Longitudinal impact of demographic and clinical variables on health-related quality of life in cystic fibrosis.

OBJECTIVES: The insights that people with cystic fibrosis have concerning their health are important given that aspects of health-related quality of life (HRQoL) are independent predictors of survival and a decrease in lung function is associated with a decrease in HRQoL over time. Cross-sectional data suggest that key variables, other than lung function, are also associated with HRQoL--although study results are equivocal. This work evaluates the relationship between these key demographic and clinical variables and HRQoL longitudinally. DESIGN: Longitudinal observational study. Observations were obtained at seven time points: approximately every 2 years over a 12-year period. SETTING: Large adult cystic fibrosis centre in the UK. PARTICIPANTS: 234 participants aged 14-48 years at recruitment. OUTCOME MEASURE: Nine domains of HRQoL (Cystic Fibrosis Quality of Life Questionnaire) in relation to demographic (age, gender) and clinical measures (forced expiratory volume in 1 s, (FEV1)% predicted, body mass index (BMI), cystic fibrosis-related diabetes, Burkholderia cepacia complex, totally implantable vascular access device, nutritional and transplant status). RESULTS: A total of 770 patient assessments were obtained for 234 patients. The results of random coefficients modelling indicated that demographic and clinical variables were identified as being significant for HRQoL over time. In addition to lung function, transplant status, age, having a totally implantable vascular access device, cystic fibrosis-related diabetes, BMI and B. cepacia complex impacted on many HRQoL domains longitudinally. Gender was important for the domain of body image. CONCLUSIONS: Demographic and changes in clinical variables were independently associated with a change in HRQoL over time. Compared with these longitudinal data, cross-sectional data are inadequate when evaluating the relationships between HRQoL domains and key demographic and clinical variables, as they fail to recognise the full impact of the CF disease trajectory and its treatments on quality of life.

Longitudinal association between lung function and health-related quality of life in cystic fibrosis.

BACKGROUND: Lung function is an important indicator of cystic fibrosis disease status and those with better forced expiratory volume in 1 s (FEV(1))% predicted have tended to report a better health-related quality of life (HRQoL) in cross-sectional studies. The relationship between lung function and HRQoL over time is unknown. This work assesses the natural progression of HRQoL reporting over many years and compares assessments across a whole decade and evaluates the relationship between lung function and HRQoL longitudinally. METHODS: Demographic (age, gender), clinical (FEV(1)% predicted, body mass index, diabetes, Burkholderia cepacia complex, intravenous access device and nutritional status) and HRQoL (Cystic Fibrosis Quality of Life Questionnaire) variables were obtained every 2 years over a 12-year period (seven time points from 1998 to 2010). RESULTS: HRQoL and lung function declined slowly over time and significant decade changes were observed for FEV(1)% predicted and the nine domains of the Cystic Fibrosis Quality of Life Questionnaire. The results of random coefficient modelling indicated that, at the population level, decreasing FEV(1)% predicted was associated with decreasing HRQoL after adjusting for confounding variables. However, the percentage of patients for whom a decrease in lung function was associated with a decrease in HRQoL differed according to the quality of life domain. CONCLUSIONS: HRQoL and FEV(1)% predicted decline slowly; nevertheless, a decrease in lung function predicted a decrease in HRQoL over time.

PmrB mutations promote polymyxin resistance of Pseudomonas aeruginosa isolated from colistin-treated cystic fibrosis patients.

Pseudomonas aeruginosa can develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of colistin (polymyxin E) resistance in laboratory strains and clinical isolates of this organism (MICs of 8 to 64 mg/liter). To explore the role of PmrAB in high-level clinical polymyxin resistance, P. aeruginosa isolates from chronically colistin-treated cystic fibrosis patients, most with colistin MICs of >512 mg/liter, were analyzed. These cystic fibrosis isolates contained probable gain-of-function pmrB alleles that conferred polymyxin resistance to strains with a wild-type or pmrAB deletion background. Double mutant pmrB alleles that contained mutations in both the periplasmic and dimerization-phosphotransferase domains markedly augmented polymyxin resistance. Expression of mutant pmrB alleles induced transcription from the promoter of the arnB operon and stimulated addition of 4-amino-l-arabinose to lipid A, consistent with the known role of this lipid A modification in polymyxin resistance. For some highly polymyxin-resistant clinical isolates, repeated passage without antibiotic selection pressure resulted in loss of resistance, suggesting that secondary suppressors occur at a relatively high frequency and account for the instability of this phenotype. These results indicate that pmrB gain-of-function mutations can contribute to high-level polymyxin resistance in clinical strains of P. aeruginosa.

