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Background

Cystic fibrosis is a genetic condition with an abnormality of the glands which produce or secrete sweat and mucus. There is a defect in the ion transport of these patients resulting in excessive amounts of salt when they sweat. The mucous is also very thick and accumulates in the intestines and lungs. Lung disease is the usual cause of death in most patients.

SYNONYMS CF
INCIDENCE

About 30,000 Americans, 3,000 Canadians, and 20,000 Europeans
Approximately 2,500 babies are born with CF each year in the United States
1 in every 20 Americans is an unaffected carrier of an abnormal CF gene

There are about 12 million people who are carriers of the genetic mutation

GEOGRAPHY
Mainly Caucasians

 

DISEASE ASSOCIATIONS CHARACTERIZATION

Cystic fibrosis phenotype evaluation and paternity outcome in 50 males with congenital bilateral absence of vas deferens.

Josserand RN, Bey-Omar F, Rollet J, Lejeune H, Boggio D, Durand DV, Durieu I.

Adult Cystic Fibrosis Care Centre, Centre Hospitalier Lyon-Sud, 69495 Pierre-Benite Cedex, France.

Hum Reprod 2001 Oct;16(10):2093-7 Abstract quote

BACKGROUND: Most infertile males with congenital bilateral absence of vas deferens (CBAVD) carry mutations on the cystic fibrosis transmembrane conductance regulator gene and may express mild cystic fibrosis (CF) symptoms. Barriers to paternity for these men can now be overcome by assisted reproduction. Our aims were to investigate the CF-related phenotype and clinical outcome for 50 patients with CBAVD seen at a CF adult centre between 1992 and 1999.

METHODS AND RESULTS: The investigation of the patients included screening for 22 CF mutations and identification of the poly-T variant of intron 8, sweat testing, clinical investigation for CF-related extra-genital manifestations, and genetic counselling. CFTR mutations were detected on 56 alleles of the 50 patients. A total of 15 (30%) was compound heterozygote and 26 (52%) heterozygote. In all, 38% of the patients had a positive sweat test. Four patients were diagnosed with typical CF not detected previously. Twenty-one patients became fathers following ICSI (eight cases), artificial insemination by donor or IVF with sperm donor (seven cases) or through adoption (six cases). A mail survey allowed the identification of CF-related clinical symptoms. Information on the occurrence of CF-related symptoms was obtained for 58.5% of patients: in the absence of initial symptoms, no new clinical signs were reported.

CONCLUSION: Patients diagnosed with CBAVD need genetic counselling before assisted reproduction. Even when no wish for paternity is expressed, CF gene screening should be associated with at least a sweat test and clinical evaluation because of possible mild forms of CF disease. Medical follow-up did not reveal any new symptoms.

Mutations of the cystic fibrosis gene in patients with chronic pancreatitis.

Truninger K, Malik N, Ammann RW, Muellhaupt B, Seifert B, Muller HJ, Blum HE.

Department of Medicine II, University of Freiburg, Germany.

Am J Gastroenterol 2001 Sep;96(9):2657-61 Abstract quote

OBJECTIVE: Several studies have reported an increased frequency of cystic fibrosis gene mutations in idiopathic but not in alcoholic chronic pancreatitis. The impact of cystic fibrosis gene mutations on the long-term course of chronic pancreatitis has not been analyzed. The aim of our study was to determine the frequency of cystic fibrosis gene mutations in patients with chronic pancreatitis with long-term follow-up and to see whether patients with mutations have a clinically different natural course compared to those without mutations.

METHODS: Eighty two patients with chronic pancreatitis and 11 patients with recurrent acute pancreatitis of our well defined pancreatitis cohort were screened for the 31 most common cystic fibrosis gene mutations. The impact of cystic fibrosis gene mutations on the long-term course of chronic pancreatitis was assessed.

RESULTS: A cystic fibrosis gene mutation was detected in five of 49 patients with alcoholic chronic pancreatitis (10.2%; 2.3 times the expected frequency) and in three of 14 patients with idiopathic-juvenile chronic pancreatitis (21.4%; 4.8 times the expected frequency). No mutations were found in the remaining patients with chronic pancreatitis of rare causes, hereditary pancreatitis, and recurrent acute pancreatitis. The frequency of pancreatic calcifications was significantly higher in patients with alcoholic chronic pancreatitis without mutations. This result was not confirmed in patients with idiopathic-juvenile chronic pancreatitis. The duration of pain and the frequency of exocrine and endocrine insufficiency was comparable in both subgroups irrespective of the mutation status.

CONCLUSION: Our data indicate a significantly increased frequency of cystic fibrosis gene mutations both in patients with alcoholic and idiopathic-juvenile chronic pancreatitis. The natural course was similar in patients with mutations compared to those without mutations.

 

PATHOGENESIS CHARACTERIZATION

Analysis of exocrine pancreatic function in cystic fibrosis: one mild CFTR mutation does not exclude pancreatic insufficiency.

Walkowiak J, Herzig KH, Witt M, Pogorzelski A, Piotrowski R, Barra E, Sobczynska-Tomaszewska A, Trawinska-Bartnicka M, Strzykala K, Cichy W, Sands D, Rutkiewicz E, Krawczynski M. Karol Marcinkowski

University of Medical Sciences, Poznan, Poland.

Eur J Clin Invest 2001 Sep;31(9):796-801 Abstract quote

BACKGROUND: Cystic fibrosis (CF) is the most common cause of exocrine pancreatic insufficiency in childhood. The aim of the present study is to evaluate the correlation between genotype and exocrine pancreatic insufficiency in CF patients. The special emphasis was put on the analysis of mild CFTR mutations.

DESIGN: The study comprised 394 CF patients and 105 healthy subjects (HS). Elastase-1 concentrations were measured in all subjects.

RESULTS: Severe pancreatic insufficiency was associated with the presence of two CFTR gene mutations (DeltaF508, N1303K, CFTR dele 2,3 (21kb), G542X, 1717-1G-A, R533X, W1282X, 621GT, 2183AAG, R560T, 2184insA and DeltaI507, G551D, 895T) and mild insufficiency with the presence of at least one mutation (R117H, 3171insC, A155P2, 138insL, 296 + 1G-A, E92GK, E217G, 2789 + 5G-A. 3849 + 1kbC-T/3849 + 1kbC-T) genotype resulted in high elastase-1-values. However, in case of patients with genotype DeltaF508/3849 + 10kbC-T, 1717-1GA/3849 + 10kbC-T as well as with DeltaF508/R334W, both high and low elastase-1 concentrations were found. Low E1 values were found in a patient with DeltaF508/R347P genotype.

CONCLUSION: Patients who carry two 'severe' mutations develop pancreatic insufficiency, whereas those who carry at least one 'mild' usually remain pancreatic sufficient. However, the presence of one mild mutation does not exclude pancreatic insufficiency.

A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models.

Chen JM, Cutler C, Jacques C, Boeuf G, Denamur E, Lecointre G, Mercier B, Cramb G, Ferec C.

Institut National de la Sante et de la Recherche Medicale EMI 01 15, Etablissement Francais du Sang-Bretagne, Universite de Bretagne Occidentale, and Centre Hospitalier Universitaire, Brest, France.

Mol Biol Evol 2001 Sep;18(9):1771-88 Books, Abstract quote

Over the past decade, nearly 1,000 variants have been identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classic and atypical cystic fibrosis (CF) patients worldwide, and an enormous wealth of information concerning the structure and function of the protein has also been accumulated. These data, if evaluated together in a sequence comparison of all currently available CFTR homologs, are likely to refine the global structure-function relationship of the protein, which will, in turn, facilitate interpretation of the identified mutations in the gene.

Based on such a combined analysis, we had recently defined a "functional R domain" of the CFTR protein. First, presenting two full-length cDNA sequences (termed sCFTR-I and sCFTR-II) from the Atlantic salmon (Salmo salar) and an additional partial coding sequence from the eastern gray kangaroo (Macropus giganteus), this study went further to refine the boundaries of the two nucleotide-binding domains (NBDs) and the COOH-terminal tail (C-tail), wherein NBD1 was defined as going from P439 to G646, NBD2 as going from A1225 to E1417, and the C-tail as going from E1418 to L1480.

This approach also provided further insights into the differential roles of the two halves of CFTR and highlighted several well-conserved motifs that may be involved in inter- or intramolecular interactions. Moreover, a serious concern that a certain fraction of missense mutations identified in the CFTR gene may not have functional consequences was raised. Finally, phylogenetic analysis of all the full-length CFTR amino acid sequences and an extended set of exon 13--coding nucleotide sequences reinforced the idea that the rabbit may represent a better CF model than the mouse and strengthened the assertion that a long-branch attraction artifact separates the murine rodents from the rabbit and the guinea pig, the other Glires.

 

LABORATORY/RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  

Cystic fibrosis: usefulness of thoracic CT in the examination of patients before lung transplantation.

Marom EM, McAdams HP, Palmer SM, Erasmus JJ, Sporn TA, Tapson VF, Davis RD, Goodman PC.

Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.

Radiology 1999 Oct;213(1):283-8 Abstract quote

PURPOSE: To evaluate the usefulness of thoracic computed tomography (CT) in the pre-lung transplantation examination of patients with cystic fibrosis (CF).

MATERIALS AND METHODS: Fifty-six patients (age range, 12-42 years) with CF were evaluated for possible lung transplantation from 1991 to 1997. Twenty-six of these patients underwent bilateral lung transplantation, 19 were awaiting transplantation at the time of the study, seven died before transplantation, and four were excluded for psychosocial concerns. Preoperative chest radiographic and CT findings were reviewed and correlated with clinical, operative, and pathology records.

