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PubMed1995

Prognosis in cystic fibrosis.

Prognosis for patients with cystic fibrosis has improved dramatically over the past three decades. In the United States, median survival age is now 28.9 years. Although genotype predicts exocrine pancreatic function, it does not correlate with pulmonary status or overall clinical outcome. However, there are a number of parameters, such as exocrine pancreatic sufficiency, male gender, absence of colonization with mucoid Pseudomonas aeruginosa, presentation with predominantly gastrointestinal symptoms, balanced family functioning and coping, and compliance with treatment regimens, that predict a more favorable outcome. The impact of early diagnosis and treatment is still controversial. Although nonblinded studies indicate decreased morbidity in the first 2 to 4 years of life among patients diagnosed by newborn screening, no data support long-term benefit in terms of pulmonary function or survival. With increased longevity, there is now evidence of a small but significantly increased risk of gastrointestinal tract cancer among patients with cystic fibrosis.

Adult↗

PubMed1992

Cystic fibrosis. Target population for lung transplantation in North America in the 1990s.

Cystic fibrosis is the most common lethal genetic disease occurring in the white population. It is estimated that 3.5% of the 20,000 individuals with cystic fibrosis in North America will die each year of end-stage lung disease. Lung transplantation (heart-lung or double lung) is becoming more frequent as more patients are referred for this procedure. Since January 1988, we have evaluated 60 patients with cystic fibrosis for lung transplantation and have accepted 30 (50%). Nine patients (30%) died while awaiting a donor. Fifteen patients underwent transplantation (13 heart-lung and two double lung procedures). Actuarial survival at 1, 2, and 3 years is 76%. All survivors are without physical limitations. Pulmonary function, as determined by forced vital capacity, forced expiratory volume in 1 second, and arterial blood gas determinations, is within the normal range. Comparing these data with those of a group of patients without cystic fibrosis who underwent transplantation during the same period did not reveal any significant differences with respect to infection, rejection, and outcome. Preliminary data suggest that obliterative bronchiolitis is less prevalent at 1 year in patients with cystic fibrosis (19%) than in those without cystic fibrosis (41%). Patients with cystic fibrosis present a number of challenges. The problems of pleural adhesions from repeated infections, pleurodesis, and previous thoracic procedures are now readily approached through the bilateral thoracosternotomy (clam shell) incision. Insulin-dependent diabetes mellitus and low-dose corticosteroid therapy are no longer considered absolute contraindications. Both septic lungs must be removed at operation, either with heart-lung transplantation or with double lung transplantation. These data support the therapeutic efficacy of lung transplantation for patients with cystic fibrosis.

Actuarial Analysis↗

PubMed1986

Abnormal respiratory epithelial ion transport in cystic fibrosis.

The respiratory epithelium of cystic fibrosis patients exhibits excessive sodium (and volume) absorption and an absence of chloride (and volume) secretion in response to usual stimuli. These abnormalities likely contribute to the pathophysiology of cystic fibrosis lung disease, and provide a rationale for a novel therapeutic approach to this problem.

Animals↗

PubMed1993

The cystic fibrosis gene and its product CFTR.

Cystic fibrosis is the commonest, fatal, inherited disease of caucasian populations occurring with a frequency of 1 in 2000 live births. The CF gene spans about 230 kb of genomic DNA and encodes a protein of 1480 amino acids named the cystic fibrosis transmembrane conductance regulator (CFTR). The primary sequence predicts that CFTR is an ABC type protein with twelve transmembrane spans, two nucleotide binding domains and a cytoplasmic regulatory domain. CFTR functions as a cyclic AMP-regulated, low conductance, chloride channel in epithelial cells, but other roles are possible. Failure of the CFTR channel in CF reduces epithelial salt and water secretion, leading to a dehydration of epithelial surfaces which initiates the pathology of the disease.

Chloride Channels↗

PubMed1996

Detection of a de novo R1066H mutation in an Italian patient affected by cystic fibrosis.

