Short-term comparative study of high frequency chest wall oscillation and European airway clearance techniques in patients with cystic fibrosis.

BACKGROUND: High frequency chest wall oscillation (HFCWO) is standard treatment for airway clearance in the USA and has recently been introduced in the UK and Europe. There is little published research comparing HFCWO with airway clearance techniques (ACTs) frequently used in the UK and Europe. The aim of this study was to compare the short-term effects of HFCWO with usual ACTs in patients with cystic fibrosis hospitalised with an infective pulmonary exacerbation. METHODS: A 4-day randomised crossover design was used. Patients received either HFCWO on days 1 and 3 and usual ACTs on days 2 and 4 or vice versa. Wet weight of sputum, spirometry and oxygen saturation were measured. Perceived efficacy, comfort, incidence of urinary leakage and preference were assessed. Data were analysed by mixed model analysis. RESULTS: 29 patients (72% male) of mean (SD) age 29.4 (8.4) years and mean (SD) forced expiratory volume in 1 s (FEV(1)) percentage predicted (FEV(1)%) 38 (16.7) completed the study. Significantly more sputum was expectorated during a single treatment session and over a 24 h period (mean difference 4.4 g and 6.9 g, respectively) with usual ACTs than with HFCWO (p<0.001). No statistically significant change in FEV(1)% or oxygen saturation was observed after either HFCWO or usual ACTs compared with baseline. 17 patients (55%) expressed a preference for their usual ACT. CONCLUSIONS: During both a finite treatment period and over 24 h, less sputum was cleared using HFCWO than usual ACT. HFCWO does not appear to cause any adverse physiological effects and may influence adherence.

An international/multicentre report on patients with cystic fibrosis (CF) over the age of 40 years.

BACKGROUND: The lifespan of patients with cystic fibrosis (CF) is increasing significantly. The objective of this international pilot study was to study the characteristics of these long-term survivors. METHODS: Four centres with large CF clinics from London (UK), Minneapolis (USA), Toronto (Canada) and Verona (Italy) identified 366 patients who had survived 40 years and longer. RESULTS: At all centres males survived longer than females. There were more pancreatic sufficient patients in Verona (60%) and Toronto (40%) than in London (16%) and Minneapolis (21%). The percentage of DeltaF508 homozygous patients varied between 47% in London and 45% in Minneapolis to only 26% in Toronto and 9% in Verona. Average FEV(1) and BMI values of the surviving population appeared to stabilise after 40 years of age. FEV(1) was on average 12% higher in patients who were pancreatic sufficient (p > 0.0001). There was no difference in survival between the centres. The overall median survival after the age of 40 was 13 years. The estimated annual death rate was approximately 3.4% from the age of 40-60 years. CONCLUSIONS: Significant numbers of patients are now surviving to 40 years or more, and it is hoped that an in-depth study of these patients may identify the factors contributing to longer survival.

A feasibility study of home telemedicine for patients with cystic fibrosis awaiting transplantation.

Sixteen patients with cystic fibrosis were randomized to either telemedicine or standard care alone. All patients were terminally ill. Patients in the telemedicine group had an ISDN line installed in their home and were given a videoconferencing unit connected to their home television set. Eleven subjects completed the baseline assessment and seven patients completed the study (4 on telemedicine and 3 in the control arm). Telemedicine patients had weekly videoconferences from home for a clinical assessment, psychological support and the opportunity for discussion with any member of the multidisciplinary team. A total of 71 home videoconferences were conducted during the study. Anxiety levels were measured before and after the conferences. After six months there were no significant differences in quality of life, anxiety levels, depression levels, admissions to hospital or clinic attendances, general practitioner calls or intravenous antibiotic use between the two groups. However, there was a significant improvement in perception of body image for those in the telemedicine group and the patients liked and valued the service. The use of telemedicine can enhance the support that a specialist unit can provide for the patient and their family, and may reduce outpatient clinic attendances.

Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis.

