Exenatide corrects postprandial hyperglycaemia in young people with cystic fibrosis and impaired glucose tolerance: A randomized crossover trial.

Impaired glucose tolerance (IGT) in cystic fibrosis (CF) manifests as postprandial hyperglycaemia. Pancreatic enzyme supplementation reduces the latter; restoring incretin secretion and slowing gastric emptying. We aimed to determine the acute effect of exenatide on postprandial glycaemia in young people with CF and IGT. Six participants with CF and IGT were studied on 2 days, in a double-blind randomized crossover trial. After overnight fasting, they received exenatide 2.5 mcg or placebo (0.9% saline) subcutaneously 15 minutes before a pancake meal labelled with 13 C octanoate and pancreatic enzyme replacement. The primary outcomes, area under the curve over 240 minutes (AUC 240 ) for blood glucose (P < 0.0001) and peak blood glucose (7.65 mM ± 0.34 [mean ± SE] vs 9.53 mM ± 0.63, P < 0.0001), were markedly lower after exenatide than placebo. AUC240 for insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) was also lower after exenatide. Gastric emptying was markedly slower after exenatide, as assessed by time for 10% gastric emptying and peak 13 CO2 excretion. We report for the first time that exenatide corrects postprandial hyperglycaemia in young people with CF and IGT. GLP-1 agonists are a candidate treatment in CF-related diabetes.

Airway clearance by exercising in mild cystic fibrosis (ACE-CF): A feasibility study.

BACKGROUND: People with cystic fibrosis (CF) are encouraged to perform airway clearance techniques on a daily basis. Whilst several short-term studies support a potential role for exercise as an airway clearance technique, to date no medium to longer term studies have investigated the use of exercise as a stand-alone airway clearance technique. OBJECTIVE: To determine the feasibility of a protocol investigating the use of exercise as a stand-alone form of airway clearance in adults with CF. METHODS: Adults with CF and a FEV1 ≥ 70% predicted were eligible. After a four week wash-in period of daily positive expiratory pressure (PEP) and exercise, adherent participants were randomised to either daily PEP plus exercise or exercise-only for three months. Pre-specified thresholds for feasibility for the primary outcomes were rates of recruitment ≥30%, randomisation ≥80% and completion ≥80%. Secondary outcomes included respiratory function tests, respiratory exacerbation rate and health-related quality of life. RESULTS: Of the 57 eligible patients identified, 17 were recruited (30%). After the wash-in period, 13 of the 17 participants (76%) were randomised and all 13 (100%) completed the final assessment. The median (IQR) change in FEV1 (L) over the intervention period was 0.00 (-0.08 - 0.15) L for the PEP plus exercise group and -0.03 (-0.19 - 0.13) L for the exercise-only group. CONCLUSION: The study achieved its a priori target feasibility rates for recruitment and completion but failed to meet the randomisation target rate. Changes in lung function and quality of life were similar between groups. Further refinement of the protocol may be required prior to expansion to a multi-centred trial.

Accumulating physical activity in at least 10-minute bouts predicts better lung function after 3-years in adults with cystic fibrosis.

Achieving physical activity guidelines by undertaking multiple bouts of moderate-vigorous physical activity ≥10 min duration, but not shorter periods of activity, was independently associated with less decline in FEV1over 3 years among adults with CF http://ow.ly/yk6930ivCV8.

Physical activity participation by adults with cystic fibrosis: An observational study.

