Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.

Sexual and reproductive health in men with cystic fibrosis: consistent preferences, inconsistent practices.

BACKGROUND: Sexual and reproductive health (SRH) is increasingly relevant for men with CF. However, the extent of similarities or differences in SRH clinical practices across different centres or states is unknown as single clinic studies are not informative about variations in male preferences or clinical practices. We wished to determine the variability of male SRH knowledge and preferences, and clinical practices across different CF clinics. METHODS: Men attending 5 adult CF clinics in Australasia completed a survey of SRH knowledge, attitudes and behaviours. RESULTS: 264 (64%) men participated, with a median age of 30 years (17-56). 65% knew of near universal infertility due to a transport problem. 43% heard about infertility from their preferred source, but significantly later than desired. Less than half had undergone semen analysis (SA), which, while varying by site, was consistently later than preferred. 57 men were fathers, of whom 29 had utilised ART. CONCLUSION: Men's preferences around SRH were more consistent than clinical practices. Clinical practice guidelines and training for health professionals would help reduce the gap between men's SRH preferences and clinical practice.

Predictors of pulmonary exacerbations in patients with cystic fibrosis infected with multi-resistant bacteria.

BACKGROUND: This study examined characteristics of adult and adolescent patients with cystic fibrosis (CF) to determine factors associated with an increased risk of pulmonary exacerbations. METHODS: 249 patients with CF infected with multidrug resistant bacteria were recruited and prospectively followed for up to 4.5 years until they experienced a pulmonary exacerbation severe enough to require intravenous antibiotics. Multivariable regression analyses were used to compare the characteristics of patients who experienced an exacerbation with those who did not. RESULTS: 124 of the 249 patients (50%) developed a pulmonary exacerbation during the first year and 154 (62%) experienced an exacerbation during the 4.5 year study period. Factors predictive of exacerbations in a multivariable survival model were younger age (OR 0.98, 95% CI 0.96 to 0.99), female sex (OR 1.45, 95% CI 1.07 to 1.95), lower forced expiratory volume in 1 second (FEV(1)) (OR 0.98, 95% CI 0.97 to 0.99), and a previous history of multiple pulmonary exacerbations (OR 3.16, 95% CI 1.93 to 5.17). Chronic use of inhaled corticosteroids was associated with an increased risk of exacerbation (OR 1.92, 95% CI 1.00 to 3.71) during the first study year. CONCLUSIONS: Patients who experience pulmonary exacerbations are more likely to be younger, female, using inhaled steroids, have a lower FEV(1), and a history of multiple previous exacerbations. It is hoped that knowledge of these risk factors will allow better identification and closer monitoring of patients who are at high risk of exacerbations.

Effect of airway clearance techniques on the efficacy of the sputum induction procedure.

Sputum induction is used in the early identification of tuberculosis (TB) and pneumocystis infections of the lung. Although manual physiotherapy techniques to clear the airways are often incorporated in the sputum induction procedure, their efficacy in this setting is unknown. This randomised, crossover trial enrolled adults referred for sputum induction for suspected TB and pneumocystis infections of the lung. All participants underwent two sputum induction procedures, inhaling 3% saline via ultrasonic nebuliser. During one randomly allocated procedure, airway clearance techniques (chest wall percussion, vibration, huffing) were incorporated. In total, 59 participants completed the trial. The airway clearance techniques had no significant effect on how the test was tolerated, the volume expectorated or the quality of the sample obtained (assessed by the presence of alveolar macrophages). The techniques did not significantly affect how often the test identified a suspected organism, nor the sensitivity or specificity of sputum induction. In conclusion, the study was unable to demonstrate any effect of airway clearance techniques on the sputum induction procedure. The results provide some justification for not including airway clearance techniques as part of the sputum induction procedure.

Supported and unsupported arm exercise capacity following lung volume reduction surgery: a pilot study.

