Stuart Elborn

European best practice guidelines for cystic fibrosis neonatal screening

There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families.

Burkholderia cepacia complex genomovars and pulmonary transplantation outcomes in patients with cystic fibrosis

Burkholderia cepacia is a group of organisms that comprises seven genotypically distinct species (B cepacia genomovars I-VII), which are collectively known as the B cepacia complex. Preoperative infection with B cepacia is associated with a poor prognosis in lung transplant recipients with cystic fibrosis. Many centres do not, therefore, offer transplants to these individuals. Our aim was to ascertain whether or not post-transplant mortality is affected by pretransplant genomovar status. We studied archived isolates with PCR-based methods, and recorded excessive mortality in patients infected with B cepacia genomovar III, but not in those infected with other genomovars.

Validity of a modified shuttle test in adult cystic fibrosis

BACKGROUND The purpose of this study was to provide some evidence of the validity of a modified shuttle test (MST) by comparing performance on the MST with peak oxygen consumption (V˙o 2peak) measured during a treadmill test in a group of adult patients with cystic fibrosis. METHOD Twenty patients with stable cystic fibrosis performed a ramped maximal treadmill test (STEEP protocol) and the MST using a randomised balanced design. RESULTS The relationship between the distance achieved on the MST andV˙o 2peak was strong (r = 0.95, p<0.01) with 90% of the variance in V˙o 2peak explained by the variance in MST distance. The relationship was represented by the regression equation (with 95% confidence intervals)V˙o 2peak = 6.83 (2.85 to 10.80) + 0.028 (0.019 to 0.024) × MST distance. CONCLUSION This study provides evidence of the construct validity of the MST as an objective measure of exercise capacity in adults with cystic fibrosis.

European Respiratory Society guidelines for the management of adult bronchiectasis

Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines. The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature. A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy. These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes. The publication of the first ERS guidelines for bronchiectasis http://ow.ly/wQSO30dU0nE

Oxidative stress during acute respiratory exacerbations in cystic fibrosis

BACKGROUND Patients with cystic fibrosis experience chronic systemic oxidative stress. This is coupled with chronic inflammation of the lung involving bronchial polymorphonuclear neutrophil accumulation and activation. We hypothesised that, during periods of acute respiratory exacerbation, free radical activity and consequent damage would be most marked and that intensive treatment of the infection would result in improvement towards values found during stable periods. METHODS Plasma and red blood cells were collected from 12 healthy normal volunteers and from 12 patients with cystic fibrosis with an acute respiratory exacerbation (increased respiratory symptoms, reduction in forced expiratory volume in one second (FEV1) of more than 10%, and a decision to treat with intravenous antibiotics). Further samples were collected from patients following two weeks of treatment. Samples were analysed for inflammatory markers, markers of free radical damage, and aqueous and lipid phase scavengers. RESULTS During respiratory exacerbations FEV1 and forced vital capacity (FVC) were lower than in controls (mean differences –2.82 (95% CI –2.12 to –3.52) and –3.79 (–3.03 to –4.55) l, respectively) but improved following treatment (mean change 0.29 (95% CI 0.18 to 0.40) and 0.33 (0.23 to 0.43) l, respectively). Inflammatory markers during exacerbations were significantly higher in patients than in controls with the following mean (95% CI) differences: C reactive protein (CRP), 46 (17 to 75) g/l; neutrophil elastase α1-antiprotease complexes (NEAPC), 4.4 (1.77 to 7.07) mg/l; white cell count (WCC), 5.3 (4.7 to 5.9) × 109/l. These markers decreased significantly following treatment with the following mean (95% CI) changes: CRP –26 (–10 to –42) g/l; NEAPC –3.1 (–1.3 to –4.9) mg/l; WCC –1.5 (–1.3 to –1.7) × 109/l. Malondialdehyde (MDA) as a marker of free radical activity was significantly higher in patients during exacerbations than in controls with a mean (95% CI) difference of 193 (107 to 279) which improved with treatment (mean change –56 (95% CI –28 to –84) nmol/mmol cholesterol). Red blood cell polyunsaturated fatty acids were significantly lower in patients than in controls with a mean difference of –4.4(95% CI –2.6 to –6.2) moles percent, but did not improve significantly after treatment. Protein carbonyls during exacerbations were not different from controls but did increase with treatment compared with levels during the exacerbation (mean change 0.39 (95% CI 0.11 to 0.67) μmol/g protein). Aqueous and lipid phase scavengers in patients during exacerbations were significantly lower than in controls with the following mean (95% CI) differences: ascorbate, –19.0 (–2.7 to –35.3) μmol/l; sulphydryls, –122 (–77 to –167) μmol/l; retinol, –237 (–47 to –427) nmol/mmol cholesterol; β-carotene, –52.8 (–11.8 to –93.8) nmol/mmol cholesterol; luteine, –50.4 (–10.4 to –90.4) nmol/mmol cholesterol; lycopene, –90.1 (–30.1 to –150.1) nmol/mmol cholesterol. Treatment resulted in improvement with the following mean (95% CI) changes: sulphydryls, 50 (32 to 68) μmol/l; retinol, 152 (47 to 257) nmol/mmol cholesterol; α- and β-carotene, 0.6 (0.0 to 1.2) and 7.6 (0.0 to 15.2) nmol/mmol cholesterol, respectively; α-tocopherol, 839 (283 to 1405) nmol/mmol cholesterol; and lycopene, 8.2 (0.0 to 16.2) nmol/mmol cholesterol. CONCLUSIONS Abnormalities of markers of inflammation, free radical activity, and radical scavengers were significantly more extreme during acute respiratory exacerbations and showed improvement with treatment. The need to provide protection from inflammation and free radical damage should therefore be dynamic and related to the inflammatory and oxidative processes.

