MEDLINE Abstracts: Cystic Fibrosis

August 05, 2003

MEDLINE Abstracts: Cystic Fibrosis

What's new concerning cystic fibrosis? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pulmonary Medicine.

Wat D, Doull I
Paediatr Respir Rev. 2003;4:172-177

Respiratory virus infections have pronounced and long-lasting effects on patients with cystic fibrosis (CF), resulting in significant declines in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and Shwachman score, significantly increasing both the frequency and duration of hospitalization. Deleterious effects on patients with CF have been reported for most viruses studied but the effects of respiratory syncytial virus and influenza appear the greatest. There is circumstantial evidence that respiratory virus infections may facilitate bacterial infections, particularly Pseudomonas aeruginosa.

Pseudomonas Aeruginosa-Induced Apoptosis Is Defective in Respiratory Epithelial Cells Expressing Mutant Cystic Fibrosis Transmembrane Conductance Regulator

Cannon CL, Kowalski MP, Stopak KS, Pier GB
Am J Respir Cell Mol Biol. 2003;29:188-197

Chronic lung infection with Pseudomonas aeruginosa constitutes the most severe manifestation of cystic fibrosis, a scenario that results from defects in early clearance of the microbe. Early clearance involves epithelial cell ingestion of bacteria, rapid activation of nuclear factor-kappa B and cellular desquamation within minutes of P aeruginosa infection, processes that are deficient in cells with mutant alleles of Cftr. Analyzing the effect of Cftr genotype on the apoptotic response of airway epithelial cells to P aeruginosa, we found that human bronchial epithelial cells expressing Delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) underwent significantly delayed apoptosis compared with cells expressing wild-type (WT) CFTR. Mice with a WT CFTR allele had apoptotic cells in their lungs after P aeruginosa infections, whereas mice homozygous for the Delta F508 or G551D Cftr alleles showed little apoptosis in response to acute infection. Pseudomonal infection induced expression of CD95 and CD95 ligand, a response that was also delayed in cells homozygous for mutant Cftr alleles. Thus, WT CFTR expression promotes a rapid expression of CD95/CD95 ligand and apoptotic response to P aeruginosa infection. Prompt apoptosis of infected epithelial cells may be critical for clearance of P aeruginosa, and CFTR-associated defects in apoptosis may contribute to the pathogenesis of the lung disease in cystic fibrosis.

Kabra SK, Kabra M, Lodha R, et al
Indian Pediatr. 2003;40:612-619

Objective: To document clinical profile of cystic fibrosis (CF) in Indian children and the prevalence of delta F508 mutation in these patients.
Design: Observational study.
Setting: Pediatric chest clinic in an urban tertiary care center in north India.
Period of Study: July 1995 to June 2002.
Methods: Clinical features of 120 children diagnosed with CF by quantitative pilocarpine iontophoresis were recorded. A polymerase chain reaction-based test for identification of delta F508 mutation was performed on all children.
Results: Out of 3500 new cases registered in Pediatric Chest Clinic during this period, 120 children (3.5%) were diagnosed with CF. Origin of parents of patients traced from almost all the States of north India. Family history suggestive of CF was present in 41 (34%) and consanguinity in 19 patients (61%). Common clinical manifestations at the time of presentation included recurrent or persistent pneumonia in 118 (98%), failure to thrive in 108 (90%), malabsorption in 96 (80%), history of meconium ileus in 10 (8%), and rectal prolapse was present in 16 (13%). History of salt craving, salty taste on kissing, and skin rashes was present in 5 patients each. Forty-nine patients (41%) were severely malnourished. Nasal polyposis was present in 5 patients (4%). Examination of chest revealed evidence of hyperinflation in 100 (83%), kyphosis 20 (17%), crepitations 110 (92%), wheezing 40 (25%), and bronchial breathing in 20 (17%) patients. Average clinical CF scores were 51 (95%; CI 20-80). Forty-eight patients (40%) had a CF score of LT40. Pseudomonas spp was cultured from respiratory secretions of 51 (42%), Staphylococcus spp in 18 (15%), Klebsiella spp in 8 (7%) and Hemophilus influenzae in 2 (2%) patients. Delta F508 mutation was positive in 45 chromosomes out of 240 tested. Patients who originated from Pakistan had more frequency of delta F508 mutations.
Conclusions: Cystic fibrosis does occur in Indian children; clinical features are classical. Diagnosis is often delayed and the disease is advanced in most patients at the time of diagnosis. Frequency of Delta F508 mutation is 19%; ie, less than that seen in Caucasian population. There is need to create awareness about occurrence of CF in Indian children.

