I. Clifton

The EMBARC European bronchiectasis registry: Protocol for an international observational study

Bronchiectasis is one of the most neglected diseases in respiratory medicine. There are no approved therapies and few large-scale, representative epidemiological studies. The EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) registry is a prospective, pan-European observational study of patients with bronchiectasis. The inclusion criterion is a primary clinical diagnosis of bronchiectasis consisting of: 1) a clinical history consistent with bronchiectasis; and 2) computed tomography demonstrating bronchiectasis. Core exclusion criteria are: 1) bronchiectasis due to known cystic fibrosis; 2) age <18 years; and 3) patients who are unable or unwilling to provide informed consent. The study aims to enrol 1000 patients by April 2016 across at least 20 European countries, and 10 000 patients by March 2020. Patients will undergo a comprehensive baseline assessment and will be followed up annually for up to 5 years with the goal of providing high-quality longitudinal data on outcomes, treatment patterns and quality of life. Data from the registry will be available in the form of annual reports. and will be disseminated in conference presentations and peer-reviewed publications. The European Bronchiectasis Registry aims to make a major contribution to understanding the natural history of the disease, as well as guiding evidence-based decision making and facilitating large randomised controlled trials. The European Bronchiectasis Registry will recruit 10 000 patients over 5 years http://ow.ly/Ul7Pd

Nutritional decline in cystic fibrosis related diabetes: The effect of intensive nutritional intervention

BACKGROUND Reports indicate that nutritional and respiratory decline occur up to four years prior to diagnosis of cystic fibrosis related diabetes (CFRD). Our aim was to establish whether intensive nutritional intervention prevents pre-diabetic nutritional decline in an adult population with CFRD. METHODS 48 adult patients with CFRD were matched to 48 controls with CF, for age, gender and lung pathogen status. Nutritional and other clinical indices were recorded at annual intervals from six years before until two years after diagnosis. Data were also analysed to examine the impact of early and late acquisition of CFRD. RESULTS No important differences in weight, height, body mass index (BMI), lung function or intravenous treatment were found between groups in the six years prior to diagnosis, nor any significant deviation over time. In those who developed diabetes, use of overnight enteral tube feeding (ETF) was four times as likely at the time of diagnosis, compared to controls [ETF 43.8% (CFRD) v 18.8% (CF Controls), OR 4.0, CI 1.3 to 16.4, p=0.01]. Age at onset of CFRD played a significant role in determining the pre-diabetic clinical course. Younger diabetics with continued growth at study onset (n=17) had a lower BMI from 2 years prior to diagnosis compared to controls [BMI 18.9 kg/m(2) (CFRD) v 20.8 kg/m(2) (CF Controls), diff=1.9, CI -0.1 to 3.7 p=0.04]. The BMI of older diabetics (completed growth at study onset) was equal to that of controls throughout. CONCLUSION Pre-diabetic nutritional decline is not inevitable in adults with CFRD, but is influenced by age of onset. In the group overall, those with CFRD are more likely to require ETF from 2 years prior to diagnosis. Despite intensive nutritional intervention, patients who continue to grow throughout the pre-diabetic years, show a level of nutritional decline absent in older adults.

Defining routes of airborne transmission of Pseudomonas aeruginosa in people with cystic fibrosis

Pseudomonas aeruginosa is a common and important pathogen in people with cystic fibrosis (CF). With the advent of modern genotyping, a number of clonal strains of P. aeruginosa have been identified, some of which are associated with increased morbidity. The route of cross-infection between people with CF is not clear, but there is evidence that an airborne route may be important. Laboratory studies have shown that P. aeruginosa can survive within droplet nuclei and can potentially remain suspended within aerosols for prolonged periods. Depending upon the air flows, this may result in the bacteria travelling significant distances. A number of clinical studies have demonstrated that people with CF can produce aerosols containing P. aeruginosa and Burkholderia cepacia complex. Infection control guidelines need to consider the possibility of droplet, including small-droplet nuclei, transmission of P. aeruginosa and other pathogens between people with CF. Further studies are needed to more accurately quantify the risk of cross-infection between people with CF and to evaluate interventions to minimize the risk.

