UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845.

Mechanisms of glucose intolerance in cystic fibrosis.

AIMS: Although cystic fibrosis-related diabetes (CFRD), a poor prognostic factor in cystic fibrosis (CF), is characterized by insulinopenia, the role of insulin resistance is unclear. Using a prospective study design, we measured insulin resistance, pancreatic beta-cell function and correlated glycaemic status with clinical parameters. METHODS: Oral glucose tolerance test was performed in 60 stable adult CF patients. Insulin sensitivity and beta-cell function were measured using the homeostatic model assessment (HOMA2), Stumvoll and oral glucose insulin sensitivity (OGIS) indices. RESULTS: Forty-two (70%) had normal glucose tolerance (NGT), 10 (17%) impaired glucose tolerance (IGT) and eight (13%) CFRD. There was no difference in insulin sensitivity among the three groups (HOMA2: NGT 280, IGT 250, CFRD 339, P = 0.42; Stumvoll: NGT 0.128, IGT 0.126, CFRD 0.129, P = 0.76; and OGIS: NGT 515, IGT 472, CFRD 472, P = 0.12). Pancreatic beta-cell function (CFRD 50% vs. NGT 67%; P < 0.05) and first-phase insulin secretion were reduced in CFRD (250 vs. NGT 509; P = 0.004). First-phase insulin secretion was inversely correlated with 1-h (r = -0.74; P < 0.0001) and 2-h glucose levels (r = -0.34; P < 0.05). There was no difference in body mass index or poor lung function (forced expiratory volume in 1 s: CFRD 54% vs. NGT 65%; P = 0.43). However, there were more hospital admissions in the CFRD group (three vs. NGT one per patient per year; P < 0.05). CONCLUSIONS: CFRD is characterized by qualitative and quantitative defects in insulin secretion, but not insulin resistance, and is associated with increased hospital admissions for pulmonary exacerbations.

Transmission of Pseudomonas aeruginosa epidemic strain from a patient with cystic fibrosis to a pet cat.

Chronic infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) and certain strains are more transmissible and virulent than others. Of these, the Liverpool Epidemic Strain (LES) is highly transmissible and cross infection has been reported between patients with CF and healthy non-CF relatives. However, the risk of transmission from humans to animals is unknown. The first report of interspecies transmission of the LES strain of P aeruginosa from an adult patient with CF to a pet cat is described. This development further complicates the issue of infection control policies required to prevent the spread of this organism.

Comparison of methods of assessment of renal function in cystic fibrosis (CF) patients.

Renal failure is increasingly being recognised in CF patients, usually as a consequence of long-term nephrotoxic therapy. There is a need for a simple method of assessment of renal function in this patient group. We compared measured creatinine clearance from validated timed urine collections (the generally accepted practical test of glomerular filtration) with 10 formulae used to estimate creatinine clearance in a group of 74 CF adult patients and 29 matched normal controls. Compared to direct measurement, formulae gave a range of values (95% CI for mean bias -13 to +27.9 ml/min). Even those with the best correlation (r=0.7) gave wide error ranges (limits of agreement: -42.3 to 45.9 ml/min). The most commonly used formulae (Cockroft-Gault [CGF] and abbreviated Modification of Diet in Renal Disease [aMDRD]) were not superior to most other formulae tested. Both CGF and aMDRD-derived estimates compared less favourably in CF patients than controls (mean bias: 9.7 vs 3.4 ml/min (p<0.05) and 4.9 vs 1.4 (p<0.05) respectively; 78% vs 95% (p<0.01) and 77% vs 97% (p<0.01) of estimates within 33% of measurement respectively). In particular, both CGF and aMDRD grossly overestimated renal function (mean bias 18.3 and 15.8 ml/min respectively, p<0.001) in CF patients with reduced creatinine clearance (<80 ml/min). CGF, aMDRD and other formulae cannot be used to reliably assess renal function in CF patients, since they will fail to detect those with renal impairment. Some form of carefully supervised direct measurement is still required.

Environmental contamination with an epidemic strain of Pseudomonas aeruginosa in a Liverpool cystic fibrosis centre, and study of its survival on dry surfaces.

