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PubMed2003

Increased expression of interleukin-9, interleukin-9 receptor, and the calcium-activated chloride channel hCLCA1 in the upper airways of patients with cystic fibrosis.

OBJECTIVES/HYPOTHESIS: Mucus overproduction is commonly found in airway disease in patients with cystic fibrosis. Interleukin-9 (IL-9) has been shown to mediate airway hyper-responsiveness and mucus overproduction. Recently, the calcium-activated chloride channel hCLCA1 has been described to be upregulated by IL-9 and has been thought to regulate the expression of soluble gel-forming mucins. We sought to examine the expression of IL-9, interleukin-9 receptor (IL-9R), and hCLCA1 in the upper airway of patients with cystic fibrosis in comparison to healthy control subjects and to demonstrate the relationship of IL-9, IL-9R, and hCLCA1 expression with mucus production. STUDY DESIGN: Prospective design. METHODS: Biopsy samples from nasal polyps of four patients with cystic fibrosis, nasal mucosa of six patients with cystic fibrosis, sinus mucosa of eight patients with cystic fibrosis, and nasal mucosa of six healthy control subjects were stained with periodic acid-Schiff (PAS) to identify mucus glycoconjugates. IL-9, IL-9R, and hCLCA1 expression was determined by immunocytochemical study. RESULTS: We demonstrated significant increases in IL-9, IL-9R, and hCLCA1 immunoreactivity in the mucosa of patients with cystic fibrosis compared with that found in control subjects (P <.05). There were no significant differences between the different locations (nasal polyps, nasal mucosa, and sinus mucosa) in the patient group (P >.05). We also observed a significant increase in the number of mucus-producing cells in biopsy specimens from patients with cystic fibrosis in comparison to control subjects. A positive correlation was found between hCLCA1-positive cells and IL-9-positive cells (correlation coefficient [r] = 0.79, P <.05) or IL-9R-positive cells (r = 0.92, P <.05). Moreover, a positive correlation was also present between PAS-positive (mucus-producing) cells and hCLCA1-positive cells (r = 0.64, P <.05) or IL-9R-positive cells (r = 0.64, P <.05). CONCLUSIONS: Increased expression of IL-9 and IL-9R, as well as upregulation of hCLCA1, in mucus-overproducing epithelium of patients with cystic fibrosis supports the hypothesis that IL-9 contributes to mucus overproduction in cystic fibrosis. Expression of hCLCA1 may also be responsible, in part, for the overproduction of mucus. These preliminary findings suggest that hCLCA1 might be an interesting new therapeutic target to control mucus overproduction in airway disease in patients with cystic fibrosis.

Biopsy↗
PubMed2003

Cystic fibrosis: current trends in respiratory care.

Cystic fibrosis is a genetic disease that typically produces malnutrition and chronic respiratory infections. Prolonged bronchial obstruction, infection, and inflammation result in bronchiectstasis and permanent lung damage. Most cystic fibrosis patients die because of this progressive respiratory disease. Thus, in the absence of a cure, effective respiratory therapy is the primary means to extend and improve the quality of life for the cystic fibrosis patient. Aerosol therapy, airway clearance techniques, and noninvasive ventilation can all improve quality of life and possibly extend survival. Close patient monitoring with pulmonary function testing, chest radiography, and induced sputum can result in earlier treatment, potentially reducing permanent lung damage. Earlier diagnosis has prevented serious complications through early initiation of preventive therapies such as improved nutrition.

Administration, Inhalation↗
PubMed2006

Faecal elastase-1 concentration in cystic fibrosis patients with CFTR I1234V mutation.

AIM: To assess the exocrine pancreatic function among cystic fibrosis patients with cystic fibrosis trans-membrane conductance regulator (CFTR) I1234V mutation. METHODS: Cross-sectional study of 40 cystic fibrosis patients with homozygous CFTR I1234V mutation belonging to a large Arab kindred family and 25 healthy subjects as a control group over a period of 12 mo. Assessment of their exocrine pancreatic function was performed by measuring faecal elastase-1 (FE1) concentration with a commercial ELISA kit using polyclonal antibodies (BioServ Diagnostics) in CF patients compared to healthy subjects. The results were compared with those obtained from a second laboratory using another commercial ELISA (ScheBo; Biotech, Germany) that uses two monoclonal antibodies against different specific epitopes of human pancreatic elastase. RESULTS: All CF patients with CFTR I1234V mutation had normal levels of faecal elastase 1. No significant difference was found between the two methods for the CF groups or between the CF patients with and without pancreatic enzyme replacement. CONCLUSION: Cystic fibrosis with homozygous CFTR I1234V mutation is associated with pancreatic sufficiency. Assessment of exocrine function using polyclonal antibodies does not significantly differ from that using two monoclonal antibodies against different specific epitopes of human pancreatic elastase.