RESULTS: In seven patients, discrete, 1-2-cm pulmonary nodules were detected at CT. Five of these patients underwent transplantation; the nodules were found to be mucous impactions. No malignancy was found in any of the patients who underwent transplantation. Pretransplantation sputum cultures grew Aspergillus fumigatus in seven patients, none of whom had radiologic findings suggestive of Aspergillus infection. Radiographic or CT findings were suggestive of mycetoma in five cases, but no such tumors were found at transplantation. The accuracies of chest radiography and CT for the detection of pleural disease in 48 hemithoraces were 81% (n = 39) and 69% (n = 33), respectively. The radiologic findings of pleural thickening did not influence the surgical approach in any patient.

CONCLUSION: Thoracic CT has little utility in the routine pre-lung transplantation examination of patients with CF.

Imaging changes in the pancreas in cystic fibrosis: a retrospective evaluation of 55 cases seen over a period of 9 years.

Feigelson J, Pecau Y, Poquet M, Terdjman P, Carrere J, Chazalette JP, Ferec C.

Radiologie, Paris, France.

J Pediatr Gastroenterol Nutr 2000 Feb;30(2):145-51 Abstract quote

BACKGROUND: Pathologic changes of the pancreas have been observed as early as the recognition of the disease termed initially "cystic fibrosis of the pancreas". Atrophy of the gland and its fatty infiltration were considered as usual features. The aim of this study was to follow-up the evolution of cystic fibrosis pancreas and to define its successive stages in correlation with the clinical, biochemical, and imaging findings.

METHODS: Fifty-five patients were followed up during 9 years. The patients' genetic backgrounds were systematically performed. Blood lipase levels were analyzed systematically at each consultation of the patients and in the event of bouts of abdominal pains. Imaging using mainly echograms and tomodensitometric scans were regularly performed: echograms every 6 months, and tomodensitometric scans every 1 to 2 years. Magnetic resonance imaging was performed in four patients.

RESULTS: Five groups of patients were identified on the basis of tomodensitometric scan findings: normal pancreas (n = 4), incomplete lipomatosis of the pancreas (n = 9), complete lipomatosis of the pancreas (n = 23), cystic pancreas (n = 5), macrocystic pancreas (n = 1), atrophic pancreas (n = 13). Pancreas exocrine function was not correlated with findings. Forty episodes of pancreatitis were observed in seven patients. They had bouts of abdominal pain and elevation of lipase levels. Five of these patients were composite heterozygotes (D508/other). Incomplete lipomatosis represents an intermediate stage leading toward complete lipomatosis or toward atrophy after pancreatitis.

CONCLUSIONS: Studies of pancreatic function should be performed routinely in cystic fibrosis, especially in pancreatic sufficiency or in patients with normal pancreas images. Acute pancreatitis should be diagnosed and properly identified to be differentiated from other acute abdominal syndromes occurring in cystic fibrosis.

LABORATORY MARKERS  
SWEAT TEST

Area of the skin (usually the forearm) is made to sweat by using a chemical called pilocarpine and applying a mild electric current

To collect the sweat, the area is covered with a gauze pad or filter paper and wrapped in plastic. After 30 to 40 minutes, the plastic is removed, and the sweat collected in the pad or paper is analyzed. Higher than normal amounts of sodium and chloride suggest that the person has cystic fibrosis

May not work well in newborns because they do not produce enough sweat.

IMMUNOREACTIVE TRYPSINOGEN TEST Blood drawn 2 to 3 days after birth is analyzed for a specific protein called trypsinogen. Positive IRT tests must be confirmed by sweat and other tests.
NEWBORN SCREENING  

Clinical outcomes of newborn screening for cystic fibrosis.

Waters DL, Wilcken B, Irwing L, Van Asperen P, Mellis C, Simpson JM, Brown J, Gaskin KJ

James Fairfax Institute of Paediatric Nutrition, Royal Alexandra Hospital for Children, Sydney, New South Wales, Australia.

Arch Dis Child Fetal Neonatal Ed 1999 Jan;80(1):F1-7 Abstract quote

AIM: To determine how early diagnosis of cystic fibrosis, using neonatal screening, affects long term clinical outcome.

METHODS: Fifty seven children with cystic fibrosis born before neonatal screening was introduced (1978 to mid 1981) and a further 60 children born during the first three years of the programme (mid 1981 to 1984), were followed up to the age of 10. The cohorts were compared on measures of clinical outcome, including height, weight, lung function tests, chest x-ray picture and Shwachman score.

RESULTS: Age and sex adjusted standard deviation scores (SDS) for height and weight were consistently higher in children screened for cystic fibrosis than in those born before screening. At 10 years of age, average differences in SDS between groups were 0.4 (95% CI -0.1, 0.8) for weight and 0.3 (95% CI -0.1, 0.7) for height. This translates to an average difference of about 2.7 cm in height and 1.7 kg in weight. Mean FEV1 and FVC (as percentage predicted) were significantly higher in the screened cohort at 5 and 10 years of age, with an average difference of 9.4% FEV1 (95% CI 0.8, 17.9) and 8.4% FVC (95% CI 1.8, 15.0) at 10 years. Chest x-ray scores were not different between the groups at any age, but by 10 years screened patients scored an average 5.3 (95% CI 1.2, 9.4) points higher on the Shwachman score.

CONCLUSION: Although not a randomised trial, this long term observational study indicates that early treatment made possible by neonatal screening may be important in determining subsequent clinical outcomes for children with cystic fibrosis. For countries contemplating the introduction of neonatal screening for cystic fibrosis, its introduction to some areas in a cluster randomised design will permit validation of studies performed to date.

Neonatal screening for cystic fibrosis in Brittany, France: assessment of 10 years' experience and impact on prenatal diagnosis.

Scotet V, de Braekeleer M, Roussey M, Rault G, Parent P, Dagorne M, Journel H, Lemoigne A, Codet JP, Catheline M, David V, Chaventre A, Dugueperoux I, Verlingue C, Quere I, Mercier B, Audrezet MP, Ferec C.

Laboratoire de Genetique Moleculaire et d'Histocompatibilite, CHU Morvan, UBO, EFS-Bretagne, Brest, France.

Lancet 2000 Sep 2;356(9232):789-94 Abstract quote

BACKGROUND: Neonatal screening for cystic fibrosis has been a subject of debate over the past few years. This study assesses 10 years of neonatal screening in Brittany, France, and examines its impact on prenatal screening of subsequent pregnancies in couples with an affected child.

METHODS: The study included all the neonates screened for cystic fibrosis in Brittany from Jan 1, 1989, to Dec 31, 1998. The screening consisted of an immunoreactive trypsinogen assay from dried blood spots, plus, from 1993, mutation analysis. Data were collected on incidence of cystic fibrosis, and genotypic and biochemical characteristics. The use of prenatal screening of subsequent pregnancies in affected families was also investigated.

FINDINGS: Of the 343,756 neonates screened, 118 children with cystic fibrosis were identified, giving an incidence of one in 2913. All mutated alleles were characterised: 34 different mutations resulting in 36 genotypes were detected. The introduction of DNA analysis into the protocol greatly reduced the recall rate and increased the sensitivity of the test. The mean cost of the screening programme was US$2.32 per screened child. 39 (34%) of the families identified by neonatal screening opted for subsequent prenatal diagnosis at least once. 12 couples would have benefited from this procedure while their first child was still symptom-free. 42 healthy children were born, and 18 pregnancies were terminated (therapeutic abortion rate of 100%).

INTERPRETATION: We have shown the feasibility of neonatal screening for cystic fibrosis in Brittany. Through the detection of a large range of mutations, neonatal screening provides the opportunity for more reliable prenatal diagnosis and cascade screening. The neonatal screening programme described here could provide a good model for other countries intending to initiate such a scheme.

Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling.

Le Marechal C, Audrezet MP, Quere I, Raguenes O, Langonne S, Ferec C.

EFS-Bretagne, CHU, Brest, France.

Hum Genet 2001 Apr;108(4):290-8 Abstract quote

More than 900 mutations and more than 200 different polymorphisms have now been reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ten years after the cloning of the CFTR gene, the complete scanning of the 27 exons to identify known and novel mutations remains challenging. Rapid accurate identification of mutated alleles is important for prenatal diagnosis, for cascade screening in families at risk of cystic fibrosis (CF) and for understanding the correlation between genotype and phenotype.

In this study, we report the successful use of denaturing ion-pair reverse-phase high performance liquid chromatography (D-HPLC) to analyse rapidly the complete coding sequence of the CFTR gene.

With 27 pairs of polymerase chain reaction primers, we optimised the temperature conditions required for the analysis of each amplicon and validated thetest conditions on samples from a panel of 1552 CF patients who came from France and other European countries and who had mutations and polymorphisms located in the various melting domains of the gene. D-HPLC identified 415 mutated alleles previously characterised by denaturing gradient gel electrophoresis and DNA sequencing, plus 74 novel mutations reported here.

This new technique for screening DNA for sequence variation was extremely accurate (it identified 100% of the CFTR alleles tested so far) and rapid (the complete CFTR gene could be analysed in less than a week). Our approach should reduce the number of untyped CF alleles in populations and thus decrease the residual risk in couples at risk of CF. This technique may be important not only for CF,but also for many other genes with a high frequency of point mutations at a variety of sites.