In animals, glucose concentrations are 3-20 times lower in lung lining fluid than in plasma. In humans, glucose concentrations are normally low (<1 mmol/l) in nasal and bronchial fluid, but they are elevated by inflammation or hyperglycemia. Furthermore, elevated bronchial glucose is associated with increased respiratory infection in intensive care patients. Our aims were to estimate normal glucose concentrations in fluid from distal human lung sampled noninvasively and to determine effects of hyperglycemia and lung disease on lung glucose concentrations. Respiratory fluid was sampled as exhaled breath condensate, and glucose was measured by chromatography with pulsed amperometric detection. Dilution corrections, based on conductivity, were applied to estimate respiratory fluid glucose concentrations (breath glucose). We found that breath glucose in healthy volunteers was 0.40 mmol/l (SD 0.24), reproducible, and unaffected by changes in salivary glucose. Breath-to-blood glucose ratio (BBGR) was 0.08 (SD 0.05). Breath glucose increased during experimental hyperglycemia (P < 0.05) and was elevated in diabetic patients without lung disease [1.20 mmol/l (SD 0.69)] in proportion to hyperglycemia [BBGR 0.09 (SD 0.06)]. Breath glucose was elevated more than expected for blood glucose in cystic fibrosis patients [breath 2.04 mmol/l (SD 1.14), BBGR 0.29 (SD 0.17)] and in cystic fibrosis-related diabetes [breath 4.00 mmol/l (SD 2.07), BBGR 0.54 (0.28); P < 0.0001]. These data indicate that 1) this method makes a biologically plausible estimate of respiratory fluid glucose concentration, 2) respiratory fluid glucose concentrations are elevated by hyperglycemia and lung disease, and 3) effects of hyperglycemia and lung disease can be distinguished using the BBGR. This method will support future in vivo investigation of the cause and effect of elevated respiratory fluid glucose in human lung disease.

Airway glucose concentrations and effect on growth of respiratory pathogens in cystic fibrosis.

BACKGROUND: Pulmonary decline accelerates in cystic fibrosis-related diabetes (CFRD) proportional to severity of glucose intolerance, but mechanisms are unclear. In people without CF, airway glucose (AG) concentrations are elevated when blood glucose (BG)> or =8 mmol L(-1) (airway threshold), and are associated with acquisition of respiratory infection. METHODS: To determine the relationship between BG and AG, 40 CF patients underwent paired BG and AG (nasal) measurements. Daily time with BG>airway threshold was compared in 10 CFRD, 10 CF patients with normal glucose tolerance (CF-NGT) and 10 healthy volunteers by continuous BG monitoring. The effect of glucose at airway concentrations on bacterial growth was determined in vitro by optical densitometry. RESULTS: AG was present more frequently (85%-vs.-19%, p<0.0001) and at higher concentrations (0.5-3 mmol L(-1)-vs.-0.5-1 mmol L(-1), p<0.0001) when BG was > or =8 mmol L(-1)-vs.-<8 mmol L(-1). Daily time with BG> or =8 mmol L(-1) was CFRD (49+/-25%), CF-NGT (6+/-5%), healthy volunteers (1+/-3%), p<0.0001. Staphylococcus aureus growth increased at > or =0.5 mmol L(-1) (p=0.006) and Pseudomonas aeruginosa growth above 1-4 mmol L(-1) glucose (p=0.039). CONCLUSIONS: BG> or =8 mmol L(-1) predicted elevated AG concentrations in CF, at least in nasal secretions. CFRD patients spent approximately 50% day with BG>airway threshold, implying persistently elevated AG concentrations. Further studies are required to determine whether elevated airway glucose concentrations contribute to accelerated pulmonary decline in CFRD.

Burkholderia cepacia complex and limited cutaneous vasculitis in patients with cystic fibrosis: a case series.

There is a high association of reactive skin presentations, mainly limited cutaneous vasculitis in patients with cystic fibrosis and Burkholderia cepcia complex chronic infection. This may be due to raised levels of circulating inflammatory mediators.

Open follow-up study of tobramycin nebuliser solution and colistin in patients with cystic fibrosis.