Malehorn DE, Telmer CA, McEwen SB, et al
Clin Chem. 2003;49:1318-1330

Background: The diversity of genetic mutations and polymorphisms calls for the development of practical detection methods capable of assessing more than one patient/one nucleotide position per analysis.
Methods: We developed a new method, based on peptide mass signature genotyping (PMSG), for the detection of DNA mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Exons of the gene were amplified, cloned, and expressed in Escherichia coli as peptide fusions, in natural as well as unnatural reading frames. Peptide analytes were purified by immobilized metal affinity chromatography and analyzed by matrix-assisted, laser desorption/ionization time-of-flight mass spectrometry. Synthetic and natural DNA samples with the 25 mutations recommended for CFTR carrier screening (Grody et al. Genet Med. 2001;3:149-154) were assessed using the PMSG test for the CFTR gene.
Results: Peptide analytes ranged from 6278 to 17,454 Da and varied 30-fold in expression; highly expressing peptides were observed by electron microscopy to accumulate as inclusion bodies. Peptides were reliably recovered from whole-cell lysates by a simple purification method. CFTR mutations caused detectable changes in resulting mass spectrometric profiles, which were more than 95% reliably detected in blinded testing of replicate synthetic heterozygous DNA samples. Mutation detection was possible with both sample pooling and multiplexing. The PMSG CFTR test was used to determine compound heterozygous mutations in DNA samples from cystic fibrosis patients, which were confirmed by direct DNA sequencing.
Conclusions: The PMSG test of the CFTR gene demonstrates unique capabilities for determining the sequence status of a DNA target by sensitively monitoring the mass of peptides, natural or unnatural, generated from that target.

Narang A, Maguire A, Nunn JH, Bush A
Arch Dis Child. 2003;88:702-707

Aim: To compare the prevalence of dental caries, dental calculus, and enamel defects in children with cystic fibrosis (CF) and children with other chronic respiratory disorders.
Methods: A cross sectional observational survey. One examiner (AN) undertook oral examinations to assess dental caries, periodontal health, and enamel defects in children attending respiratory outpatient clinics.
Results: A total of 74 patients with CF (35 male; mean age 10.7 years, range 2.5-16.5) were compared with a control group of 106 patients with other chronic respiratory disorders (52 male; mean age 9.1 years, range 3.0-16.5). There were significantly more defects of enamel in the permanent teeth of CF patients, compared with the teeth of those children with other chronic respiratory disorders. In addition, nonsignificant trends towards a lower caries prevalence in both dentitions, increased numbers of sextants with calculus deposits, and a reduced number of healthy gingival sextants were observed in the patients with cystic fibrosis.
Conclusions: Enamel defects, particularly enamel opacities, which can be disfiguring, are more common in CF patients. Early, regular dental visits may prevent such defects becoming dentally disabling and would also permit the removal of dental calculus deposits. The use of long-term antibiotics and pancreatic enzymes may confer some protection against the development and progression of dental caries in patients with cystic fibrosis. The inclusion of a specialist pediatric dentist, as part of the multiprofessional team managing the care of these children, would be an advantage.