Newborn screening for cystic fibrosis (Cochrane Review).

Merelle ME, Nagelkerke AF, Lees CM, Dezateux C.

Department of Pediatrics, Free University Hospital, De Boelelaan 1117, Amsterdam, NETHERLANDS, 1007 MB.

Cochrane Database Syst Rev 2001;3:CD001402 Abstract quote

BACKGROUND: This review was performed to test the hypothesis that presymptomatic diagnosis, for example by newborn screening, and early treatment may prevent or reduce irreversible organ damage and thereby improve outcome and quality of life in patients with cystic fibrosis.

OBJECTIVES: To determine whether there is evidence that early diagnosis of cystic fibrosis by means of neonatal screening, followed by current treatment, improves survival and long term morbidity, without unacceptable adverse effects.

SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Trials Register. Additional studies were identified by one of the reviewers from handsearching conference proceedings not included in the Cochrane Register. Pharmaceutical companies manufacturing screening tests for cystic fibrosis were also contacted to identify any trials of neonatal screening for cystic fibrosis. Date of the most recent search of the Group's specialised register: January 2001.

SELECTION CRITERIA: All randomised or pseudorandomised controlled trials, published and unpublished, comparing screening followed by early treatment to clinical diagnosis and later treatment in patients with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: Four reviewers independently assessed trial eligibility and methodological quality and two of these reviewers independently extracted data.

MAIN RESULTS: Two trials involving a total of 1,124,483 neonates met inclusion criteria. A total of 210 patients with cystic fibrosis aged from zero to 11 years with a maximum follow-up of eleven years are included. Concealment of allocation was unclear in both studies. Sequence generation was adequate in one study and unclear in the other. Method to ascertain cases was similar in one study and not similar in the other. An intention-to-screen-analysis was possible in one study, but could not be made due to lack of data and was not performed in the other. Differences in study design, variation in outcomes reported and their summary measures precluded calculation of pooled screening estimates. Only data from one study could be analysed in this review. This study reported a reduced risk of weight and height below the fifth percentile among screened patients (odds ratio control compared with screened group for: weight 6.16, 95% CI 2.44, 15.57 and height 5.03, 95% CI 1.63, 15.63). Adverse effects among parents in the screened and control populations were examined, but it is difficult to assess how meaningful these results are as the timing of the administration of the questionnaire to each group was not clear. Estimation of direct medical costs of screening suggested it was cheaper to diagnose cystic fibrosis by screening rather than other methods. The costing methods used however were not fully described and costs have not been related to effect.

REVIEWER'S CONCLUSIONS: There are few randomised controlled trials assessing the effectiveness of neonatal screening in cystic fibrosis. From the data available at this time, there is little evidence suggesting benefit from screening for cystic fibrosis in the neonatal period, although there is similarly little evidence of harm. This systematic review has identified the need for individual patient data from both included studies. Although we have not been able to perform a meta-analysis, this review provides a summary of all the information currently available from randomised controlled trials on the effectiveness of neonatal screening for cystic fibrosis.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL Sinustis
Nasal polyps
Clubbing (rounding and enlargement of fingers and toes)
Pneumothorax
Hemoptysis
Cor pulmonale
Abdominal pain and discomfort, gassiness (too much gas in the intestine), and r
Rectal prolapse
Liver disease
Diabetes, inflammation of the pancreas, and gallstones
VARIANTS  

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  
VARIANTS  

Cystic fibrosis with fibrosing colonopathy in the absence of pancreatic enzymes.

Waters BL.

Department of Pathology and Laboratory Medicine, Fletcher Allen Health Care, Burlington, VT 05401, USA.

Pediatr Dev Pathol 1998 Jan-Feb;1(1):74-8 Abstract quote

Fibrosing colonopathy, characterized by dense submucosal fibrosis in the large bowel, is a disorder associated with bowel dysfunction in patients with cystic fibrosis who receive pancreatic enzyme supplementation. Most commonly, patients present with a distended abdomen and abdominal pain. Radiographs frequently demonstrate colonic wall thickening and luminal narrowing. Here I describe a neonate with cystic fibrosis who presented with both clinical and histological features of fibrosing colonopathy who had not received pancreatic enzymes.

This report expands our understanding of the pathogenesis of fibrosing colonopathy.

Destruction and loss of bronchial cartilage in cystic fibrosis.

Ogrinc G, Kampalath B, Tomashefski JF Jr.

Department of Pathology, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, OH 44109, USA.

Hum Pathol 1998 Jan;29(1):65-73 Abstract quote

We studied by means of serial sections of intact isolated bronchi, the distribution and morphology of bronchial cartilage in lobar and segmental airways of 6 patients with cystic fibrosis (CF).

Findings were compared to those of 4 young adults without CF who served as controls. Compared to the controls, cartilage in CF airways extended for a shorter absolute distance along the bronchial tree and disappeared at a more proximal branching level. Loss of cartilage appeared to correlate with the severity of bronchiectasis. In proximal airways chronic inflammation, destruction and fibrous replacement of cartilage preceded its disappearance. Immunohistochemical staining indicated that cells of monocyte/macrophage lineage (CD68, MAC387 positive) were most closely associated with chondrolysis. Dystrophic calcification and ossification were more commonly seen in CF bronchi and dystrophic calcification was present even in the lobar branches.

Destruction of bronchial cartilage is the result of sustained bronchial infection and chronic inflammation and is an additional contributory factor to bronchiectasis and airway instability in patients with CF.

Sclerosing cholangitis in adults with cystic fibrosis: a magnetic resonance cholangiographic prospective study.

Durieu I, Pellet O, Simonot L, Durupt S, Bellon G, Durand DV, Minh VA.

Department of Internal Medicine, University of Lyon I, Centre Hospitalier Lyon-Sud, Pierre-Benite, France.

J Hepatol 1999 Jun;30(6):1052-6 Abstract quote

BACKGROUND/AIMS: Liver disease is a leading cause of morbidity in adult patients with cystic fibrosis. Diagnosis of limited liver involvement in asymptomatic patients is important since a safe and effective treatment with ursodeoxycholic acid can be used. We carried out a prospective open study to describe the intrahepatic biliary lesions using magnetic resonance cholangiography.

METHODS: Twenty-seven adult patients with cystic fibrosis were prospectively enrolled, whatever their hepatobiliary status. All patients underwent liver function tests, ultrasonography and magnetic resonance cholangiography. Magnetic resonance cholangiograms were acquired on a Philips 1.5 Tesla unit using a 3D TSE MR sequence. Acquisition parameters (120 slices, 1.6 mm thickness, interslice overlap 0.8 mm) were followed by MIP reconstruction in two orthogonal planes. Magnetic resonance cholangiography images were assessed for the presence of stenosis, dilatations and rigidity corresponding to current criteria of cholangitis. Among the 27 cystic fibrosis patients, 18 (Group I) fulfilled none of the clinical, biological or ultrasonographic criteria of liver disease; the remaining nine (Group II) fulfilled the criteria for liver disease. In every patient, current causes of secondary sclerosing cholangitis had been excluded.

RESULTS: All the Group II patients had abnormal magnetic resonance cholangiograms with features resembling those of primary sclerosing cholangitis in five, and simple biliary lesions in four. Nine Group I patients had abnormal magnetic resonance cholangiograms with primary sclerosing cholangitis-like lesions in five and simple biliary lesions in four. Magnetic resonance cholangiography anomalies were always dilatations, either isolated or associated with strictures and rigidity, both resembling those seen in cholangitis. They were seen in all the patients with known liver disease and in half the patients without evidence of liver disease.

CONCLUSION: This study confirms the high frequency of intrahepatic biliary abnormalities in CF patients, which is probably underestimated by clinical, biological and ultrasonographic evaluation. The magnetic resonance cholangiography technique could be useful to detect early intrahepatic biliary tract involvement in cystic fibrosis patients.

Histopathologic features of Burkholderia cepacia pneumonia in patients without cystic fibrosis.

Belchis DA, Simpson E, Colby T.

Department of Pathology, Penn State Geisinger Health System, Hershey Medical Center, Pennsylvania 17033, USA.

Mod Pathol 2000 Apr;13(4):369-72 Abstract quote

We present the histopathologic features of fatal Burkholderia cepacia pneumonia in three adults (one man [age 44 years] and two women [aged 40 and 43 years]). In all patients, the pulmonary infiltrates initially were localized (right middle lobe, left upper lobe, and right middle lobe) but rapidly progressed.

Two open-lung biopsies and one pneumonectomy specimen showed necrotizing granulomatous inflammation merging with areas of more conventional necrotizing bronchopneumonia In one patient, a mediastinal lymph node also showed stellate necrotizing granulomas. Vasculitis was absent. B. cepacia was cultured from the open-lung biopsies and bronchial wash specimens in two patients and from postmortem cultures of lung, subcarinal lymph nodes, and blood in the third.

The histopathology in these patients resembles that of melioidosis, which is caused by a related organism, Burkholderia pseudomallei. B. cepacia needs to be considered in the differential diagnosis of necrotizing granulomatous inflammation. In addition, given the rarity with which B. cepacia is identified as a cause of pneumonia in the immunocompetent host, isolation of B. cepacia should trigger a workup for underlying immunodeficiency or lead to an investigation to exclude the possibility of a nosocomial infection.

Evidence of chronic inflammation in morphologically normal small intestine of cystic fibrosis patients.

Raia V, Maiuri L, de Ritis G, de Vizia B, Vacca L, Conte R, Auricchio S, Londei M.

Department of Pediatrics, University Federico II of Naples, Italy.