Search for mutations in a cystic fibrosis patient, compound heterozygous for 1717-1G-->A and another uncharacterized molecular defect, revealed the presence of a de novo R1066H mutation on the affected chromosome of paternal origin. Three additional rare mutations (R1066C, R1066S and R1066L), occurring at the CpG dinucleotide at position 3328-3329 of the cystic fibrosis transmembrane conductance regulator gene, have so far been reported. The identification of a R1066H de novo mutation further suggests that this dinucleotide may constitute a mutational hotspot.

Adolescent↗

PubMed1997

Nucleotide transport through the cystic fibrosis transmembrane conductance regulator.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the superfamily of ATP-binding cassette (ABC) transporters, also known as traffic ATPases, which are implicated in the movement of various substrates. Recent studies indicate that CFTR and other closely related ABC transporters are also implicated in the movement of cellular ATP. This is the subject of current controversy. Therefore, evidence for the movement of cellular nucleotides by expression of CFTR and related molecules, as well as the potential significance of ATP-permeable channels in cell physiology, are reviewed in this study. The hypothesis is thus forwarded for the improper delivery of cellular ATP to the extracellular milieu by a dysfunctional CFTR, to be a relevant factor in the onset of cystic fibrosis.

Adenosine Triphosphate↗

PubMed1997

A prognostic model for the prediction of survival in cystic fibrosis.

BACKGROUND: The treatment for endstage cystic fibrosis is, where appropriate, double-lung, heart-lung or, occasionally, heart-lung-liver transplantation. Optimising the timing of transplantation depends upon an accurate prediction of survival, but while current criteria give some guidance to this, they are not based upon statistically derived prognostic models. METHODS: Data collected prospectively on 403 patients with cystic fibrosis, recruited between 1969 and 1987 (cohort A), were analysed by log rank and univariate Cox regression analysis to determine variables that accurately predict survival. The significant variables were then subject to time dependent multivariate Cox regression analysis to generate a prognostic model. The model was validated, within the study population, using split sample testing, and was subsequently validated in a further cohort of patients recruited since October 1988 (cohort B). RESULTS: One hundred and eighty eight (50.4%) of the study cohort died within the study period. Percentage predicted forced expiratory volume in one second (FEV1), percentage predicted forced vital capacity (FVC), short stature, high white cell count (WBC), and chronic liver disease (as evidenced by the presence of hepatomegaly) were negatively correlated with survival. These variables, when combined into a prognostic index, accurately predicted one year survival in the study population and in the cohort recruited since 1988. CONCLUSION: This prognostic index may prove valuable in predicting prognosis in other cohorts with cystic fibrosis and thereby improve the timing of transplantation.

Adolescent↗

PubMed2000

Liver disease does not affect lipolysis as measured with the 13C-mixed triacylglycerol breath test in children with cystic fibrosis.

BACKGROUND: Liver disease associated with cystic fibrosis may not only limit the solubilisation and absorption of the products of fat digestion, but also may depress the activity of pancreatic lipase. The purpose of this study was to measure the effect of liver disease on triacylglycerol lipolysis using the 13C-mixed triacylglycerol breath test. METHODS: Forty children with cystic fibrosis took 13C-mixed triacylglycerol with a standard breakfast and the child's normal pancreatic enzyme replacement therapy. Breath samples were collected before and every 30 minutes after ingestion for 6 hours. The cumulative percentage dose of 13C recovered at 6 hours was calculated from sequential measurements of 13C enrichment of breath CO2, measured by isotope ratio mass spectrometry. Liver abnormalities and portal hypertension were defined by ultrasound scan and clinical examination. RESULTS: Twenty-four children had liver abnormalities, including 5 with portal hypertension. No difference was found between cumulative percentage dose of 13C recovered at 6 hours in 16 children with no liver abnormality (mean, 21.4%+/-11.1%), 19 children with liver abnormalities (22.2%+/-10.0%) and 5 children with portal hypertension (20.9%+/-7.1%). CONCLUSION: Intestinal lipolysis is not reduced in cystic fibrosis liver disease when measured using the 13C mixed triacylglycerol breath test. These findings affirm the test's use as an indirect measure of fat digestion that is not affected by inadequate intraluminal bile salts or liver disease.

