The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice.

Aspergillus fumigatus is commonly found in the airways of patients with cystic fibrosis (CF), and allergic bronchopulmonary aspergillosis (ABPA) is the most recognized associated clinical condition. However, accurate diagnosis remains challenging, and there is a paucity of clinical trials to guide clinical management of fungal disease. The aim of this survey was to assess the variability in current practice across the UK in diagnosis and management of fungal lung disease in CF patients. A 21 question anonymous online survey was sent to 94 paediatric and adult CF consultants in the UK. The response rate was 60.6% (32 adult physicians, 25 pediatricians) with 55 full and 2 partially completed surveys. For a first diagnosis of ABPA 20 (35.1%) treat with prednisolone alone, 38 (66.7%) use prednisolone with itraconazole and 2 (3.5%) choose voriconazole. Only 5 (8.8%) treat with prednisolone alone for a 1st relapse, 33 (58%) used prednisolone with itraconazole. To reduce treatment, 21 (36.8%) decrease steroids to zero over time and maintain azole therapy, 18 (31.6%) stop the azole and steroid after a fixed time, and 5 (8.8%) stop the azole after a fixed time and maintain a small steroid dose. Thirty-eight (66.7%) respondents believe Aspergillus colonization of the airway can cause clinical deterioration, and 37 (66.1%) would treat this. Scedosporium apiospermum infection has been diagnosed and treated by 35 (61.4%) of respondents. Results of this survey highlight the variance in clinical practice and the limited evidence available to guide management of fungal infection in CF.

The outcome of pregnancies in women with cystic fibrosis--single centre experience 1998-2011.

OBJECTIVE: To describe the maternal and fetal outcomes of pregnancies in women with cystic fibrosis. DESIGN: Retrospective study. SETTING: Single obstetric hospital and adult cystic fibrosis centre. METHODS: Retrospective case-note review of pregnant women with cystic fibrosis referred for antenatal care and delivery. MAIN OUTCOME MEASURES: Maternal and fetal outcomes, mode of delivery, lung function and pregnancy complications. RESULTS: Forty-eight pregnancies were studied in 41 women. There were two miscarriages, 44 singleton pregnancies and two sets of twins. All babies were liveborn and survived. The mean gestational age at delivery was 35.9 ± 3.3 weeks. There were no fetal abnormalities or terminations of pregnancy. The median birthweight centile was 31.9 (interquartile range 14.9-55.6). Twenty-five (52.1%) of the women had pancreatic insufficiency and 17 (35.4%) required insulin. There was a positive correlation between booking predicted forced expiratory volume in 1 second (FEV(1) ) and gestational age at delivery (P < 0.01). Women with FEV(1) ≤60% were more likely to deliver earlier and by caesarean section compared with women with FEV(1) >60% (35.0 ± 3.2 weeks versus 37.1 ± 3.0 weeks; P = 0.02 and 75.0% versus 25.0%; P = 0.01). Three of the seven women with an FEV(1) <40% died within 18 months of delivery. Four of the eight women with FEV(1) 40-50% died between 2 and 8 years after delivery. CONCLUSION: Pregnancy for women with cystic fibrosis is possible and results in favourable maternal and fetal outcomes, but the incidence of preterm delivery and caesarean section is increased. Women with pre-existing poor lung function should be counselled antenatally to ensure that they understand the implications of their shortened life-expectancy and parenthood.

Population genetic structure and long-distance dispersal among seabird populations: implications for colony persistence.