Pediatr Res 2000 Mar;47(3):344-50 Abstract quote

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene and characteristically leads to prominent lung and pancreatic malfunctions. Although an inflammatory reaction is normally observed in the CF airways, no studies have been performed to establish whether a chronic inflammatory response is also present in the CF intestine.

We have investigated whether immunologic alterations and signs of inflammation are observed in CF small intestine. Fourteen CF, 20 negative, and four disease controls underwent duodenal endoscopy for diagnostic purposes. Two CF patients were rebiopsied, one after 3 mo of an elemental diet and the other after 2 wk of pancreatic enzyme withdrawal. In three CF and 10 controls, in vitro small intestine organ cultures were also performed. Expression of ICAM-1, IL-2 receptor, IL-2, IFN-gamma, CD80, and transferrin receptor was studied by immunohistochemistry before and after in vitro organ culture. In CF small intestine, an increased number of lamina propria mononuclear cells express ICAM-1 [mean 114 (SD 82.8), p < 0.001 versus controls], CD25 [20.2 (18.7), p < 0.01], IL-2 [23.6 (13.7), p < 0.05], and IFN-gamma [19 (15.9), p < 0.05], whereas villus enterocytes highly express transferrin receptor. Reduced expression of immunologic markers was observed after 24 h of in vitro culture in all three CF patients as well as in the patient kept on elemental diet for 3 mo.

These results indicate that chronic inflammation is observed in CF duodenum and suggest that the perturbation of local mucosal immune response may contribute to the overall clinical picture in CF patients.

Partial CFTR genotyping and characterisation of cystic fibrosis patients with myocardial fibrosis and necrosis.

Zebrak J, Skuza B, Pogorzelski A, Ligarska R, Kopytko E, Pawlik J, Rutkiewicz E, Witt M.

Institute of Tuberculosis and Lung Diseases, Pediatric Division, Rabka, Poland.

Clin Genet 2000 Jan;57(1):56-60 Abstract quote

Myocardial necrosis and fibrosis is a rare complication of cystic fibrosis (CF) causing sudden and unexpected death in infancy due to cardiac arrest. Characteristic morphological lesions are recognisable postmortem.

The 18 CF patients with this complication had varied clinical features including mild pulmonary involvement, early onset severe pancreatic insufficiency, and profound electrocardiogram (ECG) changes. In this group of patients, 5 were deltaF508 homozygotes, 1 was deltaF508/ N1303K and 1 was a deltaF508/M compound heterozygote. A pair of affected siblings (deltaF508 homozygotes) were fully concordant for myocardial involvement and for the general course of the disease.

The co-existence of a genetic predisposition to myocardial lesions resulting most probably from severe cystic fibrosis transmembrane (CFTR) genotypes (such as deltaF508/deltaF508, deltaF508/N1303K) and deficiency of certain trophic factors necessary for metabolism of the myocardium, are postulated to cause myocardial complications in CF leading to circulatory failure and early death.

Bone histomorphometry in adult patients with cystic fibrosis.

Haworth CS, Webb AK, Egan JJ, Selby PL, Hasleton PS, Bishop PW, Freemont TJ.

Manchester Adult Cystic Fibrosis Unit, South Manchester University Hospitals NHS Trust, Wythenshawe Hospital, UK.

Chest 2000 Aug;118(2):434-9 Abstract quote

STUDY OBJECTIVE: Low bone mineral density is a common complication of cystic fibrosis (CF), and recent studies have implicated vitamin D insufficiency as a significant etiologic factor. The aim of this study was to establish whether there was bone biopsy evidence of vitamin D deficiency osteomalacia in patients with CF and to document the general histomorphometric characteristics of CF bone.

PATIENTS AND METHODS: A retrospective descriptive and histomorphometric study of postmortem L2/L3 vertebral bone biopsy specimens was undertaken on tissue from 11 posttransplant CF patients and 4 nontransplanted CF patients. Control data were derived from postmortem bone specimens from 15 young adults.

RESULTS: Bone from all CF patients was characterized by severe osteopenia in both trabecular and cortical bone. At the cellular level, there was decreased osteoblastic and increased osteoclastic activity. The reduction in osteoblastic activity was due to both a decrease in osteoblast number and a decrease in the biosynthetic potential of osteoblasts. The osteoclastic changes were due to an increase in the number of osteoclasts. The increase in osteoclasis and the uncoupling of osteoblastic and osteoclastic activity resulted in an increase in resorptive surfaces. Although there were few significant differences between the transplanted and nontransplanted CF groups, both cortical and trabecular bone mass tended to be lower after transplantation. None of the CF undecalcified biopsy specimens showed osteoid parameters characteristic of vitamin D deficiency osteomalacia.

CONCLUSIONS: CF patients have an unusual and complex pattern of cellular changes within bone that are not typical of vitamin D deficiency osteomalacia.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
TREATMENT  

Oral steroids for cystic fibrosis.

Cheng K, Ashby D, Smyth R.

Room 1014A, Pharmaco Vigilance Assessment Group, Post Licencing Division, Medicines Control Agency, Market Towers, 1 Nine Elms Lane, London, UK.

Cochrane Database Syst Rev 2000;(2):CD000407 Abstract quote

BACKGROUND: In cystic fibrosis, airway obstruction and recurrent respiratory infection leads to inflammation and eventually long term lung damage, (bronchiectasis), respiratory failure and death. Inflammation occurs early in the disease process, hence the rationale for the use of anti-inflammatory agents such as oral steroids.

OBJECTIVES: To assess the effectiveness of oral steroids in management of respiratory complications cystic fibrosis with particular regard to lung function and occurrence of adverse events. We aimed to to examine short term use for a respiratory exacerbation separately (up to 30 days) from long term anti-inflammatory use (greater than 30 days).

SEARCH STRATEGY: We searched The Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register. Date of the most recent search of the Group's specialised register: November 1999.

SELECTION CRITERIA: All randomised or pseudorandomised trials comparing oral corticosteroids given for a period of five to 30 days for treatment of an exacerbation or for more than 30 days used long term, with placebo or no additional therapy in patients with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality.

MAIN RESULTS: Three trials were identified studying a total of 354 patients. Two of these were long term trials with four year follow up whilst one had follow up to 12 weeks only. There was a lack of data on our predefined outcomes with common outcomes examined at different time-points and also variations in the presentation of common outcomes. A meta-analysis was not possible. Oral corticosteroids at a prednisolone equivalent dose of 1 mg/kg alternate days appear to slow the progression of lung disease in cystic fibrosis. At 24 months from commencement, 70.4% patients treated with 1mg/kg prednisolone on alternate days had an increase in per cent predicted forced vital capacity (FVC) compared to 41.6% patients treated with placebo. The mean absolute change in per cent predicted forced expiratory volume at one second (FEV1) 48 months from commencement was -2% in the 1 mg/kg alternate days prednisolone group but -6% in the placebo group. In the long term, this benefit needs to be weighed against the occurrence of adverse events. Linear growth retardation was observed as early as six months from start of treatment in the 2 mg/kg alternate days prednisolone group and from 24 months of treatment in the 1 mg/kg alternate days prednisolone group. Occurrence of adverse events, particularly glucose abnormalities, cataracts and growth retardation resulted in early termination of one of the four year studies ( approximately approximately Eigen 1995 approximately approximately ), with the group taking 2 mg/kg prednisolone on alternate days being stopped first but followed by the 1 mg/kg alternate days.

REVIEWER'S CONCLUSIONS: Oral corticosteroids at a prednisolone equivalent dose of 1-2 mg/kg alternate days appear to slow the progression of lung disease in CF but this benefit needs to be weighed against the occurrence of adverse events, in particular, development of cataracts and effect on linear growth. A risk/benefit analysis of low-dose alternate days corticosteroids would be important and the role of short term use of oral steroids should be more fully evaluated.

Deoxyribonuclease for cystic fibrosis.

Kearney CE, Wallis CE.

Northwick Park Hospital, Watford Road, Harrow, Middlesex, UK, HA1 3UJ.

Cochrane Database Syst Rev 2000;(2):CD001127 Abstract quote

BACKGROUND: Recombinant human deoxyribonuclease is currently used to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis.

OBJECTIVES: To determine whether the use of recombinant human deoxyribonuclease in cystic fibrosis is associated with improved mortality and morbidity as compared to placebo and to identify any adverse events associated with its use. To compare the efficacy of recombinant human deoxyribonuclease with other mucolytics.

SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, hand searching relevant journals and abstracts from conferences. The company producing recombinant human deoxyribonuclease was also contacted. Date of the most recent search of the Group's specialised register: November 1999.

SELECTION CRITERIA: All randomised and quasi-randomised trials where recombinant human deoxyribonuclease was compared to either placebo, standard therapy or another mucolytic for any duration, dose regimen and age of patient with cystic fibrosis of any disease severity.

DATA COLLECTION AND ANALYSIS: Trials were independently assessed for inclusion criteria, methodological quality and data extraction by the two reviewers. Comparisons were between recombinant human deoxyribonuclease and placebo and recombinant human deoxyribonuclease and other mucolytics. The following outcomes were recorded: Mean % change from baseline in forced vital capacity (FVC), forced expiratory voloume at one second (FEV1) and weight, mean number of respiratory tract exacerbations, days intravenous and oral antibiotics used, mean number of days as inpatient, number of deaths, adverse events and the cost of therapy.