We conducted an environmental survey in the Liverpool adult cystic fibrosis (CF) centre in order to determine the extent of environmental contamination with an epidemic strain of Pseudomonas aeruginosa that colonizes most CF patients in Liverpool, and to identify possible reservoirs and routes of cross-infection. In addition, we studied the survival of this strain on dry surfaces, compared with that of other CF P. aeruginosa strains, to explore factors that might contribute to its high transmissibility. Samples were collected from staff, patients and the environment (drains, bath tubs, showers, dry surfaces, respiratory equipment and air) in the inpatient ward and outpatient clinic. P. aeruginosa strains were tested using a new polymerase chain reaction amplification assay specific for the Liverpool epidemic strain (LES). LES was isolated from patients' hands, clothes and bed linen. Environmental contamination with LES was only detected in close proximity to colonized patients (external surfaces of their respiratory equipment, and spirometry machine tubing and chair) and was short-lived. No persistent environmental reservoirs were found. LES was detected in the majority of air samples from inside patients' rooms, the ward corridor and the outpatient clinic. Survival of LES on dry surfaces was significantly longer than that for some other strains tested, but not compared with other strains shown not to be transmissible. Improved environmental survival on its own, therefore, cannot explain the high transmissibility of this epidemic strain. Our study suggests that airborne dissemination plays a significant role in patient-to-patient spread of LES, and confirms the need to segregate those patients colonized by epidemic P. aeruginosa strains from all other CF patients.

Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use.

Although there are reports of cases of acute renal failure occurring in cystic fibrosis (CF) patients, usually in association with the use of nephrotoxic antibiotic therapy, there have been no studies of renal function in this patient group. We hypothesized that long-term use of intravenous (IV) nephrotoxic antibiotics (aminoglycosides and colistin sulphomethate) may contribute to renal disease in CF patients. In a prospective study, we assessed creatinine clearance as an index of renal function with two techniques (24-hr urine collections and the Cockroft-Gault formula) in a group of 80 stable adult CF outpatients chronically infected with Pseudomonas aeruginosa but with no history of preceding renal disease. Using a multiple linear regression model, we evaluated their renal function in terms of their lifetime IV use of aminoglycosides and colistin. Between 31% (Cockroft-Gault formula method) and 42% (24-hr urine collection method) of patients had a creatinine clearance below normal range. Using either method, there was a strong correlation between aminoglycoside use and diminishing renal function (r=- 0.32, P=0.0055), which was potentiated by the coadministration of colistin (r=- 0.42, P <0.0002). However, there was no correlation with colistin when used in combination with other antibiotics alone (r=0.18, P=NS). Repeated IV aminoglycoside use in CF is associated with long-term renal damage. Although this effect is potentiated by colistin, colistin on its own in moderate doses does not appear to be nephrotoxic. IV aminoglycosides should be used cautiously in CF patients, with regular monitoring of renal function.

Bronchoscopic insertion of Gianturco stents for the palliation of malignant lung disease: 10 year experience.

Malignant large airway obstruction is life threatening and may not be amenable to urgent radiotherapy. Palliative airway stenting is difficult and traditionally carried out under general anaesthesia and fluoroscopy. We have shown that self expanding Gianturco metal stents can be placed under local anaesthesia using fibreoptic bronchoscopy and direct vision for the treatment of malignant airway tumours, and report our 10 year experience. All referrals for stenting referred to our unit between 1990 and 1999 were included, looking for histological type, number and site of stents, complications of the procedure, other interventions, and survival. One hundred and sixty two patients (average age 64 years, (range 21-89)) had 307 stents inserted during 167 procedures (144 primary lung tumours, 18 secondary malignancy). There were no operative deaths, but three patients developed a pneumothorax, one requiring intercostal drain insertion. Average survival following stent insertion was less for primary lung cancer than for secondary disease (103 vs. 431 days, P<0.001). There were no excess complications in a subgroup of 64 patients treated locally by oncologists, even when stenting was the primary procedure. This technique is useful in palliating life threatening airway obstruction, particularly for secondary cancer, and can be used in any centre undertaking fibreoptic bronchoscopy.

Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis.

BACKGROUND: Increasing resistance to standard antibiotics has been demonstrated in CF patients colonised by Pseudomonas aeruginosa. The antibiotic Fosfomycin has a unique mode of action against this organism, and may protect against aminoglycoside mediated renal and ototoxic effects. However, there is little published experience of this drug in IV form, and it is not licensed for use in the UK. METHODS: In combination with other antibiotics, we used Fosfomycin to treat 30 pulmonary exacerbations in 15 adult CF patients colonised by P. aeruginosa, mainly multiresistant strains. All patients gave informed consent. We cultured sputum prior to treatment and measured spirometry, renal function, and symptoms before and after treatment, and recorded any side effects. RESULTS: One patient developed nausea and Fosfomycin treatment was withdrawn. The remaining patients showed clinical resolution of their chest exacerbations (mean FEV1% predicted: pre 41.1 vs. post 49.4, P<0.001). Although there was a statistical increase in plasma urea (pre 3.9 mmol/l vs. post 4.3, P<0.03), this was still within the normal range. Plasma creatinine was unchanged. CONCLUSIONS: This study shows that IV Fosfomycin is well tolerated by adult patients with CF and can be useful in the treatment of those colonised with multiresistant P. aeruginosa.