A previous study of tobramycin nebuliser solution (TNS) compared with colistin [C] in cystic fibrosis (CF) patients, chronically infected with pseudomonas, showed benefit for the TNS treated patients over one treatment cycle only. The current report is of an extension of that study. An open randomised cross-over study of TNS compared with C was conducted on 21 patients who had previously been on the 1 cycle study. They continued for a further 5 months and then crossed over to the alternate treatment. There was an advantage for TNS over C in FEV(1) % predicted change over time. The C slope was -0.88% per month and the TNS slope 0.35% per month (p=0.0002). This suggests advantages of TNS over C in a study with a small number of patients. Larger studies are required.

Pregnancy in cystic fibrosis lung transplant recipients: case series and review.

A single centre experience of four pregnancies in four cystic fibrosis (CF) lung transplant recipients is reported. Six more cases were identified from the literature review and combined data analysis on 10 pregnancies in 10 CF lung transplant recipients was performed to determine maternal, foetal and graft outcome. There were nine live births and one therapeutic abortion. Three required caesarean sections. Five babies were premature but all nine children were well at follow-up. Five recipients who had a long, stable interval (i.e. at least three years) between transplant and pregnancy had a favourable outcome. Three recipients developed rejection during the pregnancy and one already had obliterative bronchiolitis before pregnancy. All showed progressive decline in lung function and subsequently died of chronic rejection within 38 months of delivery. Pregnancy in CF lung transplant recipients is feasible but should still be regarded as a risky undertaking.

Temocillin in the treatment of Burkholderia cepacia infection in cystic fibrosis.

BACKGROUND: Infections due to Burkholderia cepacia complex (Bcc) strains increase morbidity and mortality in cystic fibrosis (CF). Some transplant centres reject Bcc infected patients. We reviewed the results in patients treated with i.v temocillin. METHODS: Twenty-three patients who received 38 courses of temocillin (1988-1998) were identified from the CF database at Royal Brompton Hospital. In three patients' data were inadequate; therefore analysis was done in 20. Outcome was measured as improvement, deterioration or no change (compared to admission) in the following categories: clinical (temperature, dyspnoea, sputum volume, chest pain), physiological (FEV1, FVC, oxygen saturation) and inflammatory markers (WBC, ESR, CRP). Patients who improved in two categories were classified as having improved. Antibiotic sensitivities and outcome were recorded. RESULTS: In 18 of 32 courses (56.25%) improvement occurred. The organism (Bcc) in eight patients' sputum became resistant (three died). The antibiotics was changed in five patients with Bcc strains sensitive to temocillin because of no improvement and one patient due to allergy (rash). The average time to the next i.v antibiotic was 41 days. Eight patients died (in three the Bcc strain was resistant to temocillin). Fourteen patients with Bcc were transplanted and eight patients survived. Another patient who developed Bcc infection post-operatively, failing to respond to temocillin. CONCLUSIONS: These results suggest the potential benefit of i.v temocillin in CF patients with Bcc for exacerbations and at the time of transplantation.

Relationship between glycosylated haemoglobin and mean plasma glucose concentration in cystic fibrosis.

BACKGROUND: HbA(1c) is recommended for monitoring glycaemic control in people with cystic fibrosis-related diabetes (CFRD). However the relationship between HbA(1c) and mean plasma glucose concentration (MPG) has not been established in CFRD, as in other forms of diabetes mellitus. METHODS: 20 people (13 male, 29.7+/-8.8 years, 10 CFRD) with cystic fibrosis (CF) underwent HbA(1c) measurement and 48 h continuous glucose monitoring for estimation of MPG. The relationship between HbA(1c) and MPG was established and compared to the reported relationship for type 1 diabetes. RESULTS: HbA(1c) was strongly correlated with MPG (R(2)=0.888, p<0.0001) in CF. The relationship of MPG to HbA(1c) was described by the equation MPG=(1.47xHbA(1c))-1.15, giving a 1.47 mmol L(-1) change in MPG per 1% change in HbA(1c). This equation predicts that MPG in people with CF and HbA(1c) <7.0% will be similar to MPG in people with type 1 diabetes who achieve the same HbA(1c) target. CONCLUSIONS: These results imply that HbA(1c)<7.0% will predict good blood glucose control in CF as in type 1 diabetes. However, although HbA(1c) predicts complications in type 1 diabetes, further studies are required to establish the relationship between HbA(1c) and diabetic complications in people with CFRD.