MAIN RESULTS: Seven primary clinical trials were identified, totalling 1710 patients. Two further studies examined the health care cost of patients from one of the clinical trials. No eligible studies compared recombinant human deoxyribonuclease to another mucolytic. Five trials presented outcomes at up to one month, one at three months and one at six months. No reduction in mortality for treated patients was identified (Relative Risk (RR) at six month 1.01, 95%Confidence Interval (CI) 0.09, 11.11). Lung function improved to a greater extent in the treated groups (at six months Weighted Mean Difference (WMD) FEV1 5.7, 95%CI 4.18, 7.23, at three months 7.3, 95%CI 4.04, 10.65). Pooled data from the five trials of up to one month gave WMD 9.2 95%CI 0.93, 17. 6 although there was significant heterogeneity). Recombinant human deoxyribonuclease was well tolerated with no excess of serious adverse events (RR haemoptysis 0.89, 95%CI 0.54, 1.45, pneumothorax 0.97 95%CI 0.19, 4.96). Voice alteration was, however, reported more frequently in the treated groups (RR 2.33 95%CI 1.38, 3.93). No study analysed our pre-defined outcome measure for respiratory exacerbations and insufficient data was available to analyse differences in antibiotic treatment, inpatient stay and quality of life.

REVIEWER'S CONCLUSIONS: Studies are of insufficient duration to identify a reduction in mortality or number of respiratory exacerbations. Further trials are required to answer these important questions. Recombinant human deoxyribonuclease therapy is associated with an improvement in lung function after six months treatment, but it is not possible to assess whether this effect on lung function is sustained in the long-term. No studies were identified that compared recombinant human deoxyribonuclease to another mucolytic.

Vaccines for preventing infection with Pseudomonas aeruginosa in people with cystic fibrosis.

Keogan MT, Johansen HK.

Department of Immunology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland.

Cochrane Database Syst Rev 2000;(2):CD001399 Abstract quote

OBJECTIVES: To assess the effectiveness of vaccination against Pseudomonas aeruginosa in patients with cystic fibrosis.

SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search of the Group's specialised register: November 1999.

SELECTION CRITERIA: All randomised or pseudorandomised trials (published or unpublished) comparing Pseudomonas aeruginosa vaccines (oral, parenteral or intranasal) with control vaccines or no intervention in patients with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: We planned to assess the following outcomes: time to infection with Pseudomonas aeruginosa, pulmonary function, body mass index, Schwachman score, frequency of pulmonary infective exacerbations, days of antibiotic usage, days unable to carry out normal daily activities, adverse events, mortality, antibody levels to Pseudomonas aeruginosa and T cell proliferation and cytokine production in response to Pseudomonas aeruginosa.

MAIN RESULTS: One trial which included 17 vaccinated patients, with follow up reported to 10 years met the inclusion criteria. Finding only a single trial, and the lack of information on our predefined outcomes limited analysis.

REVIEWER'S CONCLUSIONS: There is a paucity of randomised controlled trials assessing the effectiveness of vaccination against Pseudomonas aeruginosa in cystic fibrosis. Increased understanding of modulation of the immune response by vaccination has led to the development of alternative vaccines. We suggest that there is an urgent need for newer vaccines to be evaluated in adequately-powered, multicentre randomised controlled trials examining clinically relevant end-points in addition to immunological variables. Such a trial should assess effectiveness over several years, and include follow-up of vaccinees who become colonised with Pseudomonas aeruginosa.

Once daily versus multiple daily dosing with intravenous aminoglycosides for cystic fibrosis.

Tan K, Bunn H.

Child Health, University of Nottingham, Clinical Sciences Building, Nottingham City Hospital, Hucknall Road, Nottingham, UK, NG5 1PB.

Cochrane Database Syst Rev 2000;(4):CD002009 Abstract quote

BACKGROUND: Patients with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require repeated courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher concentrations less often.

OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis.

SEARCH STRATEGY: We searched the Cystic Fibrosis specialist trials register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search: February 2000.

SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy and/or toxicity, in patients with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: Both reviewers independently extracted data and assessed trial quality. Authors of one study were contacted to obtain missing information.

MAIN RESULTS: Two trials reporting results from a total of 70 patients were included in this review. Both trials compared once-daily dosing with thrice-daily dosing reporting data on Forced Expiratory Volume at one second (FEV1), Forced Vital Capacity (FVC), nutritional status and side effects. There was no significant difference in efficacy or in the incidence of ototoxicity and nephrotoxicity between treatment groups.

REVIEWER'S CONCLUSIONS: Despite a lack of difference between the two groups we feel that these results should be viewed with caution as the numbers of patients involved was small and lacks the power to detect a difference between the groups. This systematic review has highlighted the need for a well designed, adequately-powered, multicentre, randomised controlled trial assessing the efficacy of once-daily versus multiple-daily dosing of intravenous aminoglycosides for pulmonary exacerbations in cystic fibrosis.

Enteral tube feeding for cystic fibrosis.

Conway SP, Morton A, Wolfe S.

Cystic Fibrosis Department, Seacroft Hospital, York Road, Leeds, Yorkshire, UK, LS14 6UH.

Cochrane Database Syst Rev 2000;(2):CD001198 Abstract quote

BACKGROUND: Enteral tube feeding is routinely used in many cystic fibrosis centres when weight for height percentage is less than 85%, when there has been weight loss for greater than a two month period or when there has been no weight gain for two to three months (under five years old) or for six months (over five years old).

OBJECTIVES: To examine the evidence that in patients with cystic fibrosis supplemental enteral tube feeding improves nutritional status, respiratory function, and quality of life without significant adverse effects.

SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialised register and contacted the companies which market enteral feeds and reviewed their databases. Date of the most recent search of the Group's specialised register: November 1999.

SELECTION CRITERIA: All randomised controlled trials comparing supplemental enteral tube feeding for one month or longer with no specific intervention in patients with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: There are no trials included in this review.

MAIN RESULTS: There are no trials included in this review.

REVIEWER'S CONCLUSIONS: Supplemental enteral tube feeding is widely used throughout the world to improve nutritional status in patients with cystic fibrosis. The methods mostly used, nasogastric or gastrostomy feeding, are invasive, expensive, and may have a negative effect on self esteem and body image. Reported use of enteral tube feeding suggests that it results in nutritional and respiratory improvement and it is disappointing that their efficacy has not been fully assessed by randomised controlled trials. With the more frequent recommendations to use enteral tube feeding as an early rather than a late intervention, this systematic review identifies the need for a multi-centre randomised controlled trial assessing both efficacy and possible adverse effects of enteral tube feeding in cystic fibrosis.

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Elphick H, Southern K.

Institute of Child Health, Alder Hey Children's Hospital, Eaton Road, Liverpool, UK.

Cochrane Database Syst Rev 2000;(4):CD002204 Abstract quote

BACKGROUND: Allergic Bronchopulmonary Aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. Corticosteroids, in high doses, are the main treatment for ABPA although the long-term benefits are not clear and their many side effects are well documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, Itraconazole is the most active. A separate antifungal compound, Amphotericin B has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated.

OBJECTIVES: The review tested the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis: 1. improve clinical status compared to placebo or standard therapy (no placebo); 2. do not have unacceptable adverse effects. If benefit was demonstrated, the optimal type, duration and dose of antifungal therapy was assessed.

SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. In addition, pharmaceutical companies were approached.

SELECTION CRITERIA: Randomised controlled trials, published or unpublished, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in patients with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: No completed randomised controlled trials were identified.

MAIN RESULTS: No completed randomised controlled trials were identified.

REVIEWER'S CONCLUSIONS: At present, there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Chest physiotherapy compared to no chest physiotherapy for cystic fibrosis.

van der Schans C, Prasad A, Main E.

Dept. Rehabilitation, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, Netherlands.

Cochrane Database Syst Rev 2000;(2):CD001401

BACKGROUND: Chest physiotherapy is widely used in patients with cystic fibrosis in order to clear mucus from the airways.

OBJECTIVES: To determine the effectiveness and acceptability of chest physiotherapy compared to no treatment or spontaneous cough alone to improve mucus clearance in cystic fibrosis.

SEARCH STRATEGY: Relevant trials are identified in the Cochrane Cystic Fibrosis and Genetic Disorders Group Specialised Register of Controlled Trials. This register was compiled by conducting computerised searches of Medline from 1966 to present and from Embase from 1974 to 1995. The register of randomised controlled trials is updated every three months. Unpublished work has been identified by searching through the abstract books of the three major cystic fibrosis conferences; the International Cystic Fibrosis Conference: the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. Date of the most recent search of the Group's specialised register: November 1999.

SELECTION CRITERIA: Randomised or quasi-randomised clinical trials in which a form of chest physiotherapy (airway clearance technique) were taken for consideration in patients with cystic fibrosis compared with either no physiotherapy treatment or spontaneous cough alone.

DATA COLLECTION AND ANALYSIS: There were no randomised controlled trials or cross over trials eligible for inclusion in the review.

MAIN RESULTS: There were no randomised controlled trials or cross over trials eligible for inclusion in the review.

REVIEWER'S CONCLUSIONS: Short-term crossover trials, which had to be excluded from this review, suggest that airway clearance regimens could have beneficial effects in patients with cystic fibrosis. However based on this review there is currently no robust scientific evidence to support the hypothesis that chest physiotherapy for the purpose of clearing airway secretions has a beneficial effect in patients with cystic fibrosis.

Oral non-steroidal anti-inflammatory drug therapy for cystic fibrosis.

Dezateux C, Crighton A.

Department of Epidemiology and Public Health, Institute of Child Health, 30 Guildford Street, London, UK, WC1N 1EH.

