Margaret E. Hodson

Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007.

Objectives To evaluate the survival of patients with cystic fibrosis whose lung function has deteriorated to a forced expiratory volume in one second (FEV1) below 30% predicted in the recent treatment era and to explore factors associated with any change in survival. Design Cohort study. Setting Adult cystic fibrosis unit in London. Participants 276 patients (147 (53%) male) whose FEV1 was first observed to be less than 30% predicted between 1 January 1990 and 31 December 2003. Main outcome measure Survival during follow-up to 31 December 2007 in two year sub-cohorts. Results Median survival improved from 1.2 years in the 1990-1 group to 5.3 years in the 2002-3 group, with a marked improvement in survival from 1994. The use of nebulised recombinant human DNase was significantly associated with a reduced risk of death (hazard ratio 0.59, 95% confidence interval 0.44 to 0.79). Significantly increased risks were associated with a body mass index under 19 (hazard ratio 1.52, 1.10 to 2.10), long term oxygen therapy (3.52, 2.49 to 4.99), and nebulised antibiotics (1.84, 1.05 to 3.22). Conclusion A marked improvement has occurred in the survival of patients with cystic fibrosis with an FEV1 less than 30% predicted. Secondary analyses suggest that some of this improvement may be due to use of recombinant human DNase.

High resolution computed tomography in adult cystic fibrosis patients with mild lung disease

Chest radiography and high resolution computed tomography (HRCT) were used to evaluate the degree of lung involvement in 38 adult cystic fibrosis patients with unusually mild pulmonary disease. Abnormal features were present on the chest radiograph and/or high resolution CT scans of 35 patients, while in three patients both investigations were normal. Thickening of the wall of proximal right upper lobe bronchi was the earliest abnormal feature on HRCT. The commonest abnormal feature in these patients, including those whose chest radiograph was normal, was mild, uniform dilatation of proximal bronchi. The lumen dilatation was always less marked than the degree of thickening. Ten of the patients were first diagnosed in adult life. Although HRCT scans were normal in two of these patients, there were features suggestive of early pulmonary disease in the remaining eight.

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.

Two years experience with recombinant Human DNase I in the treatment of pulmonary disease in cystic fibrosis

Recombinant human DNase I (rhDNase) has been shown to improve pulmonary function in patients treated for up to 6 months. A cohort of 52 cystic fibrosis patients with a FVC > 40% predicted were enrolled into an open label study in order to evaluate longer-term effects of rhDNase. They received 2.5 mg rhDNase twice daily for 6 months followed by a 2-week wash-out period, and for the subsequent 18 months were treated with rhDNase once daily. Twenty-six male and 26 female patients with a mean FVC of 2.941 and FEV1 of 1.471 were recruited. Thirteen patients did not complete the study; there were seven deaths, three patients withdrew consent and three patients were lost to follow-up. Improvement in pulmonary function was seen following treatment and changes were evaluated as mean percent change from baseline. The maximum improvement occurred in the first month followed by a plateau at a lower level of improvement. The mean improvement in FEV1 over the first month was 13.3% (range 12-14.1%), followed by a plateau at around 7.1% (range 4.6-11.0%) for the subsequent 23 months. Mean FVC was improved by 12.03% (range 9.0-14.3%) over the first month and subsequently 4.2% (range - 2.2-10.2%). The effects on pulmonary function were similar for both treatment doses of rhDNase. There was also a steady improvement in weight from a mean of 54.2 kg to 55.7 kg at the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Beyond postural drainage and percussion: Airway clearance in people with cystic fibrosis.

BACKGROUND Evidence indicates that there are no statistically significant differences in effectiveness among the airway clearance techniques (ACTs) of active cycle of breathing, autogenic drainage, positive expiratory pressure (PEP) or oscillating PEP in the short-term, but are there differences in the long-term (one year)? The objective of the study was to demonstrate non-inferiority in the long-term. METHODS Seventy-five people with cystic fibrosis entered the prospective, randomised controlled trial of these five different ACTs. The primary outcome measure was forced expiratory volume in one second (FEV(1)). Secondary outcome measures included exercise capacity and health related quality of life. RESULTS Using intention to treat, data were available on 65 subjects at the end of the study period. There were no statistically significant differences among the regimens in the primary outcome measurement of FEV(1) (p=0.35). CONCLUSION In different countries either one or several airway clearance regimens are used. This study provides evidence in support of current practices.