BACKGROUND AND OBJECTIVE: Studies in children with cystic fibrosis (CF) suggest greater physical activity (PA) is associated with a slower rate of decline in respiratory function. In adults with CF, objectively measured PA time and its relationship to long-term clinical outcomes of respiratory function and need for hospitalization are unknown. METHODS: PA measured objectively (SenseWear armband), pulmonary function, exercise capacity (Modified Shuttle Test-25) and CF-related quality of life (CFQ-R) were assessed in 65 adults (34 male; mean age 28 years) with CF during a stable phase. A sub-group of these participants undertook additional measurement of PA at hospital discharge for a respiratory exacerbation. RESULTS: Median daily habitual moderate-vigorous PA (MVPA) time was 31-min (IQR:15-53). Participants who accumulated ≥30-min MPVA daily experienced fewer hospital days (P = 0.04), better exercise capacity and higher FEV1 at 12 months (P ≤ 0.001). Daily, fewer females than males accrued ≥30-min MVPA (P = 0.02). Compared with those who did not, participants who accumulated 30-min MVPA in bouts ≥10-min (n = 21) recorded better FEV1 (P = 0.02) and exercise capacity (P = 0.006), and reduced hospital admissions (P = 0.04) and hospital days (P = 0.04) at 12 months. MVPA participation declined significantly 1 month post-hospital discharge (median 12 min (4-34); P = 0.04). CONCLUSION: Adults with CF are able to achieve recommended MVPA targets of 30mins/day; however, a significant gender difference in activity time is apparent. Greater time in MVPA is related to more positive clinical outcomes over 12 months. Whether increasing PA levels can improve clinical outcomes in adults with CF warrants further investigation. See Editorial, page 404.

Burkholderia pseudomallei in cystic fibrosis and treatment complications.

A healthy 29-year-old Australian man with cystic fibrosis (CF) grew B urkholderia pseudomallei on a routine sputum culture 1 month after returning from holiday in Thailand. He underwent a 12-month treatment regime with multiple antibiotics resulting in a number of adverse events. Sputum cultures were cleared of the pathogen and remain negative 8 years post-treatment. There were no clinical sequelae and no deterioration in lung function. Few reports have been published to date on melioidosis in CF patients. The proposed management for this infection includes multiple antibiotics regimens for prolonged periods of time, which may result in adverse events. Optimal treatment and length of treatment are currently determined on an individual basis.

Prevalence and impact of urinary incontinence in men with cystic fibrosis.

OBJECTIVES: To determine the prevalence and impact of urinary incontinence (UI) in men with cystic fibrosis (CF). DESIGN: Prospective observational study. SETTING: Adult CF clinics at tertiary referral centres. PARTICIPANTS: Men with CF (n=80) and age-matched men without lung disease (n=80). INTERVENTIONS: Validated questionnaires to identify the prevalence and impact of UI. MAIN OUTCOME MEASURES: Prevalence of UI and relationship to disease specific factors, relationship of UI with anxiety and depression. RESULTS: The prevalence of UI was higher in men with CF (15%) compared to controls (10%) (p=0.339). Men with CF and UI had higher scores for anxiety than those without UI (mean 9.1 (SD 4.8) vs 4.7 (4.1), p=0.003), with similar findings for depression (6.8 (4.6) vs 2.8 (3.4), p=0.002) using the Hospital Anxiety and Depression Scale. CONCLUSIONS: Incontinence is more prevalent in adult men with CF than age matched controls, and may have an adverse effect on mental health. The mechanisms involved are still unclear and may differ from those reported in women.

Validation of a multi-sensor armband during free-living activity in adults with cystic fibrosis.

BACKGROUND: The SenseWear Armband (SWA) provides simple and non-invasive measures of energy expenditure (EE) during physical activity, however its accuracy in adults with cystic fibrosis (CF) during free living physical activities has not been established. METHODS: 26 CF adults (mean FEV1 63% predicted; 11 males) completed a series of standardised static and active tasks with simultaneous analysis of EE via the SWA and indirect calorimetry (IC). RESULTS: Mean difference and limits of agreement between EE values from the SWA and IC across all activities were -0.02METs (95% CI -1.1 to 1.1). There was moderate agreement between the two measures (ICC 0.4; 95% CI: 0 to 0.7; p=0.03). For individual activity tasks ICC ranged from 0.1 to 0.6. CONCLUSION: Overall, the SWA demonstrated good agreement with IC for EE estimates in CF adults during a series of free-living activities, however accuracy was variable when assessing EE for specific activities of shorter duration.

