H.C. Barker

Osteoclast function, bone turnover and inflammatory cytokines during infective exacerbations of cystic fibrosis

BACKGROUND Raised levels of pro-inflammatory, pro-resorptive cytokines during pulmonary infection may contribute to osteoporosis in cystic fibrosis (CF). We assessed osteoclast number and activity during infective exacerbations and examined their relationship to serum inflammatory cytokines and bone turnover markers. METHODS Serum samples from 24 adults with CF were obtained before, during and after treatment of infection. Osteoclastic cells were generated from peripheral blood mononuclear cells and their number and activity assessed. Serum osteocalcin, type 1 collagen cross-linked N-telopeptide (NTx), interleukin-6 (IL-6), tumour necrosis factor alpha (TNFalpha), receptor activator of NFkB ligand (RANKL) and osteoprotegerin (OPG) were measured. RESULTS Osteoclast number and activity were increased at the start of exacerbation and decreased with antibiotic therapy. Significant correlations were demonstrated between osteoclast formation and serum TNFalpha, OPG, osteocalcin and NTx and between osteoclast activity and serum IL-6 and NTx. CONCLUSIONS The systemic response to infection is associated with increased bone resorptive activity in patients with CF.

Cystic fibrosis neutrophils have normal intrinsic reactive oxygen species generation

Previous studies have identified abnormalities in the oxidative responses of the neutrophil in cystic fibrosis (CF), but it is unclear whether such changes relate to loss of membrane cystic fibrosis transmembrane conductance regulator (CFTR) or to the inflammatory environment present in this disease. The aim of the present study was to determine whether neutrophils from CF patients demonstrate an intrinsic abnormality of the respiratory burst. The respiratory burst activity of neutrophils isolated from stable ΔF508 homozygote CF patients and matched healthy controls was quantified by both chemiluminscence and cytochrome C reduction. Expression of NADPH oxidase components and CFTR was determined by Western blotting and RT-PCR. The oxidative output from neutrophils from CF in response to receptor-linked and particulate stimuli did not differ from that of controls. Expression of NADPH oxidase components was identical in CF and non-CF neutrophils. While low levels of CFTR mRNA could be identified in the normal human neutrophil, we were unable to detect CFTR protein in human neutrophil lysates or immunoprecipitates. CFTR has no role in controlling neutrophil oxidative activity; previously reported differences in neutrophil function between CF and non-CF subjects most likely relate to the inflammatory milieu from which the cells were isolated.

Multicentre trial of weekly risedronate on bone density in adults with cystic fibrosis

BACKGROUND The aim of this study was to assess the efficacy, tolerability and safety of risedronate in adults with CF. METHODS Patients with a lumbar spine (LS), total hip (TH) or femoral neck (FN) bone mineral density (BMD) Z-score of -1 or less were randomised to receive risedronate 35 mg weekly or placebo, and calcium (1g)+vitamin D(3) (800IU). RESULTS At baseline, BMD Z-scores in the risedronate (n=17) and placebo (n=19) groups were similar. By 24 months, 7/17 risedronate patients vs 0/19 placebo patients stopped the study medication due to bone pain. After 24 months treatment, the mean difference (95% CI) in change in LS, TH and FN BMD between the risedronate vs placebo groups was 4.3% (0.4, 8.2) p=0.03; 4.0% (-0.5, 8.6) p=0.08; and 2.4% (-3.5, 8.2) p=0.41. CONCLUSIONS After two years treatment there was a significant increase in LS BMD with weekly risedronate compared to placebo.

Clostridium difficile pancolitis in adults with cystic fibrosis

We report three cases of Clostridium difficile pancolitis in adults with cystic fibrosis (CF) in whom the presenting symptoms were atypical. All three required treatment with systemic steroids, in addition to oral vancomycin and metronidazole to achieve resolution of the colitis. This experience suggests that C. difficile colitis should be considered in individuals with CF presenting with non-specific abdominal symptoms.

Multicentre randomised double blind placebo controlled trial assessing the effect of weekly risedronate on bone mineral density in adults with cystic fibrosis

328* Multicentre randomised double blind placebo controlled trial assessing the effect of weekly risedronate on bone mineral density in adults with cystic fibrosis C.S. Haworth1, L. Sharples2, V. Hughes3, S.L. Elkin4, M.E. Hodson5, S.P. Conway6, C. Etherington6, J.S. Elborn7, J. Rendall7, E. Wheaton2, E. Kadri8, J. Elliott1, H.C. Barker1, J. Compston9. 1Papworth Hospital, Adult Cystic Fibrosis Centre, Cambridge, United Kingdom; 2Institute of Public Health, MRC Biostatistics Unit, Cambridge, United Kingdom; 3Papworth Hospital, Research and Development, Cambridge, United Kingdom; 4St Mary’s Hospital, Respiratory Medicine, London, United Kingdom; 5Royal Brompton Hospital, Department of Cystic Fibrosis, London, United Kingdom; 6St James’s University Hospital, Cystic Fibrosis Centre, Leeds, United Kingdom; 7Belfast City Hospital, Adult Cystic Fibrosis Centre, Belfast, United Kingdom; 8Papworth Hospital, Pharmacy, Cambridge, United Kingdom; 9University of Cambridge, Department of Medicine, Cambridge, United Kingdom