Prevalence and mechanisms of gastro-oesophageal reflux in adult cystic fibrosis patients.

Gastro-oesophageal reflux (GOR) occurs frequently in children with cystic fibrosis (CF) but has not been studied in adult CF. We surveyed such symptoms by structured questionnaire in 50 adult CF patients (mean age 26 years, range 16-50; 24 male) and performed oesophageal manometry and 24-hour pH recording in 10 who had reflux symptoms (mean age 28 years, range 21-35; 8 men). 47 patients (94%) had upper gastrointestinal symptoms: 40 (80%) heartburn (27 worse when supine); 26 (52%) regurgitation; and 28 (56%) dyspepsia. At oesophageal manometry, lower oesophageal sphincter barrier pressure (LOSBP) was subnormal in 6 of the 10 patients and 3 had uncoordinated peristalsis in the mid oesophagus. 8 patients had raised DeMeester scores, indicating significant GOR. Those patients with a LOSBP < 5mm Hg had a higher DeMeester score (mean 81.0, range 47.9-128.8) than the patients with a normal LOSBP (26.9, 8.7-56.5; p < 0.002). These results show that adult CF patients have high rates of GOR symptoms, diminished LOSBP, and acid reflux.

Tracheal microaspiration in adult cystic fibrosis.

Gastro-oesophageal reflux (GOR) has been implicated in the aetiology of lung disease. Cystic fibrosis (CF) patients have a high incidence of GOR symptoms with demonstrable episodes of oesophageal acidification. We studied 24-hour ambulatory tracheal and oesophageal pH in 11 CF patients with GOR symptoms to identify any episodes of tracheal acidification and define their temporal relation to oesophageal reflux and respiratory symptoms. 8 patients had evidence of significant GOR (DeMeester score mean 58; range 17-107) and in 6 it was gross (DeMeester score > 30). 4 patients had tracheal acidification (defined as tracheal pH < 5.5): all had greatly raised DeMeester scores. Two patterns of lowered tracheal pH were seen: a gradual drift downwards of tracheal pH to < 5.5 which recovered slowly, and an acute fall in tracheal pH to < 5.5 with rapid recovery. Only one patient had a fall in peak expiratory flow in conjunction with a decline in tracheal pH, and no association was found between the presence of tracheal microaspiration and pulmonary function. We conclude that tracheal acidification occurs in adult CF patients with GOR.

Targeting of dornase alpha therapy in adult cystic fibrosis.

Although dornase alpha (recombinant human DNase) can thin the viscid pulmonary secretions of cystic fibrosis (CF), clinical trials in groups of unselected patients have shown only modest average improvements in pulmonary function. The product is very expensive, so in conjunction with purchasers we designed selection criteria and a protocol for a 2-week trial to target CF individuals who might gain most benefit. Treatment was to be continued in those showing > or = 10% improvement in pulmonary function. Those who had a trial of dornase alpha were followed up for 2 years. Of 25 patients who had a 2-week trial of dornase alpha, 17 met the criteria for continuation (average gain in forced expiratory volume 37%). The 11 of these who were still alive at 2 years had a greater initial average FEV1 improvement than those who had died (45% versus 22%), and still had an average improvement of 31% at 2 years. The 8 patients who did not meet the criteria for continuation were older and had required fewer intravenous antibiotic courses. All these were alive at 2 years with unchanged clinical indices. This method of selection for dornase alpha treatment allows targeting to those who gain most benefit without disadvantaging the remaining patients. Furthermore, production of such guidelines in conjunction with purchasers obviates funding difficulties and allows rational prescribing.

Comparison of real time diagnostic chemistries to detect Pseudomonas aeruginosa in respiratory samples from cystic fibrosis patients.