Lung transplantation in patients with cystic fibrosis.

Cystic fibrosis is one of the most common indications for lung transplantation worldwide and certainly the most common indication for all pediatric lung transplants and for bilateral lung transplantation irrespective of age. Outcomes are outstanding when compared with other indications for lung transplantation, and an increasing number of centers now report mean survival of greater than 10 years posttransplant. Hence it is important to concentrate on the broad panoply of potential systemic complications of cystic fibrosis and address proactively issues that may be associated with adverse outcomes. Optimum management of infectious, nutritional, diabetic, renal, bone, and gut complications is critical to long-term success so that recipients may realize their full potential. Timing of referral for consideration of active listing should allow sufficient time for the patient and lung transplant team to develop a productive working relationship based on best available evidence and mutual trust, which will culminate in a long-term successful outcome.

Regression of pulmonary lymphangioleiomyomatosis (PLAM)-associated retroperitoneal angiomyolipoma post-lung transplantation with rapamycin treatment.

Pulmonary lymphangioleiomyomatosis (PLAM) is an indication for lung transplantation (LTx). Angiomyolipomas occur in approximately 50% to 60% of patients with PLAM. We describe a patient presenting with hemoptysis post-LTx for PLAM. Computed tomography (CT) scan demonstrated no pulmonary abnormality, but identified a retroperitoneal mass confirmed as angiomyolipoma by CT-guided core biopsy. Based on experimental work that rapamycin may inhibit angiomyolipoma cells, we commenced the patient on low-dose rapamycin. She had no adverse reactions and follow-up CT scan after 7 months demonstrated almost complete resolution of the tumor. This suggests a role for rapamycin in routine post-LTx immunosuppression for PLAM.

Successful lung transplantation for adolescents at a hospital for adults.

OBJECTIVE: To describe the results of lung transplantation (LTx) in adolescents at a hospital for adults. DESIGN AND SETTING: Prospective cohort study set in an LTx unit at an adult tertiary referral hospital from 1991 to 2006. PATIENTS: 37 consecutive adolescent lung transplant recipients including 13 males and 24 females (mean age, 16.7+/-2.0 [SD] years; range 12-19 years) who received heart-lung (six patients) or bilateral LTx (31 patients) for cystic fibrosis (29), congenital heart disease (four), acute respiratory failure (two), or another disorder (two). Two patients were transplanted after invasive ventilation, five after non-invasive ventilation and two after extracorporeal membrane oxygenation. MAIN OUTCOME MEASURES: Overall survival compared with an adult cohort; survival free of bronchiolitis obliterans syndrome (BOS); overall and BOS-free survival in those transplanted before and after January 2000. RESULTS: Mean waiting time was 273 days (range, 5-964 days; median, 163 days), mean donor age was 28 years (range, 9-53 years). Median inpatient stay was 11 days (range, 7-94 days). Mean follow-up was 1540+/-1357 days (range, 35-5163 days). The 5-year survival rate for the 16 patients transplanted before January 2000 was 38%, versus 74% for the 21 transplanted since January 2000 (P=0.05; Mantel-Cox). Overall, 18 of 35 evaluable patients developed BOS. Only BOS was associated with an increased mortality risk (P<0.01). CONCLUSION: LTx may be performed successfully in adolescents at a hospital for adults.

Cyclosporine C2 target levels and acute cellular rejection after lung transplantation.