STUDY OBJECTIVES: Lung volume reduction surgery (LVRS) has been shown to improve lung function, leg exercise capacity and quality of life in subjects with severe COPD. This is the first study to examine the effect of LVRS on supported and unsupported arm exercise capacity. DESIGN: Eight subjects with COPD (% pred FEV1 +/- SD = 31.1 +/- 9.8%) completed testing. At baseline (T1), after eight weeks pulmonary rehabilitation (T2) and four months after LVRS (T3), each subject had tests of lung function, and performed three symptom-limited exercise tests to peak work capacity: supported arm exercise (SAE), unsupported arm exercise (UAE) and leg exercise (LE). MEASUREMENTS: The FEV1 (% pred) increased from 27.8 +/- 7.4 (mean +/- SD) at T2 to 36.3 +/- 7.1 at T3 (P < 0.05). Peak oxygen consumption (VO2) remained similar from T1 to T2 for SAE, UAE and LE (all P = 1.0) but increased from T2 to T3 (P < 0.05) (SAE: T2 = 0.59 +/- 0.2 L/min, T3 = 0.72 +/- 0.1 L/min; UAE: T2 = 0.45 +/- 0.1 L/min, T3 = 0.54 +/- 0.1 L/min; LE: T2 = 0.68 +/- 0.2 L/min, T3 = 0.81 +/- 0.2 L/min). The ratio of end-expiratory lung volume to total lung capacity was reduced at peak SAE and LE from T2 to T3 (P < 0.01) (SAE: T2 = 81 +/- 4.0%, T3 = 76 +/- 2.7%; LE: T2 = 81 +/- 5.1%, T3 = 75 +/- 3.6%). CONCLUSION: There was a significant increase in SAE and UAE capacity following LVRS. Dynamic hyperinflation was reduced during SAE following LVRS.

Method for detection of respiratory viruses in the sputa of patients with cystic fibrosis.

Since the role of respiratory viruses in lung exacerbations of patients with cystic fibrosis has been hampered by the difficulty of detecting viruses in viscous sputum specimens, a multiplex reverse transcriptase PCR (RT-PCR) assay combined with colorimetric amplicon detection was tested for the identification of seven common respiratory viruses in the sputa of cystic fibrosis patients. Of 52 sputa from 38 patients, 12 (23%) samples from 12 patients were positive for a respiratory virus (4 for influenza B, 3 for parainfluenza 1, 3 for influenza A and 2 for respiratory syncytial virus). These results suggest that the RT-PCR method carried out on sputum may provide a convenient means of investigating the role of virus infection in lung exacerbations of cystic fibrosis patients.

The impact of pan-resistant bacterial pathogens on survival after lung transplantation in cystic fibrosis: results from a single large referral centre.

Reported actuarial one-year survival for patients with cystic fibrosis (CF) after lung transplant is 55-91%. Infection is the most common cause of early death. Colonization with Burkholderia cepacia complex is associated with reduced survival and international lung transplant referral guidelines support individual unit assessment policies for patients colonized with other pan-resistant bacteria. We examined local data on survival after transplant for CF to determine the impact of colonization with pan-resistant bacteria. A retrospective review of all CF patients from Royal Prince Alfred Hospital (RPAH), Sydney, who underwent lung transplantation at St Vincent's Hospital, Sydney, 1989-2002, was performed. Sixty-five patients were listed for lung transplantation with 54 (male: female=29:25) receiving transplants. Of the 11 patients (17%) who died on the waiting list, six were colonized with pan-resistant Pseudomonas aeruginosa. Thirty of the 54 transplanted patients had at least one pan-resistant organism before transplant. In 28 this included P. aeruginosa. Overall one-year survival was 92% with a median survival of 67 months. Overall survival for the pan-resistant group (N = 30) was not significantly different to survival in those with sensitive organisms (N = 24) (Logrank chi square = 1.6, P = 0.2). Three patients colonized with B. cepacia complex pre-transplant survive at 11, 40 and 60 months post-transplant. Infection contributed to 11 of the 18 post-transplant deaths, with pre-transplant-acquired bacterial pathogens responsible in two cases. Patients continued to acquire multiresistant bacteria post-transplantation. Lung transplant survival at St Vincent's Hospital for CF adults from RPAH compares favourably with international benchmarks. Importantly, colonization with pan-resistant bacteria pre-transplant did not appear to adversely affect survival post-transplant.

Reduction in resting energy expenditure following lung volume reduction surgery in subjects with chronic obstructive pulmonary disease.