Adolescent↗
PubMed1997

Novel and characteristic CFTR mutations in Saudi Arab children with severe cystic fibrosis.

More than 600 different CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations have been identified so far that are considered to cause the fatal genetic disorder cystic fibrosis (CF). We have investigated 15 Arab children from 12 families, who were diagnosed as having CF, for mutations in the coding region and in the flanking intron sequences of the CFTR gene. Six different CFTR mutations were identified including two novel mutations, 1548delG in exon 10 and 406-2A-->G in intron 3. Prominent mutations were the splice mutation 3120 + 1G-->A (intron 16) followed by N1303K (exon 21) and 1548delG (exon 10). Most CF children were homozygotes who presented with a severe form of the disease including failure to thrive, recurrent chest infections, particularly with Pseudomonas aeruginosa, and frequent hospital admissions. Identification of the CFTR mutations facilitates molecular investigation of the disease and better understanding of its pathophysiology in Arab children, among whom CF is probably an underdiagnosed disease.

Child↗
PubMed2002

Transcriptional adaptation to cystic fibrosis transmembrane conductance regulator deficiency.

Cystic fibrosis, the most commonly inherited lethal pulmonary disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). To identify genomic responses to the presence or absence of CFTR in pulmonary tissues in vivo, microarray analyses of lung mRNAs were performed on whole lung tissue from mice lacking (CFTR(-)) or expressing mouse CFTR (CFTR(+)). Whereas the histology of lungs from CFTR(-) and CFTR(+) mice was indistinguishable, statistically significant increases in the relative abundance of 29 and decreases in 25 RNAs were identified by RNA microarray analysis. Of RNAs whose expression was consistently altered by the absence of CFTR, functional classes of genes influencing gene transcription, inflammation, intracellular trafficking, signal transduction, and ion transport were identified. RNAs encoding the transcription factor CCAAT enhancer-binding protein (CEBP) delta and interleukin (IL) 1beta, both known to regulate CFTR expression, were induced, perhaps indicating adaptation to the lack of CFTR. RNAs mediating lung inflammation including calgranulin-S100 family members, IL-1beta and IL-4, were increased. Likewise, expression of several membrane transport proteins that interact directly with CFTR were increased, suggesting that CFTR-protein complexes initiate genomic responses. Absence of CFTR influenced the expression of genes modulating diverse pulmonary cell functions that may ameliorate or contribute to the pathogenesis of CF.

Animals↗
PubMed1998

Is the hemochromatosis gene a modifier locus for cystic fibrosis?

The variable clinical manifestations of cystic fibrosis (CF) suggest the influence of modifier genes. For example, meconium ileus is present in approximately 10-15% of neonates with cystic fibrosis; however, the genetic and, or environmental factors that determine whether an individual will develop this complication have not been determined. We propose the HFE gene as a candidate modifier locus for CF based on (1) the suggestion of an association between the HLA loci and CF phenotypes; (2) the location of the HFE gene near the HLA loci and; (3) the similarity between the gastrointestinal manifestations of hereditary hemochromatosis and CF. We have determined the frequency of the C282Y and H63D mutations in a group of 89 CF patients who were homozygous for delta F508 and for whom meconium ileus status was known. The carrier frequency of C282Y among the CF patients with meconium ileus was significantly different from that of our unaffected control group (19.4% versus 7.7%). However, the difference between the meconium ileus and the nonmeconium ileus groups was not significant (19.4% versus 10.3%). There was no difference in the frequency of the H63D among the three groups that were studied. These data are suggestive of a relationship between the development of meconium ileus or other gastrointestinal diseases in CF and the HFE gene. Further study of a larger group of patients is warranted.

Adult↗
PubMed1991

Molecular analysis of cystic fibrosis in the Hungarian population.