Walkowiak J, Przyslawski J
J Hum Nutr Diet. 2003;16:225-231

Background: Poor growth and malnutrition still pose a problem in cystic fibrosis (CF). The aim of the present study was to assess nutrition, as well as clinical status, of malnourished CF patients during a nutritional care program.
Material and Methods: The study comprised 38 CF patients, aged 1 to 18 years old. The prospective annual assessment of dietary intake and clinical status was carried out during 1994-1998.
Results: The energy intake increased, in comparison with recommended daily allowances, from 83.6 ± 4.8% in 1994 to 107.9 ± 4.9% in 1998. A similar tendency was observed for the percentage of energy derived from fat (30.3 ± 0.8% versus 35.1 ± 0.8%) and protein (11.4 ± 0.4% versus 13.8 ± 0.4%). In subsequent years of the study, an improvement in the fat profile of the diet (with a higher consumption of polyunsaturated fatty acids) was observed. The observed increase of vitamin A and E consumption was related chiefly to changes in the doses of supplementation. During these 5 years, an improvement in nutritional status (Z-score: height -1.34 ± 0.13 versus -1.08 ± 0.14 and weight -1.40 ± 0.09 versus -1.12 ± 0.08) and lung function (forced expiratory volume in 1 second: 75.5 ± 2.0% versus 77.8 ± 2.2%) was observed.
Conclusion: The nutritional care program resulted in stable quantitative and qualitative changes in dietary intake. Although the diet does not reach the recommended level of high-energy intake, the positive impact of increasing nutrient intake on the nutritional and clinical status of malnourished CF patients was documented.

Ahmed N, Corey M, Forstner G, et al
Gut. 2003;52:1159-1164

Background and Aims: We tested the hypothesis that the actual or predicted consequences of mutations in the cystic fibrosis transmembrane regulator gene correlate with the pancreatic phenotype and with measures of quantitative exocrine pancreatic function.
Methods: We assessed 742 patients with cystic fibrosis for whom genotype and clinical data were available. At diagnosis, 610 were pancreatic insufficient, 110 were pancreatic sufficient, and 22 pancreatic sufficient patients progressed to pancreatic insufficiency after diagnosis.
Results: We identified mutations on both alleles in 633 patients (85.3%), on one allele in 95 (12.8%), and on neither allele in 14 (1.9%). Seventy-six different mutations were identified. The most common mutation was Delta F508 (71.3%) followed by G551D (2.9%), G542X (2.3%), 621+1G-->T (1.2%), and W1282X (1.2%). Patients were categorized into 5 classes according to the predicted functional consequences of each mutation. Over 95% of patients with severe class I, II, and III mutations were pancreatic-insufficient or progressed to pancreatic insufficiency. In contrast, patients with mild class IV and V mutations were consistently pancreatic sufficient. In all but 4 cases, each genotype correlated exclusively with the pancreatic phenotype. Quantitative data of acinar and ductular secretion were available in 93 patients. Patients with mutations belonging to classes I, II, and III had greatly reduced acinar and ductular function compared with those with class IV or V mutations.
Conclusion: The predicted or known functional consequences of specific mutant alleles correlate with the severity of pancreatic disease in cystic fibrosis.

De Soyza A, Archer L, Wardle J, et al
J Heart Lung Transplant. 2003;22:764-769

Pulmonary transplantation has emerged as a successful treatment for end-stage cystic fibrosis. Despite the chronic bronchial sepsis and often multi-resistant organisms seen in this group of recipients, death due to post-operative sepsis is relatively scarce. Identifying potential recipient risk factors for poor outcome may further improve the utilization of a scarce donor pool. We assessed the role of pre-operative clinical measures of sepsis, microbial characteristics, and recipient characteristics on post-transplant outcome in 85 cystic fibrosis patients who underwent pulmonary transplantation. Ten percent of patients died in the early post-operative period due to sepsis. The prognostic role of recipient factors including markers of sepsis, such as white cells and C-reactive protein (CRP), and the influence of multi-resistant organisms, in particular organisms from the Burkholderia cepacia complex, on outcomes were investigated. We found no prognostic effect of gender, pre-transplant CRP, forced expiratory volume in 1 second (FEV1), weight, diabetic status or infection with multi-resistant Pseudomonas organisms. A raised white cell count or temperature or a pre-transplant infection with B cepacia was, however, associated with a significantly poorer prognosis at P = .03, .03, and .001, respectively. Pre-operative B cepacia complex infection, leukocytosis, and pyrexia, but not CRP, weight, diabetes, or lung function, were found to be associated with poorer post-transplant outcome. The most clinically relevant of these to the subsequent risk of post-operative death from sepsis appear to be B cepacia infection and pyrexia.