Adolescent↗

PubMed2003

Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study.

BACKGROUND: Over 1000 mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR) that cause cystic fibrosis have been identified. We examined the effect of CFTR genotype on mortality and disease phenotype. METHODS: Using the US Cystic Fibrosis Foundation National Registry, we did a retrospective cohort study to compare standardised mortality rates for the 11 most common genotypes heterozygous for DeltaF508 with those homozygous for DeltaF508. Of the 28455 patients enrolled in the registry at the time of our analysis, 17853 (63%) were genotyped. We also compared the clinical phenotype, including lung function, age at diagnosis, and nutritional measures, of 22 DeltaF508 heterozygous genotypes. Mortality rates and clinical phenotype were also compared between genotypes classified into six classes on the basis of their functional effect on CFTR production. FINDINGS: Between 1991 and 1999, genetic and clinical data were available for 17853 patients with cystic fibrosis, which was 63% of the total cohort. There were 1547 deaths during the 9 years of follow-up. In the analysis of the 11 most common genotypes, DeltaF508/R117H, DeltaF508/DeltaI507, DeltaF508/3849+10kbC-->T, and DeltaF508/2789+5G-->A had a significantly lower mortality rate (4.7, 8.0, 11.9, and 4.4, respectively) than the genotype homozygous for DeltaF508 (21.8, p=0.0060). DeltaF508/R117H, DeltaF508/DeltaI507, DeltaF508/ 3849+10 kbC-->T, DeltaF508/2789+5G-->A, and DeltaF508/A455E have a milder clinical phenotype. Outcomes for all functional classes were compared with that of class II (containing DeltaF508 homozygotes) and classes IV and V had a significantly lower mortality rate and milder clinical phenotype. INTERPRETATION: Patients with cystic fibrosis have distinct genetic subgroups that are associated with mild clinical manifestations and low mortality. These differences in phenotype are also related to the functional classification of CFTR genotype.

Adolescent↗

PubMed1993

Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy.

Cystic fibrosis (CF) is a lethal inherited disorder affecting about 1 in 2,000 Caucasians. The major cause of morbidity is permanent lung damage resulting from ion transport abnormalities in airway epithelia that lead to mucus accumulation and bacterial colonization. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cyclic-AMP-regulated chloride channel. Cyclic-AMP-regulated chloride conductances are altered in airway epithelia from CF patients, suggesting that the functional expression of CFTR in the airways of CF patients may be a strategy for treatment. Transgenic mice with a disrupted cftr gene are appropriate for testing gene therapy protocols. Here we report the use of liposomes to deliver a CFTR expression plasmid to epithelia of the airway and to alveoli deep in the lung, leading to the correction of the ion conductance defects found in the trachea of transgenic (cf/cf) mice. These studies illustrate the feasibility of gene therapy for the pulmonary aspects of CF in humans.

Animals↗

PubMed1980

Azlocillin in respiratory tract infections with Pseudomonas aeruginosa in children with cystic fibrosis.

In 5 children with cystic fibrosis, 13 courses of lower respiratory infections due to Pseudomonas aeruginosa were treated with azlocillin, 100--200 mg/kg body weight intravenously every 8 h for 10--15 days. The clinical course during azlocillin treatment was more favourable than had been the case previously in the same patients when treated with combinations of carbenicillin and aminoglycosides. No side effects ascribable to azlocillin were observed, although one allergic reaction occurred, but this was probably elicited by another allergen. Upon repeated courses of treatment, the minimum inhibitory concentration of the infecting organisms increased steadily against both azlocillin and carbenicillin. It is concluded that azlocillin represents an important alternative in the treatment of lower respiratory tract infections due to P. aeruginosa in patients with cystic fibrosis.