STUDY OBJECTIVES: Some subjects with COPD have an elevated resting energy expenditure (REE) which may be related to an increased work of breathing at rest. The purpose of this study was to examine the effect of lung volume reduction surgery (LVRS) on REE and body weight. DESIGN: Ten subjects with COPD were recruited (mean age +/- SD = 61.4 +/- 6.1 years). At baseline (which was following preoperative pulmonary rehabilitation) and four months following LVRS (combined with postoperative pulmonary rehabilitation), each subject had tests of lung function, REE via indirect calorimetry using a canopy system, six minute walk distance (6MWD) and quality of life (QoL) using the St George's Hospital Respiratory Questionnaire (SGRQ). MEASUREMENTS: The FEV1 (% predicted) increased from 27.7 +/- 5.8% (mean +/- SD) at baseline to 33.9 +/- 7.8% following LVRS (P < 0.05). REE (% predicted) was 110 +/- 9.8% at baseline and decreased to 106 +/- 6.7% following LVRS (P = 0.04). Body mass index (BMI) following LVRS was unchanged (P = 0.67). No correlation between the change in BMI and change in REE was shown (r2 = 0.3, P = 0.1). There was a significant improvement in QoL following LVRS (P < 0.001). 6MWD also significantly increased from 354 +/- 83 m to 412 +/- 82 m following LVRS (P = 0.001). CONCLUSION: Whilst there was an increase in lung function and a reduction in REE following LVRS, there was no corresponding change to body weight. The improvement in REE following LVRS may be related to an improvement in work of breathing.

Adults with cystic fibrosis: meeting the challenge!

The number of adults with cystic fibrosis (CF) is increasing. They are striving for independence and a fulfilling life with focus on career, relationships, education and finances at a time when lung function is likely to be declining and complications of this multi-system disease are increasing. Maintaining the quality and improving the duration of life are continuing challenges for the -clinician and the patient. Increased hope and greater expectations have been provided by a number of recent clinical advances and active research into novel treatments, including gene therapy. There has been increased recognition of the necessity for early diagnosis, adequate monitoring and effective intervention for complications such as diabetes and osteoporosis. Research into multi-resistant bacteria and clonal strains of Pseudomonas aeruginosa is ongoing and attention has focused on infection control policies. Although more high-level evidence is required on many issues confronting people with CF, a considerable effort has been made over the last decade to provide a more evidence-based approach to therapy with a number of large controlled clinical trials. For the adult with CF, there are also more decisions to be made. There is focus on reproductive health, with most couples enjoying the real possibility of having children. For those with advanced disease, the option for lung transplantation is well established. Maintenance of quality care will require adequate planning, effective transition programmes from paediatric to adult care, specialized training for doctors, nurses and allied health professionals and the allocation of sufficient resources to accommodate the inevitable increase in patient numbers.

Osmotic stimuli increase clearance of mucus in patients with mucociliary dysfunction.

Mucociliary dysfunction results in mucus accumulation, airway obstruction, bacterial colonization, recurrent infective exacerbations, and an increase in morbidity and mortality. Studies in patients with cystic fibrosis, established that inhalation of hypertonic saline (HS) increases clearance of mucus acutely in a dose-dependent manner. Clearance over 90 min was 23.8 +/- 4.0% and 26.0 +/- 3.1% in response to 7% and 12% saline, which was significantly enhanced compared to 12.7 +/- 1.4% and 19.7 +/- 3.1% in response to 0.9% and 3% saline. Mannitol (approximately 300 mg) inhaled as a dry powder had a marked acute effect in patients with bronchiectasis. Clearance over 75 min was 34.0 +/- 5.0% with mannitol, 17.4 +/- 3.8% with control, and 11.7 +/- 4.4% at baseline. Further studies in patients with bronchiectasis showed that mannitol reduces the 24-h retention of radiolabeled mucus, suggesting that the effect of mannitol extends beyond the acute phase. Mannitol helped patients to clear mucus within 2 h that would have taken 24 h to clear without mannitol. A further study in CF patients showed that mannitol was equally effective as 6% HS at improving ciliary and cough clearance. The total clearance over 120 min with mannitol (27.6 +/- 3.7%) and with HS (31.0 +/- 5.5%) was significantly increased compared to their respective controls (18.6 +/- 3.8% and 20.9 +/- 3.6%). These preliminary results suggest that long-term treatment with HS or mannitol may benefit patients with mucociliary dysfunction.

Predicting sleep-disordered breathing in patients with cystic fibrosis.