Quality of life & clinical outcomes following referral to a specialist bronchiectasis service

It is currently unclear whether referral of patients with bronchiectasis to a specialist centre improves quality of life (QoL) or clinical outcomes. We therefore evaluated these outcomes in consecutive new patients referred to our service in 2010. St Georges Respiratory Questionnaires (SGRQ) were completed at their initial consultation and 12 months later. Clinical data were retrospectively collected from patient records. Of the 89 new patients, 44 (49%) completed both QoL assessments. Their mean age was 62.2±16 y and 21/44 were male. In the 12 months following referral, 27% (12) patients cultured P. aeruginosa , 25% (11) grew H. influenzae , 18% (8) S. pneumoniae , 11% (5) M. catarrhalis and 5% (2) NTM. 55% (24) patients grew no organism. There was no significant change in FEV1, however the average (median; IQR) number of infective exacerbations requiring antibiotics decreased from 5.0 (3–6) in the 12 months preceding referral to 1.0 (0 – 2) in the 12 months following initial assessment (p=0.0001). Analysis of SGRQ (where lower scores reflect a better QoL) at the beginning and end of the same period revealed significant decreases in overall scores from 44.0 (25.9-64.0) vs 36.8 (21.7-76.6; p=0.02), symptom scores from 61.4 (36.9-80.1) to 47.7 (26.3–70.3; p <0.003) and impact scores from 35.2 (19.9-54.0) to 28.4 (13.7–50.0; p=0.032). A common change to patient management was the prescription of long-term antibiotic prophylaxis which increased from 13.6% (6/44) patients at baseline to 50% (22/44) at follow up. We conclude that referral of patients to our specialist bronchiectasis service leads to significant improvements in quality of life and decreased infective exacerbations.

319 Nebulised temocillin for prophylaxis against Burkholderia vietnamiensis in an adult with cystic fibrosis

Objectives To illustrate the use of nebulised temocillin for prophylaxis in CF and chronic Burkholderia infection in a 29-year-old male. Methods Retrospective data collection from medical notes, included spirometry, CRP, frequency of IV antibiotics (14-day courses), and symptomatology. Data was collected for pre and post temocillin periods. Results Baseline spirometry: FEV1 66% pred., FVC 89% pred. Between ages 23 and 27 years, he had 2 courses of IV antibiotics yearly for exacerbations. FEV1 fell to a minimum of 55% pred., and CRP ( 100 on 3 occasions), and worsened spirometry (minimum FEV1 37% pred. and FVC 40% pred.). Worsening symptoms were recorded. Following onset of nebulised temocillin alternate months (7 months), frequency of IV antibiotics decreased to 4 courses (3 courses whilst off temocillin). Maximum CRP 42, and minimum FEV1 50% pred., significant symptom improvement was reported. Continuous nebulised temocillin was then started. No IV antibiotics were given in the following 4-month period. Conclusion Temocillin is a narrow spectrum penicillin stable to most β-lactamases and ESBLs. It demonstrates in vitro activity against B. cepacia . It does not induce β-lactamase production. Clinical data suggests benefit of IV temocillin for CF patients with B. cepacia . This case illustrates that temocillin may be a well tolerated and effective nebulised antibiotic for CF patients with Burkholderia .

162 Bronchial artery embolization (BAE) in adults with cystic fibrosis: a single-centre case series

Over the past last few decades, cystic fibrosis (CF) has changed from a disease of childhood into a disease of adults. When a chronic infection of the lungs occurs, eradication of the pathogens is almost impossible. In the Institute for Pulmonary Diseases of Vojvodina, we have started the treatment of adult patients with cystic fibrosis in the year of 2010. The aim of the study is to examine the patterns of antimicrobial susceptibility of the pathogens isolated from adult patients with cystic fibosis due to a rational use of antimicrobial therapy. The results are shown for the first six adult patients with cystic fibrosis treated in the Institute, 5 females and 1 male, at the average age of 24.8 years. The following microorganisms were isolated from sputum samples: Pseudomonas aeruginosa 15 (45.5%), Pseudomonas species 11 (33.3%), Escherichia coli 5 (15.2%), Klebsiella pneumoniae 1 (3%), Staphylococcus aureus 1 (3%). The isolated microorganisms showed high susceptibility rates to piperacillin–tazobactam (85.7%) meropenem (81.8%), imipenem (78.8%), cefepime (81.8%), ceftazidime (78.8%), ceftriaxone (72.2%). Susceptibility to ciprofloxacin was 68.7%, and to gentamicin 59.4%. Besides high susceptibility rates to carbapenems, similarly high susceptibility rates of the isolated microorganisms were registered to the third and fourth generation of cephalosporins. The goal of monitoring the resistance of pathogens isolated from the patients with cystic fibrosis and the rational use of antimicrobial therapy is to reduce the number of microorganisms and to maintain the patients’ pulmonary function and decrease an irreversible damage of the pulmonary parenchyma.