Adolescent↗

PubMed1995

Genotypic analysis of respiratory mucous sulfation defects in cystic fibrosis.

Intracellular dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) has been proposed to alter endosomal acidification. The most widely studied consequence of this defect has been alterations in the biochemical properties of cystic fibrosis (CF) respiratory mucus glycoproteins. However, studies confirming the existence of mucous processing defects in CF have been hindered by the lack of in vivo animal models by which to test these hypotheses in the absence of secondary effects of chronic bacterial infection. The human bronchial xenograft model has been useful in evaluating the pathophysiologic differences between CF and non-CF airway epithelium, in the absence of secondary disease effects such as goblet cell hyperplasia. In this study we sought to compare the extent of sulfation within secreted mucus glycoproteins from CF and non-CF human bronchial xenografts. Cumulative results of xenografts generated from 13 independent CF tissue samples demonstrated a statistically significant higher level of sulfation (1.7 +/- 0.18, P < 0.026) as compared to non-CF paired controls. Such findings add to the growing body of knowledge that primary defects in sulfation exist in CF respiratory mucin. Correlation of genotype with the extent of mucus sulfation revealed two categories of CF tissues with statistically different mucus sulfation profiles. Results from these studies demonstrated a 2.0 +/- 0.15-fold higher level of mucus sulfation produced from xenografts of five defined CF genotypes as compared to non-CF controls (P < 0.004, n= 10). Interestingly, three CF samples for which one mutant allele remained undefined (deltaoff8/unknown or G551D/unknown) demonstrated no statistical difference in the level of sulfation as compared with matched non-CF controls (n= 3). This as yet unknown allele was not identified within a screen for the 26 most common CF mutations. These results provide preliminary evidence for allelic variation within the CF population which may begin to elucidate the structure-function of CFTR with regards to intracellular mucus processing defects.

Adolescent↗

PubMed1995

Comparison of three methods for culturing throat swabs from cystic fibrosis patients.

In patients with cystic fibrosis who do not produce sputum, deep throat swabs are cultured for potential respiratory pathogens. Usually these swabs are directly streaked onto selective agar media. In a study of 50 pediatric cystic fibrosis patients, we compared this traditional method using rayon swabs with two methods having quantitative modifications: calcium alginate swabs eluted in Ringer's lactate and rayon swabs eluted in normal saline. The eluates were then processed quantitatively (three-step dilution series). The yield of potential pathogens was significantly higher with the two quantitative methods. Overall, the combination of alginate with Ringer's lactate was superior to the combination of rayon with saline, although only some of these differences achieved statistical significance.

Adolescent↗

PubMed1991

Cystic fibrosis in Japan.

A nation wide survey for cystic fibrosis was carried out in Japan from 1982 to 1989. Cystic fibrosis was determined by extended criteria including high concentration of sweat chloride (more than 60 mEq/L), digestive, and respiratory manifestations, and family history. A total of 25 cases were confirmed as cystic fibrosis during the survey. Patients' characteristics were; age ranged from 0 day to 20 years old at diagnosis, sex ratio was 11:14 (M:F). All cases had respiratory, digestive symptoms and abnormally high sweat chloride excretion. Five cases from 3 families showed familiar involvement. These results show that cystic fibrosis is rare but really exists among Japanese. Further investigation including gene analysis should be carried out.

Adolescent↗

PubMed1994

Experience of an academic reference laboratory using automation for analysis of cystic fibrosis mutations.