STUDY OBJECTIVES: To examine predictors of sleep-disordered breathing in patients with cystic fibrosis (CF) and moderate-to-severe lung disease using a comprehensive evaluation of both sleep and daytime function. DESIGN: Cross-sectional analysis of sleep studies, lung function, respiratory muscle strength, and evening and morning arterial blood gas measurements in patients with stable CF. A questionnaire addressing sleep quality was administered. Forward stepwise regression analysis was used to identify the parameters that best predict sleep-related desaturation, hypercapnia, and respiratory disturbance. SETTING: Sleep investigation unit and lung function laboratory. PATIENTS: Thirty-two patients with CF and FEV(1) < 65% predicted, in stable clinical condition. Patients were aged 27 +/- 8 years (mean +/- 1 SD) with FEV(1) of 36 +/- 10% predicted, evening PaO(2) of 68 +/- 8 mm Hg, and PaCO(2) of 43 +/- 5 mm Hg. RESULTS: Evening PaO(2) (p < 0.0001) and morning PaCO(2) (p < 0.01) were predictive of the average minimum oxyhemoglobin saturation per 30-s epoch of sleep (r(2) = 0.74; p < 0.0001). Evening PaO(2) (p < 0.001) was predictive of the rise in transcutaneous carbon dioxide (TcCO(2)) seen from non-rapid eye movement (NREM) to rapid eye movement (REM) sleep (r(2) = 0.37; p < 0.001). In addition, there was some relationship between expiratory respiratory muscle strength and the REM respiratory disturbance index (r(2) = 0.22; p < 0.01). CONCLUSION: Evening PaO(2) was found to contribute significantly to the ability to predict both sleep-related desaturation and the rise in TcCO(2) from NREM sleep to REM sleep in this subgroup of patients with CF.

Low-flow oxygen and bilevel ventilatory support: effects on ventilation during sleep in cystic fibrosis.

We measured ventilation in all sleep stages in patients with cystic fibrosis (CF) and moderate to severe lung disease, and compared the effects of low-flow oxygen (LFO2) and bilevel ventilatory support (BVS) on ventilation and gas exchange during sleep. Thirteen subjects, age 26 +/- 5.9 yr (mean +/- 1 SD), body mass index (BMI) 20 +/- 3 kg/m2, FEV1 32 +/- 11% predicted, underwent three sleep studies breathing, in random order, room air (RA), LFO2, and BVS +/- O2 with recording of oxyhemoglobin saturation (SpO2) (%) and transcutaneous carbon dioxide (TcCO2) (mm Hg). During RA and LFO2 studies, patients wore a nasal mask with a baseline continuous positive airway pressure (CPAP) of 4 to 5 cm H2O. Minute ventilation (V I) was measured using a pneumotachograph in the circuit and was not different between wake and non-rapid eye movement (NREM) sleep on any night. However, V I was reduced on the RA and LFO2 nights from awake to rapid eye movement (REM) (p < 0.01) and from NREM to REM (p < 0.01). On the BVS night there was no significant difference in V I between NREM and REM sleep. Both BVS and LFO2 improved nocturnal SpO2, especially during REM sleep (p < 0.05). The rise in TcCO2 seen with REM sleep with both RA and LFO2 was attenuated with BVS (p < 0.05). We conclude that BVS leads to improvements in alveolar ventilation during sleep in this patient group.

Regional mucociliary clearance in patients with cystic fibrosis.

This paper reports on a large retrospective analysis of mucociliary clearance (MCC) studies in a group of 59 patients with cystic fibrosis (CF) and 17 age-matched healthy subjects. As many of the CF patients were studied on multiple occasions, a total of 184 patient studies are presented. MCC was measured using a radioaerosol and gamma camera technique. In addition to whole lung clearance, MCC was measured from the central, intermediate, peripheral, basal, mid and apical regions of the lung. MCC was markedly decreased in the CF patient group. Not only was whole lung clearance (14.2 +/- 1.4% vs. 28.0 +/- 3.7%) impaired, but also clearance from the central (19.1 +/- 1.9% vs. 35.6 +/- 4.3%), intermediate (10.7 +/- 1.6% vs. 25.5 +/- 3.7%), apical (12.4 +/- 2.6% vs. 31.6 +/- 4.6%) and mid (14.0 +/- 1.9% vs. 30.4 +/- 4.0%) regions. Attempts were made to identify factors that may have influenced MCC in both the normal subjects and CF patients. Age, gender, body mass index, patient genotype, penetration index, spontaneous cough, and various lung function parameters were entered into a stepwise multiple regression model, but none of the factors proved to be statistically important in determining MCC. Both intrasubject repeatability and intersubject variability estimates are presented for the patients and normal subjects that had multiple studies. The values were found to be remarkably similar for both CF patients and normal subjects and for both intra- and intersubject repeatability. With marked deviation from normal ranges and good repeatability, the measurement of MCC in CF patients would seem to be a valuable outcome measure for clinical trials involving new pharmaceuticals and physical therapy designed to improve removal of secretions from the airways.

Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis.