Richards CS, Haddow JE
Clin Lab Med. 2003;23:503-530, x-xi

This article focuses on essential components related to prenatal screening for cystic fibrosis, including the clinical disease, inheritance, prognosis and treatment, birth prevalence, and ethnic variability. The molecular basis of this disease is presented, including a discussion of the gene, mutations, and genotype/phenotype correlations. The models that have been used for delivering prenatal screening services in pilot trials are described, along with lessons learned, expected screening performance, and relevant ELSI considerations. A realistic view of laboratory issues is considered, including current standards of performance, guidelines and oversight, and quality assurance. Examples of current laboratory technologies for cystic fibrosis testing are displayed.

Pseudomonas Aeruginosa
Obtained From Patients With Cystic Fibrosis at Different Times

Spencker FB, Staber L, Lietz T, Schille R, Rodloff AC
Clin Microbiol Infect. 2003;9:370-379

Objective: Determination of the extent of changes in quantitative resistance in Pseudomonas aeruginosa isolates from patients with cystic fibrosis over a period of approximately 2 years.
Methods: Three hundred and ninety-nine isolates of P aeruginosa collected from 34 pediatric patients in the period between April 1994 and April 1996 were investigated. During the 2 years, the children were treated with a combination of a betalactam and an aminoglycoside, approximately every 3 months. In between, they received ciprofloxacin orally, when required. The minimal inhibitory concentrations (MICs) of 38 clones of P aeruginosa defined by different patterns in macrorestriction analysis (pulse field gel electrophoresis, PFGE) were established for 12 antibiotics: gentamicin, amikacin, tobramycin, ciprofloxacin, levofloxacin, moxifloxacin, trovafloxacin, imipenem, meropenem, ceftazidime, cefepime, and piperacillin by means of broth microdilution tests according to DIN 58940.
Results: Twenty-four of the 38 clones developed increased MIC values during the time of observation, especially for aminoglycosides and quinolones. Comparatively less affected were ceftazidime, imipenem, and meropenem. An association between the number of the intravenous treatment courses and the increase of the MIC values could not be verified.
Conclusions: A trend towards an increase of the MICs against antipseudomonal agents was observed over a limited period of time. It is necessary to prevent this development possibly by employing suitable combinations of antibiotics and the introduction of new substances.

Schoni M
Swiss Med Wkly. 2003;133:297-301

This summary of the current knowledge of macrolide therapy serves as an example of recent progress in the therapeutic approach to treating patients with cystic fibrosis (CF). The benefit of macrolides in the treatment of patients with diffuse panbronchiolitis and Pseudomonas aeruginosa infections, as seen in Japan, was the rationale behind trials in patients with CF. Thus far, the majority of reports of positive trends in the therapeutic potential of macrolides have studied azithromycin. The data presented in peer reviewed journals are, however, too sparse to already justify firm recommendations for the general use of azithromycin, erythromycin, or clarithromycin on a long-term basis for the treatment of chronic lung disease in CF.

Ohbayashi H
IDrugs. 2002;5:910-923

Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are progressive and frequently fatal disorders, which have, at present, few effective therapeutic methods. The pathogenesis of these lung diseases is characterized by a neutrophil-predominant inflammation associated with excessive release of neutrophil proteases, including neutrophil elastase (NE), a terminal pulmonary tissue destroyer. Although precise pathogenic mechanisms have been under debate, the NE-mediated severe pulmonary tissue damage, based upon the protease-antiprotease imbalance hypothesis, may be a major pathogenic determinant of these diseases, in particular COPD. Novel aggressive therapeutic approaches to these lung disorders are required, and prevention of NE release may be considered as a promising strategy for disease outcome. This review mainly focuses upon the pathogenic contribution of NE to these neutrophil-predominant inflammatory lung diseases, and evaluates the experimental and clinical efficacies of the two-types of appropriate small molecular weight human neutrophil elastase (HNE) inhibitors: acyl-enzyme inhibitors and transition-state inhibitors. While much progress has been made in the investigation of these disorders and the contribution of HNE inhibitors, several fundamental questions remain to be answered, and so further studies are required.