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.

European cystic fibrosis bone mineralisation guidelines.

Patients with cystic fibrosis (CF) are at risk of developing low bone mineral density (BMD) and fragility fractures. This paper presents consensus statements that summarise current knowledge of the epidemiology and pathophysiology of CF-related skeletal deficits and provides guidance on its assessment, prevention and treatment. The statements were validated using a modified Delphi methodology.

Regimens for eradicating early Pseudomonas aeruginosa infection in children do not promote antibiotic resistance in this organism.

BACKGROUND: This study was designed to address the concern that intensive regimens to eradicate early Pseudomonas aeruginosa infection in patients with cystic fibrosis may lead to the emergence of antibiotic-resistant isolates. METHODS: Data was analysed retrospectively over a 10 year period at the Leeds Regional Paediatric Cystic Fibrosis Centre. All patients with first-ever isolation of P. aeruginosa who successfully completed an eradication regimen were included. Antibiotic sensitivities of P. aeruginosa were compared between initial and subsequent re-isolations in patients where eradication was successful and in those where treatment had failed. RESULTS: Forty one patients with first acquisitions for P. aeruginosa and who completed eradication treatment were identified. Eradication treatments consisted of oral, intravenous, nebulised antibiotics or a combination of these. The antibiotic sensitivity of P. aeruginosa in first growths was high and remained so on subsequent re-isolations. A repeated measures logistic model found no significant difference with time of isolation. There was no statistically significant difference in antibiotic sensitivity between P. aeruginosa isolated after successful and failed eradication. CONCLUSIONS: Repeated intensive regimens for P. aeruginosa eradication did not result in a significant increase in overall antibiotic resistance between initial and subsequent growths of this organism over the period of this study.

Can health-related quality of life predict survival in adults with cystic fibrosis?

RATIONALE: Advances in the management of cystic fibrosis have led to a significant improvement in survival, although marked differences between individuals are still observed. The value of patient-reported health-related quality of life scores in predicting survival in adults with cystic fibrosis is unknown. OBJECTIVES: To evaluate whether patient-reported health-related quality of life could predict survival in cystic fibrosis. METHODS: From 1996 to 1997 a consecutive series of 223 patients were recruited to evaluate the Cystic Fibrosis Quality of Life Questionnaire. Demographic (age, sex), clinical (FEV(1)% predicted, body mass index, diabetes, B. Cepacia complex, intravenous access device, nutritional and lung transplant status) and health-related quality of life variables were recorded (Cystic Fibrosis Quality of Life Questionnaire and the SF-36). These data were used as baseline measures to explore the prognostic association of health-related quality of life and subsequent survival. MEASUREMENTS AND MAIN RESULTS: At the census date (December 31, 2006) 154 (69.1%) adults were alive, 66 (29.6%) had died, and three (1.3%) were lost to follow-up. Cox proportional hazards models and bootstrapping procedures examined if health-related quality of life domains predicted survival after adjusting for the demographic and clinical factors. The physical functioning domain of the Cystic Fibrosis Quality of Life Questionnaire and the pain domain of the Short Form-36 had the strongest statistical associations with survival. CONCLUSIONS: Aspects of patient-reported quality of life serve as prognostic measures of survival beyond a number of previously known factors in cystic fibrosis. This needs to be investigated further in a larger longitudinal study.

Decision-making about pregnancy for women with cystic fibrosis.