The aim of the study was to measure the effect of a short course of recombinant human deoxyribonuclease I (rhDNase) on ciliary and cough clearance in a group of cystic fibrosis patients, using a radioaerosol and gamma camera technique. Patients were initially randomized to receive either rhDNase (2.5 mg qd) or placebo. Following the measurement of baseline clearance, patients were given a 7-day course of either rhDNase or placebo. The patient then returned on the seventh day for follow-up clearance measurements. This was followed by a 2-week washout period before the whole process was repeated with the alternative inhalation solution. On each of the study days, mucociliary clearance was initially measured for a period of 60 min (IC). This was followed by cough clearance (CC) measurements for 30 min, during which patients were requested to cough a total of 120 times. Post-cough clearance (PCC) was then measured for a further 60 min. Thirteen patients completed the study. Patients' age ranged between 18-38 years, and they had baseline values of FEV(1) of 27-103% of predicted values. Following completion of the course of rhDNase, there was a mean percent increase from baseline of 7.5% for FEV(1) and 5.4% for FVC% (P = 0. 03). There was a small, nonsignificant increase in IC (6.2 +/- 3.6%) on the rhDNase arm compared with the placebo arm (-2.3 +/- 2.9%), P = 0.1. No changes were seen in either CC (1.0 +/- 3.2% [rhDNase] vs. 1.9 +/- 2.4% [placebo], P = 0.9) or PCC (-0.7 +/- 1.5% [rhDNase] vs. 0.9 +/- 1.7% [placebo], P = 0.3). Patients who achieved a 10% or greater improvement in FEV(1) (n = 5) in response to rhDNase did not show any greater change in clearance than nonresponders. In conclusion, we were unable to demonstrate any improvements in either ciliary or cough clearance in response to a short course of rhDNase. The mechanism of action of this drug in vivo remains uncertain.

The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study.

It has been postulated that hypertonic saline (HS) might impair the antimicrobial effects of defensins within the airways. Alternative non-ionic osmotic agents such as mannitol may thus be preferable to HS in promoting bronchial mucus clearance (BMC) in patients with cystic fibrosis (CF). This study reports the effect of inhalation of another osmotic agent, dry powder Mannitol (300 mg), compared with its control (empty capsules plus matched voluntary cough) and a 6% solution of HS on BMC in 12 patients with cystic fibrosis (CF). Mucus clearance was measured using a radioaerosol/gamma camera technique. Post-intervention clearance was measured for 60 min, followed by cough clearance for 30 min. Neither mannitol nor HS improved BMC during the actual intervention period compared with their respective controls. However during the post-intervention measurement there was a significant improvement in BMC for both the mannitol (8.7+/-3.3% versus 2.8+/-0.7%) and HS (10.0+/-2.3% versus 3.5+/-0.8%). There was also a significant improvement in cough clearance with the Mannitol (9.7+/-2.4%) compared with its control (2.5+/-0.8%). Despite premedication with a bronchodilator, a small fall in forced expiratory volume in one second (FEV1) was seen immediately after administration of both the mannitol (7.3+/-2.5%) and HS (5.8+/-1.2%). Values of FEV1 returned to baseline by the end of the study. Inhaled mannitol is a potential mucoactive agent in cystic fibrosis patients. Further studies are required to establish the optimal dose and the long-term effectiveness of mannitol.

End-expiratory lung volume during arm and leg exercise in normal subjects and patients with cystic fibrosis.

There are no reports concerning the regulation of end-expiratory lung volume (EELV) and flow-volume relationships during upper limb exercise in health and disease. We studied EELV during such exercise in 22 adults with cystic fibrosis (CF) and nine age-matched healthy control subjects. Subjects with CF were grouped according to the severity of their lung disease, as follows: mild = FEV1 > 80% predicted; moderate = FEV1 40 to 80% predicted, and severe = FEV1 < 40% predicted. EELV was calculated from measurements of inspiratory capacity (IC) made at each workload during an incremental arm and leg ergometer test to peak work capacity. In the control group, the decrease in EELV was significantly smaller for arm than for leg exercise at peak work (-0.13 L versus -0.53 L, p < 0.001) and for arm than for leg exercise at an equivalent submaximal ventilation (-0.13 L versus -0.46 L, p < 0.01). In the groups with moderate and severe CF, arm exercise resulted in an increase in EELV from resting levels (dynamic hyperinflation) that was not significantly different from the increase observed for leg exercise. For CF subjects there was a significant inverse relationship between FEV1 and changes in EELV from rest to peak arm exercise (r = -0.46, p < 0.05). In normal subjects, there was a difference in the EELV response for arm versus leg exercise. In CF subjects with airflow limitation, dynamic hyperinflation occurred with both forms of exercise.