Dramatic local population decline brought about by anthropogenic-driven change is an increasingly common threat to biodiversity. Seabird life history traits make them particularly vulnerable to such change; therefore, understanding population connectivity and dispersal dynamics is vital for successful management. Our study used a 357-base pair mitochondrial control region locus sequenced for 103 individuals and 18 nuclear microsatellite loci genotyped for 245 individuals to investigate population structure in the Atlantic and Pacific populations of the pelagic seabird, Leach's storm-petrel Oceanodroma leucorhoa leucorhoa. This species is under intense predation pressure at one regionally important colony on St Kilda, Scotland, where a disparity between population decline and predation rates hints at immigration from other large colonies. AMOVA, F(ST), Φ(ST) and Bayesian cluster analyses revealed no genetic structure among Atlantic colonies (Global Φ(ST) = -0.02 P > 0.05, Global F(ST) = 0.003, P > 0.05, STRUCTURE K = 1), consistent with either contemporary gene flow or strong historical association within the ocean basin. The Pacific and Atlantic populations are genetically distinct (Global Φ(ST) = 0.32 P < 0.0001, Global F(ST) = 0.04, P < 0.0001, STRUCTURE K = 2), but evidence for interocean exchange was found with individual exclusion/assignment and population coalescent analyses. These findings highlight the importance of conserving multiple colonies at a number of different sites and suggest that management of this seabird may be best viewed at an oceanic scale. Moreover, our study provides an illustration of how long-distance movement may ameliorate the potentially deleterious impacts of localized environmental change, although direct measures of dispersal are still required to better understand this process.

The comparative biology of diving in two genera of European Dytiscidae (Coleoptera).

Surfacing behaviour is fundamental in the ecology of aquatic air-breathing organisms; however, it is only in vertebrates that the evolutionary ecology of diving has been well characterized. Here, we explore the diving behaviour of dytiscid beetles, a key group of surface-exchanging freshwater invertebrates, by comparing the dive responses of 25 taxa (Deronectes and Ilybius spp.) acclimated at two temperatures. The allometric slopes of dive responses in these dytiscids appear similar to those of vertebrate ectotherms, supporting the notion that metabolic mode shapes the evolution of diving performance. In both genera, beetles spend more time submerged than on the surface, and surface time does not vary with the temperature of acclimation. However, presumably in order to meet increased oxygen demand at higher temperatures, Deronectes species increase surfacing frequency, whereas Ilybius species decrease dive time, an example of 'multiple solutions.' Finally, widespread northern species appear to possess higher diving performances than their geographically restricted southern relatives, something which may have contributed to their range expansion ability.

Haemoptysis: diagnosis and treatment.

Haemoptysis is a common symptom in clinical practice, which requires further investigation. Fortunately, massive haemoptysis only accounts for a small proportion of these episodes. It is a medical emergency that carries a high mortality rate. There are no agreed management guidelines. This review discusses proposed methods of resuscitation as well as outlining a diagnostic algorithm and discusses treatments including bronchial artery embolization, endobronchial therapy, surgery and medical therapies.

Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study.

This international phase III study of inhaled dry powder mannitol was a randomised, double-blind, 26-week study, followed by a further 26-week, open-label (OL) extension. 324 cystic fibrosis (CF) patients were randomised, in a 3:2 ratio, to mannitol (400 mg b.i.d.) and control groups. The primary efficacy end-point was to determine the change in forced expiratory volume in 1 s (FEV1) over the double-blind phase. Secondary end-points included changes in forced vital capacity and pulmonary exacerbations. A significant improvement in FEV1 was seen over 26 weeks (p<0.001) and was apparent by 6 weeks, irrespective of concomitant recombinant human deoxyribonuclease (rhDNase) use. At 26 weeks, there was a significant improvement in FEV1 of 92.9 mL for subjects receiving mannitol compared with controls (change from baseline 118.9 mL (6.5%) versus 26.0 mL (2.4%); p<0.001). Improvements in FEV1 were maintained up to 52 weeks in the OL part of the study. There was a 35.4% reduction in the incidence of having an exacerbation on mannitol (p=0.045). The incidence of adverse events (AEs) was similar in both groups, although treatment-related AEs were higher in the mannitol compared with the control group. The most common mannitol-related AEs were cough, haemoptysis and pharyngolaryngeal pain. Mannitol showed sustained, clinically meaningful benefit in airway function in CF, irrespective of concomitant rhDNase use. Mannitol appears to have an acceptable safety profile for patients with CF.

Adult cystic fibrosis care in the 21st century.

Cystic fibrosis (CF) is the most common autosomal recessive inherited disease of Caucasian populations. As a result of a variety of diagnostic and therapeutic strategies there has been a dramatic increase in the life expectancy of patients with CF in the last decades and 50% of patients are now adults. This review will focus on the disease in adults and the provision of appropriate care. The complex care required to improve the survival and quality of life in the adult patients can best be provided in a dedicated adult cystic fibrosis unit. These units currently exist in many European countries, but more are needed in Italy.