BACKGROUND: Acute pulmonary allograft rejection (AR) is the most important risk factor for bronchiolitis obliterans syndrome (BOS), which is associated with reduced quality of life and decreased survival after lung transplantation (LTx). Trough (C0) cyclosporine (CyA) levels have a poor correlation with area-under-the-curve (AUC) measurements of cyclosporine exposure compared with 2-hour post-dose (C2) levels, but there are no published guidelines for C2 levels after LTx. Hence, we assessed the utility of C2 target levels to prevent AR. METHODS: Fifty consecutive de novo LTx patients (bilateral, 44; single, 3; heart-lung, 3; cystic fibrosis, 20; non-cystic fibrosis, 30) managed with CyA were assigned target C2 levels as follows: >800 microg/liter within 48 hours; >1,200 microg/liter from Week 1 to Month 1; >1,000 microg/liter in Month 2; >800 microg/liter in Month 3; >700 in microg/liter in Months 3 to 6; and >600 microg/liter thereafter. Surveillance transbronchial biopsies (TBBxs) were performed at 3, 6, 9 and 12 weeks. An intention-to-treat analysis was performed and results compared with our historic controls managed by C0 monitoring. RESULTS: Fifteen of 50 (30%) LTx recipients developed AR on 23 of 171 TBBxs (Grade A2:A3 = 21:2) during follow-up (mean +/- SD) of 1,185 +/- 426 days (range, 16 to 1,790 days). Eighteen of 23 AR episodes occurred after sub-target C2 levels. The 30-day, 1-, 3- and 5-year actuarial survival rates were 98%, 94%, 82% and 77%, respectively. Thirteen of 48 (27%) evaluable LTx recipients developed BOS with 1-, 3- and 5-year freedom-from-BOS rates of 96%, 79% and 59%, respectively. Only 1 patient developed severe renal dysfunction. CONCLUSIONS: Achieving and maintaining target C2 levels after LTx is associated with reduced rates of AR and BOS, preservation of renal function, and excellent short-term survival rates when compared with historic controls.

Therapeutic drug monitoring of prednisolone after lung transplantation.

BACKGROUND: Despite well-known and serious potential side-effects of corticosteroid therapy, therapeutic drug monitoring (TDM) of prednisolone is rarely performed after lung transplantation (LTx). METHODS: We measured prednisolone exposure using a 6-hour area-under-the-curve (AUC) analysis in 52 LTx recipients (41 bilateral, 9 single and 2 heart-lung), who were 99 +/- 13 (mean +/- SEM) weeks (range 4 to 380) post-LTx. Fourteen of 52 had cystic fibrosis (CF), and 36 of 52 were on cyclosporine and 16 of 52 on tacrolimus. Prednisolone dose was 9.8 +/- 0.7 mg/day (range 1 to 20). RESULTS: Only 9 of 52 LTx patients had a prednisolone AUC within the previously reported reference range for healthy adult control subjects (170 to 260 nmol x hr/liter/milligram prednisolone). Six patients had values below and 37 above this range. Prednisolone AUC was higher in patients with CF compared with non-CF patients (511 +/- 82 vs 349 +/- 27 nmol x hr/liter/milligram, p < 0.02) and 70% of LTx recipients had measurable prednisolone levels at baseline (26.5 +/- 4.5 nmol/liter), unlike normal controls. CONCLUSIONS: LTx recipients show a wide inter-individual variation in prednisolone pharmacokinetics; therefore, many are overdosed on conventional protocols. Side-effects of corticosteroid therapy remain a major clinical problem after transplantation, justifying the use of prednisolone TDM to optimize dosing and minimize morbidity.

Intravenous ribavirin is a safe and cost-effective treatment for respiratory syncytial virus infection after lung transplantation.