Time-related changes in pulmonary function after conversion to tacrolimus in bronchiolitis obliterans syndrome

BACKGROUND Bronchiolitis obliterans syndrome (BOS) is a leading cause of morbidity and mortality after lung and heart-lung transplantation. Present treatment is directed at the augmentation of pharmacologic immunosuppression. METHODS This study examines the effect of substituting cyclosporine with tacrolimus on the forced expiratory volume in 1 second (FEV(1)) and on the forced expiratory flow between 25% and 75% of vital capacity (FEF(25%-75%)) in 32 patients who developed BOS. The proportional rates of decline of FEV(1) and FEF(25%-75%) before and after treatment with tacrolimus were calculated. The actuarial survival of responders and non-responders to tacrolimus was compared. Pre-operative and post-operative factors were investigated to determine any difference between the 2 groups. RESULTS There were significant reductions in the rates of decline of FEV(1) and FEF(25%-75%) when the rates in the 3 months before conversion to tacrolimus were compared with subsequent rates at 0 to 3 months, 3 to 6 months, 6 to 9 months and 9 to 12 months after conversion. The rates of decline of FEV(1) and FEF(25%-75%) in the 3 months before conversion were 0.11 liters/month and 0.13 liters/s per month, respectively. This compares with the rates of decline for FEV(1) and FEF(25%-75%) for the 3 months after conversion to tacrolimus of 0.04 liters/month (p = 0.023) and 0.04 liters/s per month (p = 0.022), respectively. The actuarial survival at 1 year from the time of conversion to tacrolimus for the responder sub-group and the non-responder sub-group were 89.2% and 75%, respectively, and at 4 years after conversion were 61.3% and 56.3%, respectively (p = 0.92). CONCLUSIONS Tacrolimus rescue therapy is effective at stabilizing lung function in patients with BOS, and this effect is apparent up to 12 months after conversion from cyclosporine.

Linked marker haplotypes and the ΔF508 mutation in adults with mild pulmonary disease and cystic fibrosis

The frequencies of the delta F508 mutation and haplotypes at the loci linked to the cystic fibrosis (CF) gene have been compared in adult CF patients with very mild and with severe lung disease. In patients who are compound heterozygotes for the delta F508 mutation, or who lack the mutation on both chromosomes, the as yet undefined mutations may influence the severity of lung involvement. In patients homozygous for the delta F508 mutation, non-genetic factors cannot fully account for variation in the severity of lung disease. Genes outside the CF locus may influence clinical expression of the disease.

Cystic fibrosis and survival to 40 years: a case–control study

The clinical course of patients with cystic fibrosis (CF) is variable and probably determined by many interacting factors. We aimed to examine the influence of early social and clinical factors on long-term survival. A case–control study of adult CF patients was used to compare long-term survivors (aged ≥40 yrs) with patients who died before reaching 30 yrs of age. Each case (n = 78) was matched by birth date with at least one control (n = 152), after exclusion of “late diagnosis” patients. Probability-weighted logistic regression models were used to identify influences on survival. Factors resulting in increased probabilities of survival included high body mass index (OR 1.76, 95% CI 1.40–2.22), forced expiratory volume in 1 s (OR per 5% increase 1.54, 95% CI 1.32–1.80), and forced vital capacity (OR per 5% increase 1.54, 95% CI 1.33–1.78) at transfer to the adult clinic and the exclusive use of oral antibiotics (OR 8.31, 95% CI 3.02–22.88). Factors resulting in decreased probabilities of survival were Pseudomonas aeruginosa acquisition (OR 0.18, 95% 0.05–0.65) or pneumothorax before transfer to the adult clinic (OR 0.02, 95% CI 0.004–0.08) and referral from a paediatric clinic in a deprived area (OR 0.13, 95% CI 0.04–0.38). Long-term survival is associated with the clinical features present by the time of referral to an adult clinic. Even “early-diagnosis” disease appears to have different phenotypes, possibly independent of CF gene function, that have different survival patterns.

A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period.

Background: Chronic endobronchial sepsis and profuse airway secretions dominate pulmonary disease in cystic fibrosis. Recombinant human DNase I (dornase alfa) reduces the viscoelasticity of airway secretions and hence may improve clearance of airway secretions. Objectives: To evaluate the long-term influence of dornase alfa on disease progression by performing a case-controlled study with dornase alfa over a period of 4 years. Methods: A cohort of patients with cystic fibrosis who have been treated with dornase alfa were matched with a control group of patients with cystic fibrosis who had not received treatment with dornase alfa. The patients were matched by pulmonary function, age, and then sex. All available measurements of forced expiratory volume in one second (FEV1), height, weight and sputum bacteriology were collected for periods when the patients were free from respiratory exacerbations. Results: Thirty-eight patients were matched. Slopes of median changes in FEV1 were –2.19 (–3.32, –1.06) in the control group and –0.75 (–1.87, 0.36) in the dornase alfa-treated group (p = 0.076). There were more infective exacerbations per patient year in the control group [3.13 (1.25–4.25)] in comparison to the dornase alfa group [1.25 (0.63–3.0), p = 0.035] over the 4-year treatment period. Antibiotic requirements were also greater with a median 43.75 (17.5–60.0) days of intravenous antibiotic use per patient year in the control group and 16.25 (8.5–44.0) days in the dornase alfa group (p = 0.034). Conclusions: The trends suggest that dornase alfa may have some influence on disease progression but in view of the limitations of the current study the need for further long-term studies in larger cohorts of patients is emphasised.