Hungarian cystic fibrosis (CF) families (n = 33) including 114 family members have been analysed for the presence of the delta F508 mutation within the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and have been haplotyped with probes for restriction fragment length polymorphisms (RFLPs) known to be linked to the CFTR gene. The delta F508 deletion was present in 64% of CF chromosomes. As in many other populations, linkage disequilibrium was found between the CF locus and the haplotype B (XV-2c: allele 1, KM-19: allele 2), which accounts for 95% of delta F508 CF chromosomes in our families.

Cystic Fibrosis↗
PubMed1995

Mutation analysis of Western Australian families affected by cystic fibrosis.

OBJECTIVE: To document the results of mutation analysis on 160 individuals with cystic fibrosis and 31 obligate carriers of the cystic fibrosis gene in 191 Western Australian families to facilitate accurate genetic counselling. METHODS: We tested for 17 mutations of the cystic fibrosis gene by either a variation of the polymerase chain reaction amplification refractory mutation system (PCR-ARMS) or with a series of restriction enzyme cuts and dot blots using chemiluminescent probes. RESULTS: At least one of the two intragenic mutations causing cystic fibrosis was identified in 98% of affected individuals and both were detected in 68%. The delta F508 deletion occurred in 89.8% of patients: 51% were homozygous for this defect. In carriers, 85% of the mutations were detected with a panel of 16 probes, identifying 17 intragenic defects: the delta F508 deletion occurred in 72.4%. Both cystic fibrosis mutations were detected in 68% of cystic fibrosis families. CONCLUSIONS: By analysis with 16 intragenic cystic fibrosis genomic probes, we have documented the frequencies of various mutations in the Western Australian population. These data will be useful in accurate genetic counselling for affected families and carrier screening for the general population.

Adult↗
PubMed2000

Allergic bronchopulmonary aspergillosis as presenting sign of cystic fibrosis in an elderly man.

BACKGROUND: Although cystic fibrosis is the most common genetic disorder of children, its heterogeneous spectrum of severity lends itself to underdiagnosis in the older adult patient population where the index of suspicion is not high. METHODS: We report a 60-year-old Hispanic man with asthma who presented with progressive dyspnea and wheezing unresponsive to inhaled corticosteroid treatment. Additionally, he had clinical findings and a past history suggestive of cystic fibrosis. Skin testing, radiography and laboratory studies were completed to evaluate for allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis. RESULTS: Test results revealed peripheral eosinophilia and hyper IgE. Skin testing to Aspergillus fumigatus (Af) was positive. IgG, IgM, and Af specific antibodies were present. High resolution CT scan showed central bronchiectasis. Sweat tests were positive on two separate occasions and gene analysis showed our patient to have a positive gene mutation at D127ON/D127ON. CONCLUSION: Cystic fibrosis should be suspected in the older adult patient with a compatible clinical presentation.

Aspergillosis, Allergic Bronchopulmonary↗
PubMed1995

Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years.

BACKGROUND: Cystic fibrosis is usually diagnosed in childhood, but a number of patients are not diagnosed until adulthood. The aim of this study was to investigate whether patients diagnosed at an older age had a different genetic constitution, manifestations of disease, and prognosis from those diagnosed at an early age. METHODS: Clinical data and results of lung function tests and DNA analysis of 143 adult patients with cystic fibrosis were entered into a computerised database. Patients diagnosed before their 16th birthday (early diagnosis, ED) were compared with those diagnosed at 16 years of age or older (late diagnosis, LD). RESULTS: Mean age of diagnosis of the ED group was 4.6 years compared with 27.7 years for the LD group. Mean (SD) percentage predicted pulmonary function was better for the LD group than for the ED group: forced expiratory volume in one second (FEV1) 72.5 (31.1)% and 52.0 (24.8)%, and forced vital capacity (FVC) 89.8 (25.7)% and 71.9 (23.0)%, respectively. Colonisation with Pseudomonas aeruginosa was present in 70% of the ED group and 24% of the LD group. In the ED group 81% had pancreatic insufficiency compared with only 12% of the LD group. None of the LD group was homozygous for delta F508 compared with 58% of the ED group. In the LD group 72% were compound AF508 heterozygotes and 28% had two non-delta F508 mutations. CONCLUSIONS: Among this group of 143 adult patients with cystic fibrosis late diagnosis is caused mainly by delayed expression and mild progression of clinical symptoms. Late diagnosis is associated with milder pulmonary disease, less pancreatic insufficiency, and different cystic fibrosis mutations. Since mortality in cystic fibrosis depends on the progression of pulmonary disease, patients with a late diagnosis have a better prognosis than those diagnosed early.