OBJECTIVES: This study aims to generate experiential data about the decision-making process encountered by 12 women with cystic fibrosis (CF) considering pregnancy. DESIGN: This study uses a qualitative grounded theory methodology to analyse the data and develop a conceptual hierarchical model of salient issues. METHODS: Twelve women completed a semi-structured interview accompanied by quantitative self-report measures of quality of life and psychological well-being, and indicators of health and treatment status were used. RESULTS: Descriptive data demonstrated that the sample did not differ significantly from other published samples. Four core categories emerged: (1) impact of the decision; (2) preparation for making and living with the decision; (3) owning the decision; and (4) personal dilemmas. Each comprised a number of overlapping conceptual and subcategories. Influencing factors included the impact of pregnancy on participants' health, and upon their ability to care for the child, the pregnancy experiences of other women with CF, the moral implications of having a child and the support and beliefs of family members. DISCUSSION: The findings extend the current knowledge in this area. We recommend development of guidelines for supporting and advising chronically ill young women about the psychosocial and emotional issues.

Prevention of chronic Pseudomonas aeruginosa infection in people with cystic fibrosis.

Cystic fibrosis is the most common genetically inherited disease in the Caucasian population, with approximately 30,000 patients in the USA and more than 50,000 patients worldwide. The primary defect in the cystic fibrosis transmembrane regulator gene affects the production and/or function of the cystic fibrosis transmembrane regulator protein. Depending on the severity of the genetic defect, patients may have minimal disease expression (e.g., male infertility) or multisystem involvement, including recurrent respiratory infection progressing to respiratory failure, hepatobiliary disease, exocrine pancreatic insufficiency, diabetes mellitus and gastrointestinal tract motility problems. Pseudomonas aeruginosa is commonly isolated from the lower respiratory tract in early childhood. Chronic infection is associated with increased morbidity and mortality. P. aeruginosa infection may be acquired from the environment or by person-to-person contact. Clinicians should adopt a proactive protocol to prevent chronic infection. The cornerstones of such a policy are microbiological surveillance, infection control and antibiotic-based eradication regimens.

Microvascular complications in patients with cystic fibrosis-related diabetes (CFRD).

BACKGROUND: This study aims to quantitatively and qualitatively assess microvascular complications and their risk factors in patients with cystic fibrosis-related diabetes (CFRD) compared to those with type 1 diabetes mellitus (DM1). METHODS: 79 patients with CFRD were matched with 79 patients with DM1 according to sex, age and duration of insulin therapy. Retinopathy, peripheral neuropathy, nephropathy and microalbuminuria were the microvascular complications assessed. Risk factors studied were: smoking, BMI, HbA1c, cholesterol, cholesterol/HDL ratio, diastolic and systolic blood pressure. RESULTS: Both groups had the same number of microvascular complications (29%). CFRD patients showed more microalbuminuria (21% versus 4.1%; p=0.003), while retinopathy was more common in patients with DM1 (24% versus 10%; p=0.044). The prevalences of peripheral neuropathy and nephropathy were similar. Patients with CFRD had lower BMI (p<0.0001), total cholesterol (p<0.0001) and HbA1c (p=0.056) levels, and a lower prevalence of smokers (p<0.0001). Cholesterol/HDL ratio and diastolic and systolic blood pressure were similar in both groups. CONCLUSIONS: The microvascular complications shown by patients with CFRD are similar to those seen in patients with DM1 but with a lower prevalence of retinopathy and a higher prevalence of microalbuminuria. The latter may reflect the influence of other cystic fibrosis-related factors on renal function.

A cross-sectional study of bone mineral density in children and adolescents attending a Cystic Fibrosis Centre.

BACKGROUND: Low bone mineral density is common in adults with cystic fibrosis. Children with good lung function compared to controls matched for body size have normal bone mineralisation. There are few data in large unselected populations of children. METHODS: All children between five and 16 years were invited to take part. Disease severity was assessed. Bone mineral measurements using a GE-Lunar Prodigy densitometer were expressed as age and gender matched Z-scores. Bone mineral apparent density for L2-L4 was estimated and data from UK Caucasian children used to create age and gender specific reference ranges for predicted values. Z-scores were calculated. Total body analysis utilised the Molgaard method. Blood was sampled for measurement of 25-hydroxyvitamin D, and parathyroid hormone levels. RESULTS: 107 children entered the study. 18 and 10 children had low areal and apparent bone mineral density respectively. Short, narrow bones were common. Fifteen children reported 22 fractures, 20 with associated trauma. The best predictors of bone status were ZBMI and percent predicted FEV(1). CONCLUSIONS: Bone mineral density corrected for body size was normal in over 90% of children. These results are similar to previously reported results in small studies of children with well preserved respiratory function.