A laminar flow model of aerosol survival of epidemic and non-epidemic strains of Pseudomonas aeruginosa isolated from people with cystic fibrosis

BackgroundCystic fibrosis (CF) is an inherited multi-system disorder characterised by chronic airway infection with pathogens such as Pseudomonas aeruginosa.Acquisition of P. aeruginosa by patients with CF is usually from the environment, but recent studies have demonstrated patient to patient transmission of certain epidemic strains, possibly via an airborne route. This study was designed to examine the survival of P. aeruginosa within artificially generated aerosols.ResultsSurvival was effected by the solution used for aerosol generation. Within the aerosols it was adversely affected by an increase in air temperature. Both epidemic and non-epidemic strains of P. aeruginosa were able to survive within the aerosols, but strains expressing a mucoid phenotype had a survival advantage.ConclusionThis would suggest that segregating individuals free of P. aeruginosa from those with chronic P. aeruginosa infection who are more likely to be infected with mucoid strains may help reduce the risk of cross-infection. Environmental factors also appear to influence bacterial survival. Warming and drying the air within clinical areas and avoidance of humidification devices may also be beneficial in reducing the risk of cross-infection.

An aerobiological model of aerosol survival of different strains of Pseudomonas aeruginosa isolated from people with cystic fibrosis

Pseudomonas aeruginosa is a common and important pathogen in people with cystic fibrosis (CF). Recently epidemic strains of P. aeruginosa associated with increased morbidity, have been identified. The method of transmission is not clear, but there is evidence of a potential airborne route. The aim of this study was to determine whether different strains of P. aeruginosa isolated from people with CF were able to survive within artificially generated aerosols in an aerobiological chamber. Viable P. aeruginosa could still be detected up to 45min after halting generation of the aerosols. All of the strains of P. aeruginosa expressing a non-mucoid phenotype isolated from people with CF had a reduced ability to survive within aerosols compared to an environmental strain. Expression of a mucoid phenotype by the strains of P. aeruginosa isolated from people with CF promoted survival in the aerosol model compared to strains expressing a non-mucoid phenotype.

Impact of omalizumab on treatment of severe allergic asthma in UK clinical practice: a UK multicentre observational study (the APEX II study).

Objective To describe the impact of omalizumab on asthma management in patients treated as part of normal clinical practice in the UK National Health Service (NHS). Design A non-interventional, mixed methodology study, combining retrospective and prospective data collection for 12 months pre-omalizumab and post-omalizumab initiation, respectively. Setting Data were collected in 22 UK NHS centres, including specialist centres and district general hospitals in the UK. Participants 258 adult patients (aged ≥16 years; 65% women) with severe persistent allergic asthma treated with omalizumab were recruited, of whom 218 (84.5%) completed the study. Primary and secondary outcome measures The primary outcome measure was change in mean daily dose of oral corticosteroids (OCS) between the 12-month pre-omalizumab and post-omalizumab initiation periods. A priori secondary outcome measures included response to treatment, changes in OCS dosing, asthma exacerbations, lung function, employment/education, patient-reported outcomes and hospital resource utilisation. Results The response rate to omalizumab at 16 weeks was 82.4%. Comparing pre-omalizumab and post-omalizumab periods, the mean (95% CIs) daily dose of OCS decreased by 1.61 (−2.41 to −0.80) mg/patient/day (p<0.001) and hospital exacerbations decreased by 0.97 (−1.19 to −0.75) exacerbations/patient (p<0.001). Compared with baseline, lung function, assessed by percentage of forced expiratory volume in 1 s, improved by 4.5 (2.7 to 6.3)% at 16 weeks (p<0.001; maintained at 12 months) and patient quality of life (Asthma Quality of Life Questionnaire) improved by 1.38 (1.18 to 1.58) points at 16 weeks (p<0.001, maintained at 12 months). 21/162 patients with complete employment data gained employment and 6 patients lost employment in the 12-month post-omalizumab period. The mean number of A&E visits, inpatient hospitalisations, outpatient visits (excluding for omalizumab) and number of bed days/patient decreased significantly (p<0.001) in the 12-month post-omalizumab period. Conclusions These data support the beneficial effects of omalizumab on asthma-related outcomes, quality of life and resource utilisation in unselected patients treated in ‘real-world’ clinical practice.