BACKGROUND: Community-acquired viral infections, such as respiratory syncytial virus (RSV), represent a risk factor for bronchiolitis obliterans syndrome (BOS), the major limiting factor for long-term survival after lung transplantation (LTx). RSV often presents with acute bronchiolitis and may be fatal in 10% to 20% of patients. Standard therapies for RSV include nebulized ribavirin with or without steroids, but are costly and inconvenient. We investigated the utility of intravenous (IV) ribavirin with steroids for the treatment of RSV infection after LTx. METHODS: RSV was identified in nasopharyngeal and throat swabs (NPS) using indirect fluorescent antibody (IFA) testing in 18 symptomatic patients, which was confirmed by viral culture in 14. Data were collected for the period between April 2002 and October 2004. The study included 10 men and 8 women, mean age 42 +/- 15 (range 18 to 63) years. Transplant procedures were 5 single LTx and 13 bilateral LTx. RSV diagnosis was made on Day 1,374 +/- 1,270 (range 61 to 4,598, median 935) post-operatively. Underlying diagnoses included cystic fibrosis (n = 9), emphysema (n = 7) and pulmonary fibrosis (n = 2). All 18 patients received intravenous (IV) ribavirin (33 mg/kg on Day 1 and 20 mg/kg/day thereafter in 3 divided doses) with oral prednisolone (1 mg/kg) until repeat NPS were negative for RSV on IFA. Median therapy was 8 days (6 to 15). RESULTS: The mortality rate was 0%. Mean FEV1 fell from 2.1 +/- 1.0 liter (0.7 to 3.7 liters) to 1.8 +/- 0.9 liter (0.5 to 3.6 liters) (p < 0.001), but recovered to 2.1 +/- 0.9 (0.7 to 3.7 liters) within 3 months and was maintained at follow-up of 521 +/- 328 days (141 to 1,023 days, median 302). Only 1 patient developed bronchiolitis obliterans syndrome (BOS). Complications included mild hemolytic anemia (blood hemoglobin fell from 122 +/- 22 [84 to 154] g/liter to 107 +/- 18 [75 to 138] g/liter, p = 0.02). Cost savings per 8-day course were $US15,913 when compared with nebulized therapy at 6 g/day (p < 0.001). CONCLUSIONS: This is the largest reported series of treated RSV cases after LTx and the first to show that therapy with IV ribavirin and oral corticosteroids is well tolerated and effective. Cost utility vs nebulized therapy has been established. Early diagnosis and management are essential to prevent airway epithelial injury and subsequent BOS.

Cyclosporine C2 monitoring improves renal dysfunction after lung transplantation.

BACKGROUND: Cyclosporine (CyA) toxicity is a potential cause of renal dysfunction, which occurs in 38% of lung transplant (LTx) recipients within 5 years. Reducing CyA to "sub-therapeutic" trough (C0) levels increases the risk of rejection. The 2-hour post-dose concentration (C2) is favored as the best single-point surrogate measure of CyA area under the curve (AUC), which reflects drug exposure. In this investigation we assess the effect of conversion to CyA C2 monitoring on renal dysfunction after LTx. METHODS: Fifteen patients (M:F = 12:3), aged 47 +/- 14 years (range 28 to 62), 3.5 +/- 2.7 (0.2 to 9.0) years post-LTx, with C0 in the therapeutic range (maintenance 100 to 200 microg/liters) (Behring/EMIT immunoassay) and abnormal renal function, were converted from C0 monitoring to C2 monitoring with dose reductions targeting C2 levels of 300 to 600 microg/liter over a 12-month period. RESULTS: CyA dose was reduced from 6.4 +/- 7.3 (1.2 to 27.9) to 3.1 +/- 2.7 (0.8 to 9.0) mg/kg/day (p = 0.04), with a reduction in C2 levels from 799 +/- 341 (299 to 1,466) to 390 +/- 148 (195 to 675) microg/liter (p < 0.001). Improvements in serum creatinine (0.20 +/- 0.07 [0.12 to 0.35] vs 0.16 +/- 0.04 [0.11 to 0.22] mmol/liter [p = 0.005]) were maintained during the study follow-up period of 1 year. Only 1 patient developed acute rejection and group mean forced expiratory volume in 1 second (FEV(1)) remained stable (2.4 +/- 1.0 [1.1 to 4.0] vs 2.4 +/- 1.2 [1.1 to 4.6] liters). CONCLUSIONS: C2 monitoring is a practical method of improving renal dysfunction that allows safe dose reductions of CyA when formal AUC monitoring is not feasible. Extended use of this strategy is associated with long-term benefits.