Adolescent↗
PubMed2003

[Cystic fibrosis: relationship between genotype and phenotype].

Cystic fibrosis (CF) is one of the most common lethal autosomal recessive disease among the Caucasian population. It is caused by defects in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. More than 1000 different CF mutations have been described. This large heterogeneity of mutations could explain in part the great variability of clinical expression of the disease. However, the severity of the lung disease is very different among patients with similar CFTR genotype, even from the same family. These discrepancies in phenotypes within patients of the same genotype suggest the influence of nongenetic environmental factors and genetic modifiers outside the CF locus.

Cystic Fibrosis↗
PubMed1996

Direct assessment of gastrointestinal inflammation and mucosal immunity in children with cystic fibrosis.

Fibrosing colonopathy is a recently described complication of cystic fibrosis, of unknown aetiology but possibly related to treatment with high-dose pancreatic enzyme supplements. We have used a whole gut perfusion technique to study subclinical gut inflammation in cystic fibrosis patients; concentrations of haemoglobin, IgG, albumin, alpha-1-antitrypsin, granulocyte elastase, IL1 beta, and IL8 were measured in whole gut lavage fluid: 23 tests were performed in 17 children with cystic fibrosis (20 elective tests, three lavages to treat distal intestinal obstruction syndrome (DIOS)). None has had fibrosing or haemorrhagic colitis. There were 12 tests in control children with constipation or precolonoscopy. Moderately abnormal results were obtained for many of the parameters studied, in specimens from all the cystic fibrosis children; however there were no significant differences between tests on high-dose and low-dose enzyme supplements of the same brand in the five children who had duplicate tests performed electively. The lavage fluid specimens from two cystic fibrosis children were strikingly abnormal in all tests apart from haemoglobin and alpha-1-antitrypsin. These were two of the three children with DIOS, and were also the only cases in the series taking Nutrizym 22. These data suggest that the majority of cystic fibrosis children, including those on high-dose enzyme supplements, do not have clinically significant colitis, but that there is subclinical mucosal inflammation in a minority (two of 17 in this series), for which DIOS and/or Nutrizym 22 treatment may be risk factors. Alternatively, inflammation and dysmotility in the proximal colon may be directly produced by a drug or other agent, producing a clinical syndrome indistinguishable from DIOS. Tests for indices of inflammation in gut lavage fluid offer a new approach to the detection and measurement of iatrogenic intestinal and colonic injury.

Adolescent↗
PubMed2005

Skin prick test reactivity to supplemental enzymes in cystic fibrosis and pancreatic insufficiency.

BACKGROUND: Patients with cystic fibrosis and pancreatic insufficiency take supplemental pancreatic enzymes of porcine or plant origin on a daily basis. OBJECTIVE: The frequency of immediate skin prick hypersensitivity reactions to such enzymes and the correlations to gastrointestinal symptoms and nutritional status were assessed in a single center prospective descriptive study. METHODS: Skin prick tests using five different freshly prepared porcine pancreatic enzyme preparations, one enzyme preparation of fungal origin, porcine meat and cat epithelia were performed in patients with cystic fibrosis and pancreatic insufficiency and in healthy control subjects. RESULTS: Positive skin tests in the 48 patients with cystic fibrosis were no more frequent than in 21 control subjects. No correlations with the frequency of gastrointestinal symptoms, nutritional status and lung function were found. CONCLUSION: Although immediate hypersensitivity reactions to pancreatic enzyme preparations in subjects with cystic fibrosis are not common, individuals with possible allergic reactions to supplemental enzymes should be identified by skin prick tests and in unclear cases by double-blind placebo-controlled provocation tests.

Adolescent↗
PubMed1987

Colonization of the respiratory tract with Pseudomonas cepacia in cystic fibrosis. Risk factors and outcomes.