HbA1c as a screening tool for cystic fibrosis related diabetes.

AIMS: Early diagnosis of cystic fibrosis (CF) related diabetes (CFRD) is important to improve outcomes. International guidelines recommend an oral glucose tolerance test (OGTT) for all CF patients aged ≥10 years - this approach is controversial. The aim of this study was to develop an effective screening tool and reduce the need for a universal OGTT. METHODS: Adult CF patients (without CFRD) attending an annual review assessment were recruited prospectively (March 2009-July 2012) into two sequential studies - a primary investigative study followed by validation study. All patients underwent an OGTT and were simultaneously screened by predetermined biochemical/clinical criteria to identify their risk of CFRD. A sensitivity/specificity analysis was performed using the World Health Organisation diabetes criteria as gold standard; modifications were made to improve the screening tool's accuracy and determine the optimal screening thresholds. This was tested in the validation study. RESULTS: 429 patients (primary, n=94; validation, n=335: mean age=31.7 ± 10.4(SD), 43% female, 77% on pancreatic supplements). Primary study: in predicting a positive OGTT, the test sensitivity was 66.7% and specificity 60%. HbA1c was carried over to the validation study as it was the most discriminative (optimal threshold ≥5.8% (40 mmol/mol); receiver operating curve, ROC, score 0.60). Validation study: the number of patients with a normal, impaired and diabetic OGTT was 268(80%), 51(15.2%) and 16(4.8%), respectively. HbA1c provided a test sensitivity, specificity and ROC score of 93.8%, 53.0% and 0.73, respectively. CONCLUSIONS: The use of HbA1c ≥ 5.8%(40 mmol/mol) is an effective tool for CFRD screening and reduced the need for an OGTT by 50.7%.

The prevalence of "risky behaviour" in adults with cystic fibrosis.

BACKGROUND: The prevalence of "risky-behaviour" including alcohol and illicit drug use, smoking and unprotected sexual intercourse, of adults with cystic fibrosis (CF) is unknown. We conducted this prospective questionnaire-based study to further explore this issue. METHODS: An anonymous 71-point questionnaire was sent to all adult patients aged ≥18 years attending the Royal Brompton CF Unit. Results were compared to national (non-CF) data. RESULTS: 83% (n=151) drink alcohol and 13% (n=23) drink more than recommended by national guidelines. 46% (n=84) have tried smoking and 3% (n=5) continue to smoke regularly. 35% (n=64) have tried illicit drugs and 3% (n=6) continue to use them. 86% (n=154) are sexually active; 60% use contraception (males 46%, females 62%). Compared with the general (non-CF) UK population, less CF patients drink heavily (13 vs. 23%; p<0.001), smoke (3 vs. 21%; p<0.001), have tried illicit drugs (35 vs. 37%; p<0.001) and are sexually active (86 vs. 97%; p<0.001).The same proportion use contraception (60 vs. 61%; p=0.8). CONCLUSION: Participation in risky behaviour was modest. With improved life expectancy this may increase. Awareness of this is important so that health promotion measures can be introduced early.

Musculoskeletal techniques for clinically stable adults with cystic fibrosis: a preliminary randomised controlled trial.