Chapman E
Community Genet. 2002;5:110-119

Objectives: A primary objective of this paper is to present data on subjective perceptions of health and quality of life in individuals living with early- or late-onset genetic conditions (cystic fibrosis [CF], and Huntington's disease [HD], respectively). The paper will also discuss the social and ethical dilemmas raised by advances in reproductive and testing technology, consider the different emphases in definitions in quality of life, and speculate on criteria used to make reproductive decisions following prenatal testing.
Methods: Adults suffering from CF and HD attending 2 regional centres in the UK took part in semi-structured interviews between late 1999 and summer 2001. Self-report data on how a specific body image is constructed were also collected. Interviews were analysed using thematic qualitative analysis, and the body data were analysed using SPSS.
Results: Qualitative analysis uncovered themes relating to the question of how we value life, and exposed broad ethical dilemmas arising from advances in testing and treatment technology. These data are supported by findings from a body chart analysis that highlight a discrepancy between the quality of life experienced by this group of respondents and the way they believe the wider public perceives them, particularly in reference to pain.
Conclusions: Although some of the data support previous findings, such as the disability paradox, other voices contradict this view. Due to their unique experiences, the accounts of individuals currently living with genetic conditions should be considered in the wider bio-ethical debates.

Hayakawa T, Naruse S, Kitagawa M, Ishiguro H, Jin CX, Kondo T
J Hepatobiliary Pancreat Surg. 2002;9:669-674

Chronic pancreatitis is a continuing inflammatory disease characterized by irreversible morphological change and, typically, by pain and permanent impairment of function. The pathogenesis of pancreatitis, either acute or chronic, is still controversial. There have been no widely accepted concepts to provide a reasonable explanation linking the known etiological factors and the pathophysiological aspects of the disease. Alcohol is undoubtedly the major etiological factor in most countries, and the relative importance of alcohol as a cause of chronic pancreatitis ranges from 40% to 90% in various countries. As fewer than 10% of alcoholics develop chronic pancreatitis, other nutritional or genetic influences are likely to be involved in the pathogenesis of alcoholic pancreatitis. Accessory pancreas incidentally found in patients with chronic alcoholic pancreatitis does not always have the pathological findings seen in the main pancreas. Integrity of the pancreatic duct seems to be another important factor for chronic alcoholic pancreatitis. Gene mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen, and pancreatic secretory trypsin inhibitor have been investigated in idiopathic chronic pancreatitis. Molecular and cell biology research during the past few years has elucidated pathophysiological factors that are involved in the pathogenesis of chronic pancreatitis, but cannot demonstrate a common pathway between etiological factors and the pathogenesis or development of the disease.

Kanda A, Ueki S, Chihara J
Rinsho Byori. 2002;Suppl 123:178-183

Technological advances in molecular biology, as well as in genetic engineering, have created a revolutionary movement in both clinical and diagnostic methodologies. With progress in human genome analysis, the genes responsible for various diseases have been analyzed at a rapid pace. Research involving respiratory disease is no exception. Emphasis in this area has shifted from respiratory physiology to molecular biology. One example is cystic fibrosis (CF). However, CF is relatively rare in Japan. Furthermore, the search for universal genes that trigger bronchial asthma has not been successful. Genetic testing for respiratory disease has not been conducted as a component of general, routine clinical tests in Japan, due to the aforementioned reasons. Therefore, I would like to take this opportunity to introduce genetic respiratory diseases, the present state of genetic testing, and prospects for the future.


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