oral glucose tolerance test in spite of normal fasting glycemia were found to have decreased first phase insulin release and started low dose insulin therapy (median age 15.4 years). Sex and age matched CFpts with normal glucose tolerance (NGT) were observed for comparison. Whereas nutritional status improved following 3 years of insulin administration, FEV1 stabilized in insulin-treated insulinopenic subjects (73.8±4.3% vs. 73.5±4.4%), but decreased in the parallel group with NGT who remained without insulin treatment (71.1±3.8% vs. 61.0±4.0%; p=0.001). We conclude that low dose insulin improves nutritional status and stabilizes pulmonary functions. Regular estimation of stimulated insulin secretion in CFpts may allow optimizing treatment.

Pilot newborn screening project for cystic fibrosis in the Czech Republic: defining role of the delay in its symptomatic diagnosis and influence of ultrasound-based prenatal diagnosis on the incidence of the disease.

The objective need for cystic fibrosis (CF) newborn screening (NBS) in the Czech Republic has recently been substantiated by a significant delay of its symptomatic diagnosis. This trend most likely resulted from the process of decentralisation of health care which led to the deterioration of care for patients who need specialised approaches. Applied newborn screening model (IRT/DNA/IRT) was efficacious enough to detect CF cases with median age at diagnosis of 37 days. The incidence of CF (1 in 6946 live births) ascertained in this project was lower than that established previously by epidemiological studies (1 in 2700-1 in 3300). However, adjustment for broadly applied ultrasound-based prenatal diagnosis (PND) in the 2nd trimester of pregnancy, that was performed within the period of the project (1/2/2005-2/11/2006), rendered an incidence estimate of 1 in 4023. This value is closer to that observed in other CF NBS programmes and reflects influence of PND on the incidence of CF.

Quality assessment of expert answers to lay questions about cystic fibrosis from various language zones in Europe: the ECORN-CF project

BackgroundThe European Centres of Reference Network for Cystic Fibrosis (ECORN-CF) established an Internet forum which provides the opportunity for CF patients and other interested people to ask experts questions about CF in their mother language. The objectives of this study were to: 1) develop a detailed quality assessment tool to analyze quality of expert answers, 2) evaluate the intra- and inter-rater agreement of this tool, and 3) explore changes in the quality of expert answers over the time frame of the project.MethodsThe quality assessment tool was developed by an expert panel. Five experts within the ECORN-CF project used the quality assessment tool to analyze the quality of 108 expert answers published on ECORN-CF from six language zones. 25 expert answers were scored at two time points, one year apart. Quality of answers was also assessed at an early and later period of the project. Individual rater scores and group mean scores were analyzed for each expert answer.ResultsA scoring system and training manual were developed analyzing two quality categories of answers: content and formal quality. For content quality, the grades based on group mean scores for all raters showed substantial agreement between two time points, however this was not the case for the grades based on individual rater scores. For formal quality the grades based on group mean scores showed only slight agreement between two time points and there was also poor agreement between time points for the individual grades. The inter-rater agreement for content quality was fair (mean kappa value 0.232 ± 0.036, p < 0.001) while only slight agreement was observed for the grades of the formal quality (mean kappa value 0.105 ± 0.024, p < 0.001). The quality of expert answers was rated high (four language zones) or satisfactory (two language zones) and did not change over time.ConclusionsThe quality assessment tool described in this study was feasible and reliable when content quality was assessed by a group of raters. Within ECORN-CF, the tool will help ensure that CF patients all over Europe have equal possibility of access to high quality expert advice on their illness.

WS5.5 Economic burden of cystic fibrosis (CF): prevalence based cost of illness analysis related to the lung disease severity in Czech CF patients

WS5.5 Economic burden of cystic fibrosis (CF): prevalence based cost of illness analysis related to the lung disease severity in Czech CF patients J. Klimes1, T. Dolezal1, V. Vavrova2, M. Turnovec3, V. Skalicka2, T. Mlcoch1, J. Jircikova1, P. Drevinek4, M. Macek5. 1Institute of Health Economics and Technological Assessment (iHETA), Prague, Czech Republic; 2Department of Pediatrics, Charles University − 2nd Faculty of Medicine and Faculty Hospital Motol, Prague, Czech Republic; 3Department of Biology and Medical Genetics, Charles University − 2nd Faculty of Medicine and Faculty Hospital Motol, Prague, Czech Republic; 4Department of Medical Microbiology, Charles University − 2nd Faculty of Medicine and Faculty Hospital Motol, Prague, Czech Republic; 5Charles University Prague-2 Faculty of Medicine, Department of Biology and Medical Genetics, Prague, Czech Republic

Wilson disease as a cause of liver injury in cystic fibrosis

Cystic fibrosis-related liver disease affects approximately one third of all patients with cystic fibrosis. Initial signs of other liver diseases including the genetically determined disorders of the liver co-inherited with cystic fibrosis may be obscured by or ascribed to cystic fibrosis-related liver disease. We report a patient shown to suffer simultaneously from cystic fibrosis and hepatic Wilson disease. Our case documents that in patients with cystic fibrosis presenting with liver disease, when unusual clinical and/or laboratory abnormalities appear and fail to respond to standard therapy, a second disease, including rare inherited metabolic disorders such as the hepatic form of Wilson disease or alpha(1)-antitrypsin deficiency, should be suspected.