AIMS: To assess the sensitivity of selected outcome measures to any change resulting from treatment of adults with cystic fibrosis with physiotherapy musculoskeletal techniques, use the data for sample size calculations for future studies and assess the acceptability of the methods to potential participants. DESIGN: Preliminary, prospective, single-blind, randomised controlled trial. SETTING: Specialist cystic fibrosis centre. PARTICIPANTS: Adults recruited from a cystic fibrosis outpatient clinic. INTERVENTIONS: The control group received normal optimal physiotherapy care and the intervention group received weekly musculoskeletal treatment for 6 weeks in addition to normal optimal physiotherapy care. OUTCOME MEASURES: Recorded at baseline, 3, 6 and 12 weeks. The outcome measures were posture (thoracic index), chest wall excursion, forced expiratory volume in 1 second (FEV1), visual analogue scale for pain, modified shuttle test and Cystic Fibrosis Quality of Life Questionnaire--Section One (physical functioning). STATISTICAL ANALYSIS: Descriptive statistics [using medians and interquartile ranges (IQRs)] and linear regression mixed model. RESULTS: From a total of 20 subjects, 10 were randomised to each group. Fifty percent of subjects were male, with a median age of 27 years (IQR 25 to 34), median FEV(1) of 1.75 l (IQR 1.4 to 2.4) and median body mass index of 20.8 (IQR 20.0 to 23.5). Baseline differences between groups in thoracic index and modified shuttle test made any differences difficult to interpret, but the results for thoracic index and chest wall excursion at the third rib in the treatment group showed a trend towards improvement. The usefulness of FEV1, the visual analogue scale for pain and the Cystic Fibrosis Quality of Life Questionnaire as measures is unclear. CONCLUSION: Further musculoskeletal studies in people with cystic fibrosis should consider using thoracic index and a measure of lung function in addition to FEV1. The musculoskeletal techniques appear to be acceptable to people with cystic fibrosis, and do not seem to have associated adverse effects.

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.

Growing old with cystic fibrosis - the characteristics of long-term survivors of cystic fibrosis.

BACKGROUND: The proportion of patients with cystic fibrosis (CF) who are middle-aged is increasing - and is likely to continue to do so. We surveyed a population of long-term CF survivors to assess their burden of illness and profile their disease characteristics. METHODS: A case series (n=112) of patients from one specialist centre who had reached their 40th birthday without transplantation. Hospital records and annual review data were examined. RESULTS: The median age of the group was 43.1 years (range 40-71.1); 57% were men. 68% were diagnosed before 16 years of age. 30% were DeltaF508/DeltaF508, 76% having at least one DeltaF508 allele. When compared with the total adult CF population, the older patients were significantly less likely to have a DeltaF508 mutation or colonisation with Stenotrophomonas maltophilia and MRSA; but more likely to have pancreatic sufficiency, colonisation with Pseudomonas aeruginosa or allergic bronchopulmonary aspergillosis. On average they required less than one hospital admission a year; lung function and body mass index were relatively well preserved. Many were married and working. CONCLUSIONS: We describe one of the largest surveys to date of CF patients aged more than 40 years. The full spectrum of disease is represented in this population and, importantly, 30% are DeltaF508 homozygous. Provision needs to be made for the healthcare needs of this increasing population of older patients.

Adult cystic fibrosis patients with and without infective exacerbations and their factor XII levels.

We investigated haemostatic and inflammatory parameters in patients with cystic fibrosis in an attempt to understand a previous finding of low factor XII levels in this patient population. We selected two groups of patients, adults attending outpatient annual review clinic who were well, chronically inflammed and adult patients with an infective exacerbation requiring antibiotics or admission to hospital, acutely inflammed. We measured known positive acute phase haemostatic factors, fibrinogen and factor VIII. Antithrombin and factor XII were also measured as both these factors have been proposed to be negative acute phase proteins in in-vitro cell models. Interleukin-6 was also measured as the proposed modulator of these factors during inflammation. Activated factor XII was measured to exclude XII activation as a cause of the low XII activity levels. Cystic fibrosis patients admitted to hospital with infective exacerbations, showed significantly more evidence of inflammation than the annual review patients. Fibrinogen and factor VIII were higher and factor XII was lower in these patients. This work suggests that factor XII behaves as a negative acute phase protein with no signs of elevated activated XII levels in either group. This supports similar findings from in-vitro cell culture. This study also shows low antithrombin levels in both patient populations, although there was no statistical difference between groups, which is probably related to their liver disorder.

Predicting survival in end-stage cystic fibrosis.

