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.
| 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.
|
| 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 |
| PSEUDOMONAS INFECTION |
|
-
Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis.
Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, Collins J, Rock MJ, Splaingard ML.
Department of Pediatrics, University of Wisconsin, Madison 53705-2221, USA.
|
-
| JAMA. 2005 Feb 2;293(5):581-8. Abstract quote |
|
CONTEXT: Although Pseudomonas aeruginosa is the most common virulent respiratory pathogen in cystic fibrosis (CF), the longitudinal development of P aeruginosa infection and its effect on antibody responses and lung disease progression in children with CF remain unclear.
OBJECTIVE: To prospectively examine the epidemiology of P aeruginosa infection and its impact on CF pulmonary morbidity.
DESIGN, SETTING, AND PATIENTS: We prospectively evaluated 56 CF patients at 2 CF centers in Madison and Milwaukee, Wis, from birth up to age 16 years between April 15, 1985, and April 15, 2004, with diagnoses made through the Wisconsin CF Neonatal Screening Project.
MAIN OUTCOME MEASURES: Timing of nonmucoid P aeruginosa and mucoid P aeruginosa acquisition was assessed by first positive result. Longitudinal development from no P aeruginosa to nonmucoid P aeruginosa and from nonmucoid P aeruginosa to mucoid P aeruginosa was examined. Outcome measurements included antibody titers, respiratory symptoms, quantitative chest radiography, and pulmonary function tests.
RESULTS: Sixteen patients (29%) acquired nonmucoid P aeruginosa in the first 6 months of life. The age-specific prevalence of mucoid P aeruginosa increased markedly from age 4 to 16 years. Nonmucoid and mucoid P aeruginosa were acquired at median ages of 1.0 and 13.0 years, respectively. In contrast with the short transition time from no P aeruginosa to nonmucoid P aeruginosa, the transition time from nonmucoid to mucoid P aeruginosa was relatively long (median, 10.9 years) and could be slightly extended by brief/low anti-P aeruginosa antibiotic treatment. Antibody titers increased with both transitions, but the deterioration in cough scores, chest radiograph scores, and pulmonary function correlated best with transition from nonmucoid to mucoid P aeruginosa.
CONCLUSIONS: Early prevention and detection of nonmucoid and mucoid P aeruginosa are critical because of early acquisition and prevalence. There is a window of opportunity for suppression and possible eradication (by aggressive anti-P aeruginosa treatment) of initial nonmucoid P aeruginosa. Mucoid P aeruginosa plays a much greater role in CF lung disease progression than nonmucoid P aeruginosa. Antibody titers, cough scores, and chest radiographs are early signs of nonmucoid P aeruginosa and especially mucoid P aeruginosa stages.
|
| 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.
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Deoxyribonuclease for cystic fibrosis.
Kearney CE, Wallis CE.
Northwick Park Hospital, Watford Road, Harrow, Middlesex, UK, HA1
3UJ.
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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.
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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.
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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.
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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.
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|
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.
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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.
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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
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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.
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|
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.
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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.
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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.
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|
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.
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Prophylactic antibiotics for cystic fibrosis (Cochrane Review).
Smyth A, Walters S.
Department of Paediatrics, Nottingham City Hospital, Hucknall Road,
Nottingham, UK, NG5 1PB.
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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.
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| LUNG TRANSPLANTATION |
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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| GENE THERAPY |
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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.
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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.
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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.
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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.
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