Pulmonary function, inflammation, exercise capacity and quality of life in cystic fibrosis

The aim of the study was to determine the extent to which treatment induced changes in exercise capacity and quality of life (QoL) are related to spirometric measures of lung function and other measures of disease impairment. Twenty patients admitted to hospital with an exacerbation of pulmonary disease were recruited. Measures of disease impairment, disability and QoL were obtained at the beginning and end of an intravenous course of antibiotic therapy. Intravenous antibiotic treatment resulted in a significant improvement in all measures of disease impairment, disability and handicap. The only significant predictor of treatment induced change in exercise capacity was C-reactive protein (CRP) and this explained 28% of the variance in change in exercise capacity. In the case of QoL, two predictors (change in exercise capacity and sputum output) contributed significantly to the change in QoL and collectively explained 54% of the variance in QoL. Lung function provides a limited index of treatment outcome. Exercise capacity and quality of life assessment have the potential to make a significant contribution to the decision making process regarding treatment choices in cystic fibrosis and should be measured directly if a comprehensive evaluation of the effect of treatment is required.

Changing epidemiology and clinical issues arising in an ageing cystic fibrosis population.

Improvements in the quality and implementation of medical care for individuals with cystic fibrosis (CF) have resulted in a dramatic improvement in survival. Many of these strategies have focused on the effective management of pulmonary disease which has delayed its manifestations into later years. With an increasing number of patients surviving to later years the impact of chronic inflammation and nutritional compromise on other organ systems over a lifetime are increasingly manifest. This review highlights the changing epidemiology of the ageing CF population and the complications that may ensue.

Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial.

Objective:To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy. Background:One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI. Methods:We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin–creatinine ratio. Results:Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin–creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P = 0.1). Conclusions:In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.

The adaptations of a quality of life questionnaire for routine use in clinical practice: the Chronic Respiratory Disease Questionnaire in Cystic Fibrosis.

The assessment of quality of life (QoL) is to assessment of spirometric measures of lung function. Those patients whose lung function was stable at the time of study and who could attend for a retest within 14 days were asked to complete the questionnaire at a subsequent visit (n=10). The mean interval between visits was 7 days (range 5–14 days). Correlations between spirometry and CRDQ dimensions ranged from −0.003 to 0.426. The fatigue, emotion and mastery dimensions showed high internal consistency and adequate construct validity. In the small number of patients suitable for retest, the results indicated that the dimensions exhibited adequate test–retest reliability. In contrast, low internal consistency was demonstrated for the dyspnoea dimension. The fatigue, emotion and mastery dimensions could be reduced, in terms of their number of items, without a substantial loss in explanatory power. This study suggests that QoL measurement can be made convenient and, thus, more easily accessible for routine clinical assessment.

Highlights of a workshop to discuss targeting inflammation in cystic fibrosis

A workshop to discuss anti-inflammatory approaches in the treatment of CF was held at Novartis Institutes for Biomedical Research (NIBR, Horsham, UK) in March 2008. Key opinion leaders in the field (Hugo De Jonge, Stuart Elborn, Erich Gulbins, Mike Konstan, Rick Moss, Scott Randell and Adriano Rossi), and NIBR scientists were brought together to collectively address three main aims: (i) to identify anti-inflammatory targets in CF, (ii) to evaluate the pros and cons of targeting specific cell types and (iii) to discuss model systems to profile potential therapeutic agents. The highlights of the workshop are captured in this review.