The natural history of cystic fibrosis (CF) is unpredictable and the optimal timing for lung transplantation in end-stage disease uncertain. Predicting survival based on FEV1 alone remains controversial and therefore the aim of this study was to assess the value of walk test performance in pre-transplant assessment. Retrospective review of adult patients with end-stage CF who underwent transplant assessment between 1988 and 2004 including a documented walk test on room air, but who died before transplant. The six-minute walk test (6MWT) was used between 1988 and 1993 and the shuttle walk test (SWT) thereafter, the two cohorts were therefore individually assessed. A total of 121 patients were identified. The median (IQR) survival in patients performing SWT (n=77) and 6MWT (n=44) was 363 days (226, 566) and 433 days (232, 844), respectively, with survival in both cohorts significantly associated with pre-test (resting) heart rate (HR) (p<0.03), but not distance walked, pre-test SpO2, FEV1 or BMI. It was predicted that 85% of patients performing SWT with a resting HR of 120 bpm, 70% of those with a HR of 109 bpm (cohort median) but only 25% with a HR of 72 bpm would die within 500 days. Distance walked in the SWT was significantly related to pre-test HR (p<0.01), SpO2 (p<0.01) and Borg score (p=0.016) when performing linear regression. Only pre-test HR remained significant when performing multiple regression. Resting heart rate was the only consistent parameter in this study at predicting a high risk of dying on the transplant waiting list.

A woman with cystic fibrosis, severe hypoxaemia, an atrial thrombus and a patent foramen ovale: a case report.

INTRODUCTION: Cystic fibrosis is usually associated with chronic pulmonary sepsis and frequent infective exacerbations. We report a very unusual cause of severe hypoxaemia in a woman with cystic fibrosis caused by thrombus formation in the right atrium. CASE PRESENTATION: A 21-year-old Caucasian woman with cystic fibrosis and a totally implantable venous access device presented with severe hypoxaemia. This was initially treated with antibiotics but her oxygen levels did not improve significantly. Subsequently, a transient ischaemic attack occurred. Further investigations, including a contrast echocardiogram and a cardiac magnetic resonance scan, revealed the presence of a large right atrial thrombus and right-to-left intracardiac shunt through a patent foramen ovale. CONCLUSION: This case highlights the need to consider a right-to-left shunt in chronic respiratory diseases when hypoxaemia is out of proportion to the degree of lung function impairment. Totally implantable venous access devices should always be considered as a source of thrombus formation.

Lung transplantation for non-cystic fibrosis bronchiectasis: analysis of a 13-year experience.

BACKGROUND: Lung transplantation is a well-established treatment for end-stage cystic fibrosis, and there are considerable data on medium- and long-term results. However, less information exists about transplantation for non-cystic fibrosis bronchiectasis. METHODS: Between December 1988 and June 2001, 22 patients (12 men, 10 women) underwent transplantation for bronchiectasis not due to cystic fibrosis. Procedures were bilateral sequential single-lung transplants (BSSLTX) in 4 patients, en bloc double lung transplants (DLTX) in 5, heart-lung transplants (HLTX) in 6, and single-lung transplants (SLTX) in 7. Lifelong outpatient follow-up was continued at a minimum of every 6 months. RESULTS: One-year Kaplan-Meier survival for all patients was 68% (95% confidence interval [CI], 54%-91%), and 5-year survival was 62% (95% CI, 41-83%). One-year survival after SLTX was 57% (95% CI, 20%-94%) vs 73% (95% CI, 51-96%) for those receiving 2 lungs. At 6 months, mean forced expiratory volume in 1 second was 73% predicted (range, 58%-97%), and mean forced vital capacity was 68% predicted (range, 53%-94%) after receiving 2 lungs (n = 10); in the SLTX group at 6 months, mean forced expiratory volume in 1 second was 50% predicted (range, 34%-61%), and mean forced vital capacity was 53% predicted (range 46-63%) (n = 4). CONCLUSIONS: Survival and lung function after transplantation for non-cystic fibrosis bronchiectasis was similar to that after transplantation for cystic fibrosis. A good outcome is possible after single lung transplantation in selected patients.