Cochrane Database Syst Rev 2000;(2):CD001505 Abstract quote

BACKGROUND: Maintenance of optimal lung function is an important therapeutic goal in cystic fibrosis as it is lung damage that, in the long term, is responsible for most premature death among affected people. It has been hypothesised that lung damage results from inflammation and that prolonged use of non-steroidal anti-inflammatory drugs may prevent progressive pulmonary deterioration and respiratory morbidity in cystic fibrosis. It is thus important to establish the current level of evidence about the potential benefits and harms of treatment with non-steroidal anti-inflammatory drugs.

OBJECTIVES: The aim of this systematic review is to assess the effectiveness of treatment with non-steroidal anti-inflammatory agents in cystic fibrosis.

SEARCH STRATEGY: Trials were ascertained from the Cochrane Cystic Fibrosis and Genetic Disorders Specialised Register of Controlled Trials which includes published and unpublished trials identified through electronic databases such as Medline and Embase as well as those identified from handsearching of journals and conference proceedings. Pharmaceutical companies manufacturing non-steroidal anti-inflammatory drugs were also contacted to identify any trials of non-steroidal anti-inflammatory drugs in cystic fibrosis. Date of the most recent search of the Group's specialised register: November 1999.

SELECTION CRITERIA: All randomised or pseudorandomised controlled trials, published and unpublished, comparing non-steroidal anti-inflammatory drugs, administered orally at any dose for a period of at least two months, to placebo in patients with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: The following outcomes were assessed: objective measures of lung function, nutritional status, radiological assessment of pulmonary involvement, use of intravenous antibiotics, hospital admissions, survival, frequency of major and minor adverse effects and compliance with therapy.

MAIN RESULTS: Three trials involving 145 patients aged from five to 39 years with a maximum follow up of four years met the inclusion criteria. Methodological quality was deemed good or adequate in two. Two trials, both reporting effectiveness of ibuprofen in subjects with mild lung disease, were from the same centre and included some patients in common, while the third assessed piroxicam in subjects with more severe impairment of respiratory function. Variation in outcomes reported and their summary measures precluded calculation of pooled treatment estimates. Only one trial reported within-subject changes in pulmonary function and the findings of this trial suggested that there was a greater absolute annual decline in percentage predicted forced expiratory volume in one second among controls than among those treated with ibuprofen. In a post-hoc sub-group analysis this effect was confined to children aged five to 13 years. In addition, in this one trial long term use of high dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported but the power of the trials to identify clinically important differences in the incidence of adverse effects was low.

REVIEWER'S CONCLUSIONS: While there is preliminary evidence to suggest that non-steroidal anti-inflammatory drugs may prevent pulmonary deterioration in subjects with mild lung disease due to cystic fibrosis, currently their routine use cannot be recommended. Further trials are required to confirm that their use prevents pulmonary deterioration and is associated with improved nutritional status. Such trials should also address the age group of subjects most likely to benefit, the prevalence of important adverse effects and the optimal dosage schedule as well as any reduction in concomitant therapy. Multi-centre trials will add to the validity of findings by enhancing their generalisability. The question of whether anti-inflammatory treatment prevents lung damage in pre-symptomatic

Oral calorie supplements for cystic fibrosis.

Smyth R, Walters S.

Institute of Child health, University of Liverpool, Alder Hey Children's Hospital, Eaton Road, Liverpool, Merseyside, UK, L12 2AP.

Cochrane Database Syst Rev 2000;(2):CD000406 Abstract quote

BACKGROUND: Poor nutrition occurs frequently in children and adults with cystic fibrosis and is associated with a number of other adverse outcomes. Oral calorie supplements are used to try and increase total daily calorie intake and improve weight gain. However, they are expensive and there are concerns that they may lead to a reduction in the amount of food eaten and no overall improvement in energy intake.

OBJECTIVES: To examine the evidence that in patients with cystic fibrosis, oral calorie supplements increase daily calorie intake, improve overall nutritional intake, nutritional indices, lung function, survival and quality of life. To assess possible adverse effects associated with use of oral calorie supplements.

SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. The companies which market oral calorie supplements were also contacted. Date of the most recent search of the Group's specialised register: November 1999.

SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing use of oral calorie supplements for at least one month to increase calorie intake with no specific intervention or additional nutritional advice in patients with cystic fibrosis. DATA

COLLECTION AND ANALYSIS: The following outcomes were assessed: indices of nutrition and growth, anthropometric measures of body composition, calorie intake (total, from oral calorie supplements and from food), nutrient intake, eating behaviour, quality of life, specific adverse effects, lung function and mortality.

MAIN RESULTS: Two trials which reported results from a total of 29 patients were suitable for inclusion in the review. From the data provided in the published reports only one item (change in weight) could be extracted from one trial for inclusion in the review. This showed no difference between intervention and comparison group.

REVIEWER'S CONCLUSIONS: Oral calorie supplements are very widely used around the world in an attempt to improve nutritional status in patients with cystic fibrosis, at some considerable cost. It is therefore very disappointing that their effectiveness has not been assessed by adequate clinical trials. No conclusions can be made about the use of oral calorie supplements in cystic fibrosis from the information currently available and clinicians must balance potential benefits against possible adverse effects of treatment in making decisions about individual patients. This systematic review has clearly identified the need for a well designed, adequately-powered, multicentre, randomised controlled trial assessing the effectiveness and possible adverse effects of oral calorie supplements in cystic fibrosis.

Home intravenous antibiotics for cystic fibrosis.

Marco T, Asensio O, Bosque M, de Gracia J, Serra C.

Department of Pediatrics, Corporacio Sanitaria Parc Tauli de Sabadell, Parc Tauli, s/n, Sabadell, Spain, 08208.

Cochrane Database Syst Rev 2000;(4):CD001917 Abstract quote

BACKGROUND: Recurrent endobronchial infection in cystic fibrosis requires treatment with intravenous antibiotics for several weeks, which is usually administered in hospital, affecting health costs and quality of life for patients and their families. It is not known whether patients receiving intravenous treatment at home have better or equivalent health outcomes, if costs are reduced or if it is preferred than in-hospital treatment. Home treatment requires training to patients and carers and usually needs a few previous days in hospital.

OBJECTIVES: To determine whether home intravenous antibiotic therapy in cystic fibrosis is as effective as in-patient intravenous antibiotic therapy and if it is preferred by patients and/or families.

SEARCH STRATEGY: References to trials were obtained from the specialist cystic fibrosis trials register held by the editorial base of the Cochrane Cystic Fibrosis and Genetic Disorders Group. Handsearching of the abstracts books of all Spanish Conferences on cystic fibrosis and the last European Conference (Stockholm, 2000) was carried out by authors.

SELECTION CRITERIA: Randomised controlled trials where home intravenous antibiotic treatment for patients with cystic fibrosis was compared with in-hospital intravenous antibiotic treatment, including adults and children with cystic fibrosis. All kinds of antibiotics and regimens administered intravenous were included.

DATA COLLECTION AND ANALYSIS: Three reviewers independently selected the trials to be included in the review, assessed methodological quality of each trial and extracted data using a standardised form. Because of several limitations, narrative synthesis was used at this stage.

MAIN RESULTS: One study was included with 17 patients aged 10 to 41 years with an infective exacerbation by Pseudomonas aeruginosa. All their 31 admissions were analysed as independent events. Outcomes were measured at 21 days of follow-up after initiation of treatment. Home patients had fewer investigations performed than hospital patients (p<0.002) and general activity was higher in the home group. No differences were found for clinical outcomes, adverse events, complications of intravenous lines or line changes or time to next admission. Home patients received less low-dose home maintenance antibiotic. Quality of life measures showed no differences for dyspnoea and emotional state, but fatigue and mastery were worse for home patients, possibly due to a higher general activity and need of support. Personal, family, sleeping and eating disruptions were less important for home than hospital admissions. Home therapy was cheaper for families and the hospital. Indirect costs were not determined.

REVIEWER'S CONCLUSIONS: The current evidence is restricted to one small study. It suggests that in the short term home therapy does not harm patients and in general reduces social disruptions. The decision to attempt home treatment should be based on an individual basis and appropriate local resources. More research is urgently required.

Inhaled corticosteroids for cystic fibrosis.

Dezateux C, Walters S, Balfour-Lynn I.

Department of Epidemiology and Public Health, Institute of Child Health, 30 Guildford Street, London, UK, WC1N 1EH.

Cochrane Database Syst Rev 2000;(2):CD001915 Abstract quote

BACKGROUND: Maintenance of optimal lung function is an important therapeutic goal in cystic fibrosis as it is lung damage that, in the long term, is responsible for most premature death among affected people. Inhaled corticosteroids are being increasingly used to treat children and adults with cystic fibrosis. The rationale for their use is that they have the potential to reduce lung damage arising from inflammation. However chronic use of inhaled steroids may also have adverse effects. It is thus important to establish the current level of evidence about the potential benefits and harms of this practice.

OBJECTIVES: The objective of this review is to assess the effectiveness of regular use of inhaled corticosteroids when compared to no inhaled corticosteroids, in the management of patients with cystic fibrosis.

SEARCH STRATEGY: Trials were ascertained from the Cochrane Cystic Fibrosis and Genetic Disorders Specialised Register of Controlled Trials which includes published and unpublished trials identified through electronic databases such as Medline and Embase as well as those identified from handsearching of journals and conference proceedings. Pharmaceutical companies manufacturing inhaled corticosteroids were also contacted to identify any trials of inhaled corticosteroids in cystic fibrosis. Date of the most recent search of the Group's specialised register: November 1999.