Enhanced clinical utility of de novo cyclosporine C2 monitoring after lung transplantation.

BACKGROUND: The 2-hour post-cyclosporine (CyA) dose concentration (C2) is favored as the best single-point correlate of CyA area-under-the-concentration curve. CyA nephrotoxicity is a prominent cause of renal dysfunction that affects 38% of lung transplant (LTx) recipients at 5 years. METHODS: We assessed the utility of de novo C2 monitoring after LTx by comparing 2 sequential groups of 18 bilateral LTx recipients followed with traditional de novo trough CyA (C0) monitoring and de novo C2 monitoring, respectively. Target C0 levels were 450 microg/liter and 250 microg/liter at 1 week and 3 months (3/12). Target C2 levels were 1,200 microg/liter and 800 microg/liter. Groups were matched for anthropometrics and diagnoses. Baseline serum creatinine (Cr) was lower in the C0 group than in the C2 group (65 +/- 17 vs 81 +/- 21 micromol/liter, p = 0.02). RESULTS: At 3 months, survival for both groups was 100%, but the C0 group had a greater increase in Cr from baseline (90 +/- 54% vs 33 +/- 23%, p < 0.001) despite similar CyA dosage (6.6 +/- 3.8 vs 6.5 +/- 2.9 mg/kg/day, p = 0.94). There was no difference in forced expiratory volume in 1 second (% predicted) (71 +/- 16 vs 69 +/- 14, p = 0.68), mean acute vascular rejection score per patient (2.61 +/- 2.12 vs 1.44 +/- 1.72, p = 0.079), mean bronchial rejection score per patient (3.72 +/- 1.81 vs 2.83 +/- 1.58, p = 0.126) or rate of infection (1.85 vs 1.79 events per 100 patient-days). CONCLUSIONS: De novo C2 monitoring, which reduces both the risk of CyA toxicity and the risk of sub-therapeutic dosing, is a safe and effective technique for short-term preservation of renal function after LTx.

Impaired muscle Ca2+ and K+ regulation contribute to poor exercise performance post-lung transplantation.

Lung transplant recipients (LTx) exhibit marked peripheral limitations to exercise. We investigated whether skeletal muscle Ca2+ and K+ regulation might be abnormal in eight LTx and eight healthy controls. Peak oxygen consumption and arterialized venous plasma [K+] (where brackets denote concentration) were measured during incremental exercise. Vastus lateralis muscle was biopsied at rest and analyzed for sarcoplasmic reticulum Ca2+ release, Ca2+ uptake, and Ca2+-ATPase activity rates; fiber composition; Na+-K+-ATPase (K+-stimulated 3-O-methylfluorescein phosphatase) activity and content ([3H]ouabain binding sites); as well as for [H+] and H+-buffering capacity. Peak oxygen consumption was 47% less in LTx (P < 0.05). LTx had lower Ca2+ release (34%), Ca2+ uptake (31%), and Ca2+-ATPase activity (25%) than controls (P < 0.05), despite their higher type II fiber proportion (LTx, 75.0 +/- 5.8%; controls, 43.5 +/- 2.1%). Muscle [H+] was elevated in LTx (P < 0.01), but buffering capacity was similar to controls. Muscle 3-O-methylfluorescein phosphatase activity was 31% higher in LTx (P < 0.05), but [3H]ouabain binding content did not differ significantly. However, during exercise, the rise in plasma [K+]-to-work ratio was 2.6-fold greater in LTx (P < 0.05), indicating impaired K+ regulation. Thus grossly subnormal muscle calcium regulation, with impaired potassium regulation, may contribute to poor muscular performance in LTx.