Survival of Mycobacterium abscessus isolated from people with cystic fibrosis in artificially generated aerosols

Non-tuberculous mycobacterium (NTM) are increasingly found in the sputum of people with cystic fibrosis (CF), both in Europe and North America [1]. Specifically, Mycobacterium abscessus has emerged as a potentially important pathogen, with evidence of accelerated lung function decline [2]. Studies from two CF centres have found evidence of cross-infection between individuals with CF [3, 4], whereas studies from other centres have not replicated this finding [5–7]. M. abscessus has been isolated from household water and has been previously isolated from shower aerosols of people with pulmonary NTM disease [8, 9]. M. abscessus survives aerosolisation suggesting airborne transmission between people with CF may occur http://ow.ly/K2x6302JpAW

Pharmacokinetics of oral voriconazole in patients with cystic fibrosis

Sir, Aspergillus fumigatus may cause allergic bronchopulmonary aspergillosis (ABPA), aspergillomas or Aspergillus bronchitis in patients with cystic fibrosis (CF). Oral corticosteroids provide the mainstay of treatment for ABPA, but there are concerns about the side effects of long-term corticosteroid use. Itraconazole has been used as a steroid-sparing agent, but absorption in people with CF is poor and unreliable. Voriconazole, a broadspectrum triazole antifungal agent, may be useful for the management of fungal infections in people with CF. We undertook an open-label Phase IV pharmacokinetic study, which aimed to recruit 10 adults with CF, hospitalized for routine antibiotic therapy and with pancreatic insufficiency. Each subject received 400 mg of oral voriconazole (VFEND, Pfizer) 12 hourly on day 1, followed by 200 mg 12 hourly for the subsequent 13 days of the study. Venous blood samples were obtained for drug analysis pre-dose and at 1, 2, 4, 6, 8 and 12 h post-dose on days 1 and 14 of the study. Serum voriconazole levels were determined using liquid chromatography–tandem mass spectrometry. On days 1, 7 and 14, routine haematology, liver function tests and blood chemistry samples were taken. All suspected unexpected serious adverse reactions and serious adverse events were recorded. Data were expressed as the mean and standard deviation (SD). The maximum concentration (Cmax) and the time of maximum concentration (Tmax) were determined by visual inspection of the data. The area under the plasma concentration–time curve during the dosing interval (AUC0 – 12) was determined using trapezoidal summation. Determination of the elimination constant (kel) and half-life (t12) were undertaken using least squares non-linear regression of the experimental data (GraphPad Prism 5.02, GraphPad Inc., USA). The clearance for the fraction of drug absorbed (CL/F) for voriconazole was calculated as the dose/AUC0 – 12 ratio. The volume of distribution for the fraction of drug absorbed (V/F) was estimated as dose/(kel .AUC0 – 12). This study was approved by the Leeds (East) Research Ethics Committee. Regulatory approval was obtained from the UK Medicines and Healthcare products Regulatory Agency. Informed written consent was obtained from all subjects. Data were available from nine patients (seven males and two females). The study subjects had a mean percentage predicted forced expiratory volume in 1 s (FEV1%) (SD), percentage predicted forced vital capacity (FVC%) (SD) and weight (SD) of 38.7% (16.3%), 50.7% (17.1%) and 53.6 kg (7.1 kg), respectively. On day 1, the Cmax (SD) was 3.8 mg/L (1.6 mg/L) and occurred at 2.3 h (1.2 h). At the end of the study, the Cmax was 2.7 mg/L (0.8 mg/L) and occurred at 2.3 h (1.3 h) (see Figure 1). At day 14, all subjects achieved a peak serum voriconazole level of .1.0 mg/L and a trough level of .0.25 mg/L. The AUC0 – 12 (SD) was 24.0 h.mg/L (16.2 h.mg/L) and 15.5 h.mg/L (8.1 h.mg/L) on days 1 and 14, respectively. On days 1 and 14, the t1 2 (SD) for oral voriconazole was 8.0 h (5.8 h) and 5.4 h (3.4 h), respectively. The V/F (SD) was 200.8 L (82.1 L) and 100.3 L (48.2 L) on days 1 and 14, respectively. The CL/F (SD) was 26.2 L/h (19.0 L/h) and 14.9 L/h (8.2 L/h) on days 1 and 14, respectively. Three subjects withdrew due to side effects; two subjects due to visual disturbance on days 1 and 3 (both had peak levels .5 mg/L), and one on day 7 due to liver function test derangement. All symptoms resolved on cessation of voriconazole. Purkins et al. reported the V/F and CL/F for 200 mg of voriconazole orally to be 160.2 L and 19.9 L/h, respectively. The data from the present study would suggest that voriconazole has a higher volume of distribution, but slower clearance in patients with CF. Patients with CF are almost always pancreatic insufficient, resulting in poor absorption from the gastrointestinal tract, and may have an increased volume of distribution and faster drug clearance. Berge et al. documented 14% and 30% of patients with CF developed neurological and hepatic