SELECTION CRITERIA: All trials, both published and unpublished, in which inhaled corticosteroids were compared to either placebo or standard treatment in patients with cystic fibrosis. Trials employing random treatment allocation and those using quasi-random allocation methods such as alternate allocation to treatment and control group were included.

DATA COLLECTION AND ANALYSIS: The following outcomes were assessed: objective measures of lung function, respiratory exacerbations, use of intravenous antibiotics, hospital admissions, nutritional status, symptoms, quality of life, survival and frequency of adverse effects. Methodological quality of trials was assessed independently using established criteria by two reviewers, who also extracted relevant data independently using standard proformas. Differences were resolved by discussion. MAIN

RESULTS: Nine trials were identified reporting the use of inhaled steroids in 266 subjects aged between seven and 45 years with cystic fibrosis. Methodological quality was difficult to assess from published information, specifically with respect to concealment of allocation and method used to generate random sequence. Trials were heterogeneous with respect to inclusion criteria, specifically age, severity of pulmonary involvement, clinical diagnosis of asthma and pulmonary colonisation with Pseudomonas aeruginosa. Trials also differed in type and duration of treatment. Beclomethasone was given for periods of between four and 22 weeks in four trials, budesonide for six weeks and six months respectively in two, and fluticasone for periods of between six weeks and two years in the remaining three. Measures of the volume of air breathed out on a forcible expiration (forced expiratory volumes) were reported in most trials but these data could not be combined for this review partly because reports differed in the way data were summarised and partly because some data were not included in published reports. Outcomes of potentially greater relevance to affected individuals such as nutritional status or quality of life were not reported in any trial. Survival was not reported in any trial, but this may reflect the fact that maximum duration of follow up was too short to allow this outcome to be meaningfully assessed. Adverse effects were systematically documented in only two trials. Although one trial was halted prematurely because a proportion of all those taking part had acquired chronic lung infections with Pseudomonas aeruginosa, no conclusions can be reached from this one small trial as to whether this risk is increased.

Macrolide antibiotics for cystic fibrosis.

Southern KW, Barker PM, Solis A.

Child Health, University of Liverpool, Alder Hey Children's Hospital, Eaton Road, Liverpool, Merseyside, UK, L12 2AP.

Cochrane Database Syst Rev 2000;(3):CD002203 Abstract quote

BACKGROUND: Cystic Fibrosis is characterised by chest infection, the antibiotic treatment of which has significantly improved the outlook for people with this condition. The unusual nature of organisms that infect the chest of individuals with cystic fibrosis has restricted antibiotic choice. In particular the bacteria, Pseudomonas aeruginosa, is resistant to nearly all antibiotics that can be taken by mouth. There is laboratory evidence and evidence from other disease processes that macrolide antibiotics, whilst not directly active against Pseudomonas aeruginosa, may have indirect actions against this bacteria.

OBJECTIVES: This review aimed to test the hypotheses that macrolide antibiotics; 1) Improve clinical status compared to placebo or another antibiotic 2) do not have unacceptable adverse effects If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy.

SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. In addition, Principal Investigators, known to work in the field and previous authors were contacted for unpublished or follow up data. Pharmaceutical companies, that manufacture macrolide antibiotics, were approached.

SELECTION CRITERIA: Randomised controlled trials, published or unpublished, of macrolide compared to placebo, another class of antibiotic or another macrolide. Studies which compare regimes of the same macrolide at different doses will also be included.

DATA COLLECTION AND ANALYSIS: No completed randomised controlled trials were identified.

MAIN RESULTS: Three open studies excluded. Four ongoing randomised controlled trials were identified. No completed randomised controlled trials were identified. REVIEWER'S

CONCLUSIONS: At present, there are no randomised controlled trials to evaluate the use of macrolide antibiotics for the treatment of chest infection in people with cystic fibrosis. Such trials, with clear outcome measures, are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Elective versus symptomatic intravenous antibiotic therapy for cystic fibrosis (Cochrane Review).

Breen L, Aswani N. Alder Hey

Children's Hospital, Eaton Road, Liverpool, Merseyside, UK, L12 2AP.

Cochrane Database Syst Rev 2001;4:CD002767 Abstract quote

BACKGROUND: Pseudomonas aeruginosa is the commonest micro-organism associated with respiratory infections in cystic fibrosis. Retrospective studies have suggested that survival is increased by using an aggressive policy of intravenous antipseudomonal antibiotics at regular intervals, irrespective of symptoms.

OBJECTIVES: To determine whether there is evidence that an elective (regular) versus symptomatic intravenous antibiotic regime is associated with an improvement in clinical status and survival rates in patients with cystic fibrosis. To identify any adverse effects associated with the use of elective intravenous antibiotics, including an increase in the development of resistant organisms.

SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetics Disorders Group Specialist Trials Register was used. This comprises references identified from comprehensive electronic database searches, hand searching relevant journals and abstracts from conference proceedings. Date of the most recent search of the Group's specialised register: October 2000.

SELECTION CRITERIA: All randomised or pseudo-randomised controlled trials describing the use of elective compared with symptomatic intravenous antibiotic policies for any duration or dose regimen. Elective versus symptomatic intravenous antibiotic regimes against any organisms were considered. Patients with cystic fibrosis were of any age or disease severity.

DATA COLLECTION AND ANALYSIS: Trials were independently assessed for inclusion criteria, methodological quality and data extraction by the two reviewers. MAIN

RESULTS: Three trials were identified by the initial search. Two trials reporting results from a total of 79 patients were included in the review. Differences in study design and objectives meant that data could not be pooled for meta-analysis. Neither trial demonstrated significant differences in outcome measures between intervention and comparison groups.

REVIEWER'S CONCLUSIONS: Studies are insufficient to identify conclusive evidence favouring a policy of elective intravenous antibiotic administration, despite its widespread use. Neither are the potential risks adequately evaluated. The results should be viewed with caution as patient numbers are small. Clearly there is a need for a well-designed, adequately powered, multi-centred randomised controlled trial to evaluate these issues.

Prophylactic antibiotics for cystic fibrosis (Cochrane Review).

Smyth A, Walters S.

Department of Paediatrics, Nottingham City Hospital, Hucknall Road, Nottingham, UK, NG5 1PB.

Cochrane Database Syst Rev 2001;3:CD001912 Abstract quote

BACKGROUND: Cystic fibrosis blocks the airways with mucus and causes frequent respiratory infections. This leads to inflammation and lung disease, which frequently causes death from breathing failure. People with cystic fibrosis are sometimes given antibiotics regularly, in an attempt to prevent infections. However, antibiotics also have adverse effects, and longterm use might lead to the development of infections that can no longer be cleared by antibiotics. The review found some evidence from trials that preventive antibiotics for babies continued to two years may have some benefits. However, there is no evidence of the effects on adults or of longterm use.

OBJECTIVES: We aimed to compare continuous oral antibiotic prophylaxis with no prophylaxis (short courses of oral antibiotics given as clinically indicated) in patients with cystic fibrosis. This review considers both the effectiveness of prophylaxis (bacteria isolated from the respiratory tract, requirement for additional antibiotic treatment, lung function, survival) and the adverse effects.

SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetic Disorders Group clinical trials register was used. This comprises references identified from a comprehensive search of electronic databases, as well as hand searching relevant journals and conference abstracts. Companies manufacturing anti-staphylococcal antibiotics were also approached for unpublished data. Date of the most recent search of the Group's specialised register: February 2001.

SELECTION CRITERIA: All randomised or pseudo-randomised trials where continuous oral prophylactic antibiotics, given for a period of at least one year, were compared to intermittent antibiotic therapy given "as required." Cystic fibrosis patients of any disease severity were considered.

DATA COLLECTION AND ANALYSIS: Trials were assessed for eligibility, methodological quality and data extraction by the reviewers. The following outcomes were assessed: lung function; nutrition (weight standard deviation score); survival; requirement for additional antibiotic treatment; isolates of pathogens from the respiratory tract; occurrence of adverse reactions to prophylactic antibiotics.

MAIN RESULTS: Three studies, totaling 177 patients aged 0-7 years on enrolment, were suitable for inclusion in the review. A reduced prevalence of Staphylococcus aureus in the respiratory secretions was seen in children receiving anti-staphylococcal antibiotic prophylaxis, although no effect was seen on other common pathogens. One eligible study showed a shorter duration of hospital admissions in the second year of life, in patients receiving prophylaxis. No effect on infant lung function has been shown after one year of prophylactic treatment. Data are not available on adverse effects of the interventions. There was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group, after three years. However, as the duration of the studies reviewed has been of three years or less, conclusions cannot be drawn about the long term effects of prophylaxis on acquisition of P. aeruginosa and survival.

REVIEWER'S CONCLUSIONS: Anti-staphylococcal antibiotic prophylaxis may be of benefit when commenced early in infancy and continued up to three years of age. There is insufficient evidence from this review to say whether use in older children, or adults, or for periods of over three years is beneficial.

LUNG TRANSPLANTATION  

High incidence of posttransplant lymphoproliferative disease in pediatric patients with cystic fibrosis.

Cohen AH, Sweet SC, Mendeloff E, Mallory GB Jr, Huddleston CB, Kraus M, Kelly M, Hayashi R, DeBaun MR.

Georgia Pediatrics, Pulmonology Associates, Atlanta, Georgia, USA.