British Thoracic Society guideline for non-CF bronchiectasis.

The diagnosis, investigation and particularly management of bronchiectasis has been largely empirical and the subject of relatively few controlled clinical trials. There are no clear guidelines, although an Australian position statement has been published concerning bronchiectasis in children. The purposes of these guidelines were therefore threefold: (1) to identify relevant studies in non-cystic fibrosis (CF) bronchiectasis; (2) to provide guidelines on management based on published studies where possible or a consensus view; and (3) to identify gaps in our knowledge and identify areas for future study.

Cystic fibrosis neutrophils have normal intrinsic reactive oxygen species generation.

Previous studies have identified abnormalities in the oxidative responses of the neutrophil in cystic fibrosis (CF), but it is unclear whether such changes relate to loss of membrane cystic fibrosis transmembrane conductance regulator (CFTR) or to the inflammatory environment present in this disease. The aim of the present study was to determine whether neutrophils from CF patients demonstrate an intrinsic abnormality of the respiratory burst. The respiratory burst activity of neutrophils isolated from stable DeltaF508 homozygote CF patients and matched healthy controls was quantified by both chemiluminscence and cytochrome C reduction. Expression of NADPH oxidase components and CFTR was determined by Western blotting and RT-PCR. The oxidative output from neutrophils from CF in response to receptor-linked and particulate stimuli did not differ from that of controls. Expression of NADPH oxidase components was identical in CF and non-CF neutrophils. While low levels of CFTR mRNA could be identified in the normal human neutrophil, we were unable to detect CFTR protein in human neutrophil lysates or immunoprecipitates. CFTR has no role in controlling neutrophil oxidative activity; previously reported differences in neutrophil function between CF and non-CF subjects most likely relate to the inflammatory milieu from which the cells were isolated.

Do differences in developmental mode shape the potential for local adaptation?

Future climate change is leading to the redistribution of life on Earth as species struggle to cope with rising temperatures. Local adaptation allows species to become locally optimized and persist despite environmental selection, but the extent to which this occurs in nature may be limited by dispersal and gene flow. Congeneric marine gastropod species (Littorina littorea and L. saxatilis) with markedly different developmental modes were collected from across a latitudinal thermal gradient to explore the prevalence of local adaptation to temperature. The acute response of metabolic rate (using oxygen consumption as a proxy) to up-ramping and down-ramping temperature regimes between 6°C and 36°C was quantified for five populations of each species. The highly dispersive L. littorea exhibited minimal evidence of local adaptation to the thermal gradient, with no change in thermal optimum (Topt ) or thermal breadth (Tbr ) and a decline in maximal performance (max ) with increasing latitude. In contrast, the direct developing L. saxatilis displayed evidence of local optimization, although these varied idiosyncratically with latitude, suggesting a suite of selective pressures may be involved in shaping thermal physiology in this relatively sedentary species. Our results show that the biogeography of thermal traits can differ significantly between related species, and show that interpopulation differences in thermal performance do not necessarily follow simple patterns that may be predicted based on latitudinal changes in environmental temperatures. Further research is clearly required to understand the mechanisms that can lead to the emergence of local adaptation in marine systems better and allow improved predictions of species redistribution in response to climate change.

Upper airway 2: Bronchiectasis, cystic fibrosis and sinusitis.

The nose and paranasal sinuses are contiguous with the lower respiratory tract. Patients with bronchiectasis and cystic fibrosis commonly have sinonasal disease, which is thought to have the same aetiology and pathophysiology as the chronic lung disease. Despite this, the conditions are rarely considered together and there is very little literature on the treatment of sinonasal disease in bronchiectasis. In addition to being a common cause of comorbidity, there is evidence suggesting that sinonasal disease may directly influence the bronchial condition. This article reviews sinonasal disease in bronchiectasis and cystic fibrosis and addresses the possible interactions between the health and disease of the upper and lower airways.

Variable antibiotic susceptibility in populations of Pseudomonas aeruginosa infecting patients with bronchiectasis.