Between 1981 and 1983, some 85 patients with cystic fibrosis at Rainbow Babies and Childrens Hospital, Cleveland, developed colonization or infection of the respiratory tract with Pseudomonas cepacia. Twenty-nine (34 percent) of the colonized patients died; four were female patients with fulminant bacteremia with P cepacia prior to death. Case-control studies showed that increasing severity of underlying cystic fibrosis, increasing age, having a sibling with cystic fibrosis who was colonized with P cepacia, and previous hospitalizations were associated with increased risk of colonization. In patients with mild cystic fibrosis, no differences in clinical outcome were seen during the period of study; however, patients colonized with P cepacia who had moderate or advanced cystic fibrosis were hospitalized longer and died sooner after colonization, compared with control subjects with similar severity of cystic fibrosis. The excess mortality associated with such colonization varied in magnitude and trend according to the patient's sex and severity of underlying cystic fibrosis, reflecting the combined influence of colonization with P cepacia, sex, and severity of cystic fibrosis on the mortality of the patients. The source and mode of transmission of P cepacia were not determined, but the data suggest a possible nosocomial source. The results of this investigation showed that colonization with P cepacia most often affected patients with moderate or advanced cystic fibrosis and was associated with an adverse clinical outcome in these patients.

Adolescent↗
PubMed2000

[Swiss registry for patients with cystic fibrosis: design, programming, implementation and first examples of use].

The Swiss Registry for Cystic Fibrosis (SRCF) was designed to collect demographic, clinical and therapeutic data from patients with cystic fibrosis (CF) in Switzerland. It was designed, programmed and implemented for standalone application in Swiss cystic fibrosis centres. It is part of the European Registry for Cystic Fibrosis (ERCF), which has been implemented in Europe to collect data on the use and safety of dornase alpha (Pulmozyme) in the treatment of cystic fibrosis. At the time of first evaluation 245 cystic fibrosis patients are registered, their mean age is 13 years, and 17% are over 18. In larger databases in Germany or North America we observe comparable demographic data, similar degrees of severity and similar therapeutic approaches to those in Swiss cystic fibrosis patients. The aim of the Swiss Registry is to cover the maximum possible number of cystic fibrosis patients from this country.

Adolescent↗
PubMed2003

Approach to resistant gram-negative bacterial pulmonary infections in patients with cystic fibrosis.

PURPOSE OF THE REVIEW: Patients with cystic fibrosis are living longer with chronic pulmonary bacterial infections. One consequence of antibiotic treatment of these chronic infections has been the increasing prevalence of antibiotic resistance seen in bacterial isolates recovered from patients with cystic fibrosis. RECENT FINDINGS: Bacteria such as Pseudomonas aeruginosa and Burkholderia cepacia are able to acquire antibiotic resistance by either spontaneous mutation or gene transfer via plasmids or integrins. In addition, bacteria survive by forming antibiotic-resistant biofilms within the airways of patients with cystic fibrosis. Therapeutic approaches to dealing with antibiotic-resistant bacterial pulmonary infections include the use of in vitro synergy testing to determine optimal double antibiotic combinations or multiple-combination bactericidal testing to determine bactericidal double and triple antibiotic combinations to use against the bacteria in the clinical setting of acute exacerbations. SUMMARY: Therapy for antibiotic-resistant bacterial infections in cystic fibrosis involves the use of new laboratory methods (synergy testing or multiple-combination bactericidal testing) to optimize antibiotic treatment strategies. Clinical trials are required to address whether treatment guided by susceptibility testing improves clinical outcomes. Future novel approaches will likely include drugs that can disrupt bacterial biofilm formation and the use of cationic peptide antimicrobial compounds.

Anti-Bacterial Agents↗
PubMed2001

The mannose binding lectin gene influences the severity of chronic liver disease in cystic fibrosis.

Chronic liver disease is a major complication of cystic fibrosis. Its incidence and severity show marked heterogeneity, even among the homogeneous group of homozygous DeltaF508 patients, suggesting that environmental or genetic factors other than the deletion DeltaF508 may influence the development of cystic fibrosis related liver disease. We investigated whether the allelic variants of mannose binding lectin, an important protein of the immune system, could be associated with the presence of cirrhosis in a population of 216 homogeneous homozygous DeltaF508 patients. Analysis of the data shows that the presence of cirrhosis in cystic fibrosis patients is significantly associated with a mutated mannose binding lectin genotype (homozygous or compound heterozygous for mannose binding lectin variants). The modulating role of mannose binding lectin in the occurrence of cirrhosis in cystic fibrosis could be explained by the fact that hepatotoxic damage from viruses or bacteria might be increased by the immunodeficiency associated with mannose binding lectin variants and might facilitate the degradation of liver status. These data highlight the crucial role of mannose binding lectin in the clinical outcome of cystic fibrosis, as it has recently been shown that the mannose binding lectin gene is a modulating gene of the respiratory involvement in cystic fibrosis patients.

Alleles↗