Nutritional intake and status in children with cystic fibrosis: does age matter?

OBJECTIVES: To determine whether nutritional intake and status vary with age in children with cystic fibrosis (CF). METHODS: Case-control study examining differences in nutritional parameters and intakes in 58 children with CF recruited from a regional centre (2000-2001) and 45 controls. Participants were divided into age groups of 5-8 years, 9-12 years and 13-16 years. Weight, height, body mass index and standard deviation scores were recorded. A 4-day food diary (51 CF, 31 controls) was calculated for macronutrients and micronutrients. RESULTS: Energy intakes (%EAR) increased with age (112%, 115% and 116%, respectively) and were significantly higher in children with CF than controls. Lower weight and growth trends were observed in children ages 5 to 8 years (NS). Weight gain and growth was normal in children with CF ages 9 to 12 years but declined at 13 to 16 years (weight z score -0.85 vs 0.68 P = 0.003, height z score -0.54 vs 0.53 P = 0.002, body mass index z score -0.72 vs 0.41 P = 0.03). Lung function was the most significant predictor of nutritional status at 9 to 12 years (r2 = 0.37, P = 0.006) and 13 to 16 years (r2 = 0.31, P = 0.01), but was not significant in children ages 5 to 8 years. CONCLUSION: Energy intakes increased with age in children with CF and exceeded that of healthy peers in all age groups. Weight gain and growth equaled that of healthy peers at 9 to 12 years but was suboptimal at 5 to 8 years and dramatically declines at 13 to 16 years. Energy intakes were unable to meet the clinical demands of children in these age groups. Both remain vulnerable and require greater nutritional targeting.

Nutritional status, perceived body image and eating behaviours in adults with cystic fibrosis.

BACKGROUND & AIMS: Achieving and maintaining an ideal nutritional status is the primary aim of the nutritional management of cystic fibrosis (CF). It is unclear how nutritional interventions impact on patients' perceptions and behaviours concerning body image and eating. This work aimed to provide a psychosocial profile and compare CF patients receiving (a) enteral tube feeding, (b) nutritional supplements, (c) no nutritional interventions, and (d) healthy controls. METHODS: A cross-sectional questionnaire design was employed. Age, gender, lung function, and body mass index were recorded. Subjects completed measures of eating attitudes, perceived and desired body shape, body image, self-esteem and quality of life (QoL). RESULTS: A minority of CF patients reported disordered eating. Those receiving nutritional interventions engaged in less dieting behaviour. All CF groups, especially intervention groups, received more pressure from others to eat. For females, control groups desired to be slimmer whereas intervention groups desired to be heavier. Healthy males were content with their body whereas CF males wished to be heavier. Patients receiving enteral tube feeding were less satisfied with their body image, reported lower self-esteem and poorer QoL. CONCLUSION: Body image and eating behaviours are important considerations of nutritional interventions for maintaining QoL.

Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis--caution with trough concentrations.

BACKGROUND: : Once daily intravenous aminoglycoside dosing (ODD) is widely used to treat acute Pseudomonas aeruginosa exacerbations in patients with cystic fibrosis. Controversy exists as to what is the most appropriate method of therapeutic drug monitoring (TDM) of such therapy with recommendations including trough plasma concentrations of <1 mg/L or <2 mg/L, area under curve (AUC) and various nomograms. This study aimed to compare the exposures to ODD of tobramycin in adults and children with cystic fibrosis using the AUC and trough TDM approaches. METHODS: : Using a mono-exponential software program to calculate AUC from 2 plasma concentrations, AUCs were determined in 22 adults with pre-dose tobramycin concentrations <1 mg/L. The exposure of 5 children with reduced tobramycin clearances was simulated at the usual recommended dose of 10 mg/kg/daily but retaining a trough <1 mg/L. RESULTS: : A tobramycin dose of 10 mg/kg of tobramycin in these patients with normal serum creatinine and a trough concentration <1 mg/L resulted in exposures in excess of those associated with conventional 8-hourly dosing. CONCLUSIONS: : The TDM approach of a trough <1 mg/L, as used with conventional 8-hourly tobramycin dosing, is not relevant to ODD.

Aspergillus bronchitis in cystic fibrosis.