BACKGROUND: Early eradication therapy is key to keeping the airways Pseudomonas aeruginosa infection-free and rapid identification is essential. METHODS: We used rapid DNA extraction and qPCR assays to detect bacterial, P. aeruginosa and strain-specific targets in samples using two qPCR chemistries. Using 459 respiratory samples from adult and children CF patients, we compared two qPCR methods to culture-based methods in terms of sensitivity and time to result. RESULTS: For adult samples, there was 100% concordance between methods. There was no clear pattern in fluctuations in P. aeruginosa number during exacerbation. In child samples, qPCR methods identified additional P. aeruginosa positive samples. The time-to-result was reduced by over 24h and copy number and colony forming unit could differ dramatically in some samples. CONCLUSION: If adopted, these methods could significantly improve early P. aeruginosa detection in diagnostic laboratories and therefore play a pivotal role in prolonging infection-free airways in CF patients.

Inhibition of neutrophil oxidant secretion by D-penicillamine: scavenging of H2O2 and HOCl.

D-Penicillamine inhibited oxidant secretion from human neutrophils after activation by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe), as assessed by luminol dependent chemiluminescence. In contrast, this drug had little effect on either intracellular oxidant production or lucigenin dependent chemiluminescence activated by the same agonist. The drug was shown to scavenge both H2O2 and HOCl in a cell free luminol chemiluminescence system, though its ability to scavenge HOCl was greater than that for H2O2. Both these oxidants could oxidise the drug, but again HOCl was more potent than H2O2. When D-penicillamine was oxidised by exposure to H2O2 it could no longer serve as a scavenger of secreted oxidants from neutrophils. These data suggest that in vivo the preferential scavenging of HOCl may be important under pathological conditions where secreted myeloperoxidase may be functional.

Chronic Burkholderia cepacia bronchiectasis in a non-cystic fibrosis individual.

Infection with Burkholderia cepacia due to social contact is well described in patients with cystic fibrosis. However, social transmission to non-cystic fibrosis individuals or chronic colonisation in non-cystic fibrosis individuals has not been described. A report of B cepacia bronchiectasis is presented where a previously healthy mother of two cystic fibrosis children colonised with B cepacia became infected by the same epidemic strain. The implications of this for parents, siblings, and partners of individuals with cystic fibrosis are discussed.

Nebulized heparin in Burkholderia cepacia colonized adult cystic fibrosis patients.

Viscous negatively charged cystic fibrosis (CF) sputum allows colonization by pathogens, inducing a chronic inflammatory response. Heparin thins sputum by decreasing the mucin molecule amino group negative charge, altering its intermolecular hydrogen bonding, and ionically shielding its polyionic moieties. It also has an anti-inflammatory effect within the lung. It may, therefore, be useful in the treatment of CF patients. In order to test this, six fully informed Burkholderia cepacia colonized stable adult CF patients, received 25,000 IU nebulized heparin sulphate daily for 7 days. Subjective sputum parameters, spirometry, platelets, coagulation parameters, and serum and sputum interleukin (IL)-6 and -8 were measured before and after treatment. All patients tolerated the heparin with no evidence of bleeding, thrombocytopenia or change in coagulation parameters. There was no change in spirometry, but a reduction in interleukins (sputum IL-6, p=0.01; sputum IL-8, p=0.002; serum IL-6, p=0.02; serum IL-8, p=0.02). Sputum was easier to expectorate (p < 0.04), with a trend towards thinner sputum (p=0.07) but no change in sputum volume. Heparin therapy was well tolerated and had an anti-inflammatory effect, with subjective sputum mucolysis. Further studies are necessary to define the role of heparin in the treatment of cystic fibrosis patients.

A large pelvic arteriovenous malformation in an adult patient with cystic fibrosis.

We present a prepubertal male cystic fibrosis patient with high circulating oestrogen levels (as a consequence of sever cystic-fibrosis-related hepatobiliary disease) who subsequently developed a large pelvic arteriovenous malformation. This has not previously been described in patients with cystic fibrosis, despite the association between high oestrogen levels and arteriovenous malformations. The aetiology and treatment options of arteriovenous malformations are discussed.

Epithelioid haemangioendothelioma.

Epithelioid haemangioendothelioma is a rare pulmonary neoplasm with less than 40 cases described world wide. We describe the only case to have presented with hypertrophic pulmonary osteoarthropathy who has been treated with azathioprine and has remained alive and well with no deterioration in pulmonary function since being diagnosed 16 years ago. The progression of the chest radiograph and spiral CT appearances of this rare neoplasm are described, and current views regarding the cellular origin of the neoplasm, its cytological appearance, clinical presentation and prognosis are discussed.