OBJECTIVES: To investigate variability in colony morphology and antibiotic susceptibility in populations of Pseudomonas aeruginosa from sputa of patients with bronchiectasis without cystic fibrosis (CF) compared with P. aeruginosa isolated from patients with CF, and from other infections as controls. METHODS: P. aeruginosa was cultured from 31 patients with non-CF bronchiectasis, 24 with CF, 7 ventilated patients and 9 skin swabs. Four colonies of each morphotype of P. aeruginosa were tested for susceptibility to 12 antibiotics by disc diffusion. The variability in susceptibility between the isolates in each patient's population of P. aeruginosa was investigated. RESULTS: The classic morphotype of P. aeruginosa was cultured from control samples with an average variation in zone size of 2 mm (range 0-4 mm) for the four colonies tested. Non-CF bronchiectasis sputa contained 1-3 colonial morphotypes of P. aeruginosa; the average difference between the largest and smallest zone sizes found in all examples of the morphotypes present in each sample varied from 3 mm (1-9 mm) for colistin to 8 mm (0-24 mm) for piperacillin/tazobactam. CF sputa contained 2-6 morphotypes of P. aeruginosa with a wider variation of susceptibility. There was variation between bacteria of the same morphotype from non-CF bronchiectasis and CF sputa. CONCLUSIONS: Phenotypic variation in colonial form and antibiotic susceptibility is not unique to chronic infection in CF but is also found in non-CF bronchiectasis. This questions the use of current susceptibility testing methods for the complex populations of bacteria found in chronic lung infection.

Investigating the effects of long-term dornase alfa use on lung function using registry data.

BACKGROUND: Dornase alfa (DNase) is one of the commonest cystic fibrosis (CF) treatments and is often used for many years. However, studies have not evaluated the effectiveness of its long-term use. We aimed to use UK CF Registry data to investigate the effects of one-, two-, three-, four- and five-years of DNase use on lung function to see if the benefits of short-term treatment use are sustained long term. METHODS: We analysed data from 4,198 people in the UK CF Registry from 2007 to 2015 using g-estimation. By controlling for time-dependent confounding we estimated the effects of long-term DNase use on percent predicted FEV1 (ppFEV1) and investigated whether the effect differed by ppFEV1 at treatment initiation or by age. RESULTS: Considering the population as a whole, there was no significant effect of one-year's use of DNase; change in ppFEV1 over one year was -0.1% in the treated compared to the untreated (p = 0.51) and this did not change with long-term use. However, treatment was estimated to be more beneficial in people with lower lung function (p < 0.001); those with ppFEV1 < 70% at treatment initiation, showed an increase in lung function over one year that was sustained out to five years. The estimated effect of DNase did not depend on age (p = 0.35). CONCLUSIONS: DNase improved lung function in individuals with reduced lung function, bringing a step-change in lung function, but no change in the slope of decline. There was no evidence for a benefit in lung function in those initiating treatment with ppFEV1 > 70%.

The emerging burden of liver disease in cystic fibrosis patients: A UK nationwide study.

OBJECTIVE: Cystic fibrosis associated liver disease (CFLD) is the third largest cause of mortality in CF. Our aim was to define the burden of CFLD in the UK using national registry data and identify risk factors for progressive disease. METHODS: A longitudinal population-based cohort study was conducted. Cases were defined as all patients with CFLD identified from the UK CF Registry, 2008-2013 (n = 3417). Denominator data were derived from the entire UK CF Registry. The burden of CFLD was characterised. Regression analysis was undertaken to identify risk factors for cirrhosis and progression. RESULTS: Prevalence of CFLD increased from 203.4 to 228.3 per 1000 patients during 2008-2013. Mortality in CF patients with CFLD was more than double those without; cirrhotic patients had higher all-cause mortality (HR 1.54, 95% CI 1.09 to 2.18, p = 0.015). Median recorded age of cirrhosis diagnosis was 19 (range 5-53) years. Male sex, Pseudomonas airway infection and CF related diabetes were independent risk factors for cirrhosis. Ursodeoxycholic acid use was associated with prolonged survival in patients without cirrhosis. CONCLUSIONS: This study highlights an important changing disease burden of CFLD. The prevalence is slowly increasing and, importantly, the disease is not just being diagnosed in childhood. Although the role of ursodeoxycholic acid remains controversial, this study identified a positive association with survival.

Cystic fibrosis liver disease: to transplant or not to transplant?