Aspergillus fumigatus, a widely distributed spore-bearing fungus, is commonly grown in sputum cultures of patients with cystic fibrosis (CF). A fumigatus may cause allergic bronchopulmonary aspergillosis (ABPA), a complex condition that leads to worsening of airway inflammation and progressive damage and is diagnosed by specific criteria. In this report, we present six CF patients with respiratory deterioration that did not respond to appropriate antibiotic treatment. All had had A fumigatus in sputum cultures but did not fulfill the criteria of ABPA. Treatment with antifungal agents was followed by improvement in clinical condition. We suggest that in patients with CF, A fumigatus should be considered as a pathogen that may directly cause respiratory exacerbations. Antifungal therapy should be considered when deteriorating respiratory function is not responding to antibacterial therapy and A fumigatus is growing in sputum cultures.

Diagnosis and treatment of intestinal malabsorption in cystic fibrosis.

Intestinal malabsorption is severe and of early onset in virtually all people who have cystic fibrosis. The main cause is deficiency of pancreatic enzymes. Bicarbonate deficiency, abnormal bile salts, mucosal transport problems, motility differences, and anatomical structural changes are other contributory factors. Effective treatment should allow a normal to high-fat diet to be taken, control symptoms, correct malabsorption, and achieve a normal nutritional state and growth. Appropriate pancreatic enzyme replacement therapy will achieve normal or near-normal absorption in most people with cystic fibrosis. Early identification and treatment of intestinal malabsorption is critical to achieving optimal nutritional status. The occurrence of fibrosing colonopathy in a few patients on very high doses of those enzymes which have the copolymer Eudragit L30 D55 in their covering resulted in guidelines in the UK to avoid doses equivalent to more than 10,000 IU lipase per kg per day, and also to avoid preparations containing this copolymer in children and adolescents. For patients not responding to 10,000 IU lipase per kg per day review of adherence to treatment, change of enzyme preparation, variation in time of administration, and reduction in gastric acid may improve absorption. The importance of early investigation to exclude other gastrointestinal disorders as a cause of the patient's symptoms, rather than merely increasing the dose of enzymes, is stressed. With modern pancreatic enzymes in doses up to or only slightly in excess of 10,000 IU lipase per kg per day, adequate control of gastrointestinal symptoms and absorption can be achieved, and a normal nutritional state and growth rate maintained in most people with cystic fibrosis.

Vitamin K status among children with cystic fibrosis and its relationship to bone mineral density and bone turnover.

OBJECTIVE: The aim of this study was to assess vitamin K status in an unselected population of children with cystic fibrosis (CF) and to investigate any vitamin K effect on bone turnover and bone mineral status. METHODS: Children > or =5 years of age who were attending the CF unit were invited to enter the study. Fasting blood samples were analyzed for levels of vitamin K1 and prothrombin produced in vitamin K absence; total, undercarboxylated, and carboxylated osteocalcin (OC); and bone-specific alkaline phosphatase and procollagen I carboxy-terminal propeptide (bone formation markers). Levels of N-telopeptide and free pyridinoline and deoxypyridinoline (bone breakdown products) were measured in urine samples. Bone mineral density and bone mineral content were measured at the lumbar spine and for the total body with a GE Lunar Prodigy densitometer. Statistical analyses were performed with Minitab version 9.1. RESULTS: One hundred six children entered the study. Sixty-five of 93 children (70%) from whom blood samples were obtained showed suboptimal vitamin K status, on the basis of low serum vitamin K1 levels, increased prothrombin produced in vitamin K absence levels, or both abnormalities. Vitamin K1 levels showed a significant negative correlation with undercarboxylated OC levels but showed no significant correlation with any marker of bone turnover or measurement of bone mineral status. Undercarboxylated OC levels were correlated significantly with bone turnover markers, which themselves showed a significant negative correlation with measurements of bone mineral density and content. There were no significant correlations between carboxylated or undercarboxylated OC levels and bone density measurements. CONCLUSIONS: Vitamin K1 deficiency is common among children with CF, and routine supplements should be considered. Through its role in the carboxylation of OC, vitamin K deficiency may be associated with an uncoupling of the balance between bone resorption and bone formation. A cause-effect relationship between vitamin K deficiency and low bone mass has not been proved.