Am J Respir Crit Care Med 2000 Apr;161(4 Pt 1):1252-5 Abstract quote

A major cause of morbidity and mortality following lung transplantation is posttransplant lymphoproliferative disease (PTLD).

In a retrospective cohort analysis of pediatric patients, we evaluated the risk factors associated with PTLD in 128 first-time lung transplant recipients from 1990 to 1997. The greatest risk factor for PTLD was a diagnosis of cystic fibrosis (CF). Of the 16 patients in our analysis who had PTLD, 13 had a diagnosis of CF (odds ratio [OR]: 5.8; confidence interval 95% [CI]: 1.6 to 21.4). Because of the high frequency of PTLD in patients with CF (13 of 61; 23%), we performed a retrospective cohort analysis in which patients with CF and PTLD were designated as cases and patients with CF and without PTLD served as controls. In patients with CF, the only risk factor associated with PTLD was two or more episodes of acute rejection within 3 mo after transplantation (OR: 11.0; 95% CI: 2.7 to 55.7). Age, recipient Epstein-Barr virus or cytomegalovirus status, induction with antilymphocyte globulin or antithymocyte globulin (ATG), or use of ATG or OKT3 for acute rejection episodes were not risk factors for PTLD.

The high frequency of PTLD in the subgroup of patients with two or more episodes of graft rejection within 2 mo after lung transplantation was unexpected, and warrants further investigation in prospective clinical studies and basic laboratories.

Significance of blood stream infection after lung transplantation: analysis in 176 consecutive patients.

Palmer SM, Alexander BD, Sanders LL, Edwards LJ, Reller LB, Davis RD, Tapson VF.

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Transplantation 2000 Jun 15;69(11):2360-6 Abstract quote

BACKGROUND: Although infection is a leading cause of death after lung transplantation, very little is known about the incidence, epidemiology, and clinical significance of bloodstream infections in lung transplant recipients.

METHODS: All blood cultures were reviewed in 176 consecutive lung transplant recipients over a 6-year period. Data were obtained from a prospectively collected microbiological database.

RESULTS: Bloodstream infection (BSI) occurred in 25% (44/176) of all lung transplant recipients over the 6-year study period. Staphylococcus aureus, Pseudomonas aeruginosa, and Candida species were the most common bloodstream isolates after lung transplantation. The epidemiology of posttransplant BSI, however, varied considerably between early and late posttransplant time periods and also differed between cystic fibrosis (CF) and non-CF patients. BSI infection after transplantation was associated with significantly worse survival by Kaplan-Meir analysis (P value log rank test=0.0001). In a multivariable logistic regression model, posttransplant BSI was a significant predictor of posttransplant death (odds ratio 5.62, CI 2.41-13.11, P=0.001), independent of other pre- and posttransplant factors.

CONCLUSIONS: Bloodstream infection represents a serious complication after lung transplantation, occurring more frequently than previously recognized, and independently contributing to posttransplant mortality.

Cystic fibrosis patients with and without central nervous system complications following lung transplantation.

Goldstein AB, Goldstein LS, Perl MK, Haug MT, Arroliga AC, Stillwell PC.

Section of Pediatric Pulmonary Medicine, Ohio State University College of Medicine, Columbus, Ohio, USA.

Pediatr Pulmonol 2000 Sep;30(3):203-6 Abstract quote

Central nervous system (CNS) complications occur more frequently in cystic fibrosis (CF) patients than other lung transplant recipients.

The purpose of this study was to compare CF patients with and without CNS complications following lung transplantation, to identify risk factors for CNS events.

Records of 21 patients with CF who underwent lung transplant between 1991-1996 were reviewed. Data were collected on multiple variables, including: age at transplant; gender; cytomegalovirus (CMV) status; cholesterol and triglyceride levels; sinusitis; percent ideal body weight (IBW); body mass index (BMI); augmented immunosuppression, acute lung rejection episodes (ALR); cyclosporine doses; electrolytes; magnesium, blood urea nitrogen (BUN), and creatinine levels; and 6-month survival. CNS complications identified were seizures, severe headaches (HA), strokes, or confusional episodes. Eleven of 21 patients (52%) with CF had CNS events: eight had seizures, five HA, three strokes, and one confusional episode. There was no difference in age at transplant, pretransplant percent IBW or BMI, cholesterol and triglyceride levels, or number of ALR. CMV mismatch and clinical sinusitis had no effect. Cyclosporine doses did not differ between groups at 30 days, or 3 or 6 months posttransplant. Both BUN and creatinine concentrations showed a rise over time that did not differ between groups. Potassium levels were within normal limits for both groups. While sodium levels did not differ between groups pretransplant, or at 30 days or 6 months posttransplant, a decrease in sodium values was seen at the time of CNS events.

There was no difference in 6-month survival. We could not identify any pre- or posttransplant risk factors that predicted CNS events. It is likely that cyclosporine toxicity is the major cause of CNS complications. Despite the high rate of CNS events, the overall prognosis was good, and 6-month survival was not affected.

Prediction of mortality and timing of referral for lung transplantation in cystic fibrosis patients.

Augarten A, Akons H, Aviram M, Bentur L, Blau H, Picard E, Rivlin J, Miller MS, Katznelson D, Szeinberg A, Shmilovich H, Paret G, Laufer J, Yahav Y.

National Center for Cystic Fibrosis, The Chaim Sheba Medical Center, Tel-Hashomer, Israel 52621.

Pediatr Transplant 2001 Oct;5(5):339-42 Abstract quote

Lung transplantation (Tx) is an optional treatment for cystic fibrosis (CF) patients with end-stage lung disease. The decision to place a patient on the Tx waiting list is frequently complex, difficult, and controversial.

This study evaluated the current criteria for lung Tx and assessed additional parameters that may identify CF patients at high risk of death.

Data were extracted from the medical records of 392 CF patients. Forty of these patients had a forced expiratory volume in 1 s (FEV(1)) less than 30% predicted, and nine of these 40 patients were transplanted. A comparison was performed between the survival of those transplanted (n = 9) and those not transplanted (n = 31), by means of Kaplan-Meier survival curves. The influence on survival of age, gender, nutritional status, sputum aspergillus, diabetes mellitus, recurrent hemoptysis, oxygen use, and the decline rate of FEV(1), were investigated by means of univariate and multivariate analyses. The rate of decline of FEV(1) was evaluated employing the linear regression model. CF patients with a FEV(1)< 30% and who did not receive a lung transplant had survived longer than CF patients who did receive a lung transplant (median survival 7.33 vs. 3.49 yr, 5-yr survival 73% vs. 29%). Two factors--rate of decline in FEV(1) values and age < 15 yr--were found to influence the mortality rate, while the other parameters examined did not.

Our results indicate that the current criterion of FEV(1)< 30% predicted, alone is not sufficiently sensitive to predict the mortality rate in CF patients and time of referral for Tx, as many of these patients survive for long periods of time. Additional criteria to FEV(1)< 30%, should include rapidly declining FEV(1) values and age < 15 yr.

GENE THERAPY  

Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial.

Alton EW, Stern M, Farley R, Jaffe A, Chadwick SL, Phillips J, Davies J, Smith SN, Browning J, Davies MG, Hodson ME, Durham SR, Li D, Jeffery PK, Scallan M, Balfour R, Eastman SJ, Cheng SH, Smith AE, Meeker D, Geddes DM.

Department of Gene Therapy, Imperial College at National Heart and Lung Institute, London, UK.

Lancet 1999 Mar 20;353(9157):947-54 Abstract quote

BACKGROUND: We and others have previously reported significant changes in chloride transport after cationic-lipid-mediated transfer of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to the nasal epithelium of patients with cystic fibrosis. We studied the safety and efficacy of this gene transfer to the lungs and nose of patients with cystic fibrosis in a double-blind placebo-controlled trial.

METHODS: Eight patients with cystic fibrosis were randomly assigned DNA-lipid complex (active) by nebulisation into the lungs followed 1 week later by administration to the nose. Eight control patients followed the same protocol but with the lipid alone (placebo). Safety was assessed clinically, by radiography, by pulmonary function, by induced sputum, and by histological analysis. Efficacy was assessed by analysis of vector-specific CFTR DNA and mRNA, in-vivo potential difference, epifluorescence assay of chloride efflux, and bacterial adherence.

FINDINGS: Seven of the eight patients receiving the active complex reported mild influenza-like symptoms that resolved within 36 h. Six of eight patients in both the active and placebo groups reported mild airway symptoms over a period of 12 h following pulmonary administration. No specific treatment was required for either event. Pulmonary administration resulted in a significant (p<0.05) degree of correction of the chloride abnormality in the patients receiving active treatment but not in those on placebo when assessed by in-vivo potential difference and chloride efflux. Bacterial adherence was also reduced. We detected no alterations in the sodium transport abnormality. A similar pattern occurred following nasal administration.

INTERPRETATION: Cationic-lipid-mediated CFTR gene transfer can significantly influence the underlying chloride defect in the lungs of patients with cystic fibrosis.

A Phase I Study of Aerosolized Administration of tgAAVCF to Cystic Fibrosis Subjects with Mild Lung Disease.

Aitken ML, Moss RB, Waltz DA, Dovey ME, Tonelli MR, McNamara SC, Gibson RL, Ramsey BW, Carter BJ, Reynolds TC.

Department of Medicine and Pediatrics, University of Washington, Seattle, WA 98195.

Hum Gene Ther 2001 Oct 10;12(15):1907-16 Abstract quote

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene.

A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study.

All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA.

This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.

Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.


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