OBJECTIVE: To examine the use of partial automation for molecular analysis of cystic fibrosis and to evaluate the diagnostic experience gained. DESIGN: Twenty-four cystic fibrosis mutations, with cumulative mutation detection of 89% in North American whites and of 97% in the Ashkenazim, were tested by multiplex amplification and allele-specific oligonucleotide hybridization. SETTING: A university-based DNA diagnostic laboratory. SUBJECTS: More than 700 serial specimens were analyzed for cystic fibrosis mutations over a 5-month period. The study included 377 individuals tested for carrier status, of which 288 had no family history for cystic fibrosis; prenatal diagnosis for 17 fetuses at a one in four risk and eight pregnancies at lower risk; fetal or parental samples for 33 pregnancies with fetal ultrasound abnormalities; 40 individuals diagnosed with cystic fibrosis; and 87 individuals with a possible diagnosis of the disease. RESULTS: Automation has permitted increasing numbers of mutations while decreasing personnel time and cost. Mutation testing identified 10 carriers with no family history for cystic fibrosis, four couples at a one in four risk, and five affected fetuses, one ascertained by abnormal fetal ultrasound. Mutation analysis also identified two mutant copies of the gene in 26 of 40 individuals with a clinical diagnosis of cystic fibrosis, and in two of 87 patients with possible cystic fibrosis. CONCLUSION: This partially automated, direct mutation analysis provides DNA diagnostic laboratories with the capacity to process a larger number of samples at lower cost with greater sensitivity for mutation detection. As pilot screening programs are reported, it is appropriate to reevaluate recommendations regarding population-based carrier screening for cystic fibrosis.

Automation↗

PubMed2001

Infertility in men with cystic fibrosis.

The majority of men with cystic fibrosis (CF) have associated congenital bilateral absence of the vas deferens (CBVAD). This congenital defect results in the absence of the anatomic ducts through which spermatozoa pass from the testes to the urethra. No spermatozoa are found in the semen, a condition referred to as obstructive azoospermia. This abnormality of the genital-urinary system is associated with the same genetic mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR ), which leads to the classic presentation of a patient with CF. However, patients may have CBVAD and CFTR mutations without symptoms of CF. Screening for the common mutations may miss a milder rare gene alteration: a DNA variant in the 5T allele. With the advent of assisted reproductive technologies, fertility is now possible for these men. The National Institutes of Health recommend genetic counseling for any couple attempting assisted reproductive techniques when the man has CF or presents with obstructive azoospermia and is positive for a CF mutation.

Alleles↗

PubMed1976

Hypertrophic osteoarthropathy in adults with cystic fibrosis.

Three adult patients with cystic fibrosis presented with arthralgia, and investigation for the usual causes of arthritis proved negative. Radiographs of long bones revealed periostitis and new bone fromation characteristic of hypertrophic osteoarthropathy. Symptomatic improvement occurred after analgesic and anti-inflammatory therapy. In patients with cystic fibrosis and bone or joint pain, the diagnosis of hypertrophic osteoarthropathy should be considered and long bone radiographs obtained.

Adult↗

PubMed1986

Ciprofloxacin in the treatment of Pseudomonas infection in cystic fibrosis patients.

Ten patients with cystic fibrosis received 19 therapeutic courses of ciprofloxacin at a dose of 750 mg orally twice daily. The length of therapy ranged from two to five weeks except for one patient who was treated for six weeks. The mean peak serum concentration of ciprofloxacin was 3.41 mg/l and the mean trough level was 1.11 mg/l. For comparison nine patients were treated with the combination of azlocillin at a dose of 350 mg/kg/day in four divided doses and tobramycin at an initial dose of 9 mg/kg/day in three divided doses. All patients were infected with Pseudomonas aeruginosa except for one patient in whom P. cepacia grew in the sputum cultures; the MICs of ciprofloxacin ranged from 0.05 to 1.56 mg/l. The results obtained with these two therapeutic regimens were comparable. The patient treated for P. cepacia infection developed resistance to ciprofloxacin (MIC greater than 6.24 mg/l) during the course of treatment. Ciprofloxacin appears to be an alternative treatment to the use of an aminoglycoside and a penicillin in cystic fibrosis patients.

Adolescent↗