Concurrent pulmonary zygomycosis and Mycobacterium tuberculosis infection: a case report

A non-smoking 77-year old gentleman of Indian origin was admitted with a 4-month history of intermittent night sweats, haemoptysis and 6 kg of weight loss. CT scan of thorax demonstrated a 2.5 cm mass in the right middle lobe with multiple small nodules within the right lung and confirmed the presence of mediastinal and hilar lymph nodes.Fibreoptic bronchoscopy demonstrated a distorted right main bronchus, anterior shift of the right upper lobe and occlusion of the right middle lobe bronchus with a black necrotic ulcer. Mycobacterium tuberculosis was found in the bronchoalveolar lavage and histology demonstrated numerous fungal hyphae with a morphological appearance of zygomycetes within necrotic areas of tissue. Medical management with anti-fungal and anti-mycobacterial treatment was instigated as the patients pre-existing IHD did not permit surgical intervention. Subsequently CT imaging following completion of therapy demonstrated improvement of the mass and a resolution of the associated nodules. The patient has been followed for 6 months to date and there has been no recurrence of symptoms. Recent bronchoalveolar lavage cultures have been negative for M. tuberculosis and zygomycetes.

Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre

BACKGROUND The increased prevalence of multi-drug resistant strains of P.aeruginosa and allergic reactions among adult patients with cystic fibrosis (CF) limits the number of antibiotics available to treat pulmonary exacerbations. Fosfomycin, a unique broad spectrum bactericidal antibiotic, might offer an alternative therapeutic option in such cases. AIM To describe the clinical efficacy, safety and tolerability of intravenous fosfomycin in combination with a second anti-pseudomonal antibiotic to treat pulmonary exacerbations in adult patients with CF. METHOD A retrospective analysis of data captured prospectively, over a 2-years period, on the Unit electronic medical records for patients who received IV fosfomycin was performed. Baseline characteristics in the 12 months prior treatment, lung function, CRP, renal and liver function and electrolytes at start and end of treatment were retrieved. RESULTS 54 patients received 128 courses of IV fosfomycin in combination with a second antibiotic, resulting in improved FEV1 (0.94 L vs 1.24 L, p < 0.01) and reduced CRP (65 mg/L vs 19.3 mg/L, p < 0.01). Renal function pre- and post-treatment remained stable. 4% (n = 5) of courses were complicated with AKI at mid treatment, which resolved at the end of the course. Electrolyte supplementation was required in 18% of cases for potassium and magnesium and 7% for phosphate. Nausea was the most common side effect (48%), but was well controlled with anti-emetics. CONCLUSION Antibiotic regimens including fosfomycin appear to be clinically effective and safe. Fosfomycin should, therefore, be considered as an add-on therapy in patients who failed to respond to initial treatment and with multiple drug allergies.