Biliary cirrhosis complicates some adults with cystic fibrosis (CF) and may require transplantation. Cardio-respiratory disease severity varies such that patients may require liver transplantation, heart/lung/liver (triple) grafts or may be too ill for any procedure. A 15-year experience of adults with CF-related liver disease referred for liver transplantation is presented with patient survival as outcome. Twelve patients were listed for triple grafting. Four died of respiratory disease after prolonged waits (4-171 weeks). Eight underwent transplantation (median wait 62 weeks); 5-year actuarial survival was 37.5%. Four died perioperatively; only one is alive at 8-years. Eighteen patients underwent liver transplant alone (median wait 7 weeks); 1- and 5-year actuarial survival rates were 100% and 69%. Three long-term survivors required further organ replacement (two heart/lung and one renal). Two others were turned down for heart/lung transplantation and four have significant renal impairment. Results for triple grafting were poor with unacceptable waiting times. Results for liver transplant alone were satisfactory, with acceptable waiting times and survival. However, further grafts were required and renal impairment was frequent. The policy of early liver transplantation for adults with CF with a view to subsequent heart/lung or renal transplantation needs assessment in the context of long-term outcome.

Exacerbations in cystic fibrosis: 4--Non-cystic fibrosis bronchiectasis.

Bronchiectasis unrelated to cystic fibrosis (CF) is increasingly recognised as an important and major primary respiratory disease in developing countries. In affluent countries, bronchiectasis is also increasingly recognised in subsections of communities (such as indigenous peoples) as well as a co-existent disease/co-morbidity and disease modifier in respiratory diseases such as chronic obstructive pulmonary disease. The epidemiology, pathogenesis, prevention and management of exacerbations of non-CF bronchiectasis are reviewed. There are few data on all aspects of exacerbations in bronchiectasis. Some of the management issues are common to non-CF and CF bronchiectasis, but it would be unwise to extrapolate from CF studies to non-CF bronchiectasis. In some situations this may be harmful.

Clostridium difficile pancolitis in adults with cystic fibrosis.

We report three cases of Clostridium difficile pancolitis in adults with cystic fibrosis (CF) in whom the presenting symptoms were atypical. All three required treatment with systemic steroids, in addition to oral vancomycin and metronidazole to achieve resolution of the colitis. This experience suggests that C. difficile colitis should be considered in individuals with CF presenting with non-specific abdominal symptoms.

A single centre experience of liver disease in adults with cystic fibrosis 1995-2006.

BACKGROUND: Liver disease is an important cause of death in adults with cystic fibrosis (CF). Ursodeoxycholic acid (UDCA) may slow progression. Managing varices and timely evaluation for liver transplantation are important. METHODS: Adults with CF underwent annual review. Abnormalities of liver function tests or ultrasound prompted referral to the CF/liver clinic where UDCA was commenced. Endoscopic surveillance for varices was undertaken if ultrasound suggested portal hypertension. RESULTS: 154 patients were followed for a median 5 years. 43 had significant liver disease, 29 had cirrhosis with portal hypertension and 14 had ultrasound evidence of cirrhosis without portal hypertension. All started UDCA. Only one patient developed chronic liver failure and none required liver transplantation. 27 underwent endoscopy; 1 required variceal banding, the others had insignificant varices. Ultrasound was normal in 97 patients while five had steatosis; nine further patients had splenomegaly but no other evidence of portal hypertension. Neither spleen size nor platelet count correlated with portal hypertension. CONCLUSIONS: Liver disease was common in adults with CF but disease progression was rare. Thus liver disease detected and closely monitored in adults appeared to have a milder course than childhood CF. Splenomegaly, unrelated to portal hypertension may be a consequence of CF.

Does plasticity in thermal tolerance trade off with inherent tolerance? The influence of setal tracheal gills on thermal tolerance and its plasticity in a group of European diving beetles.

In the face of global warming, both the absolute thermal tolerance of an ectotherm, and its ability to shift its tolerance level via acclimation, are thought to be fundamentally important. Understanding the links between tolerance and its plasticity is therefore critical to accurately predict vulnerability to warming. Previous studies in a number of ectotherm taxa suggest trade-offs in the evolution of thermal tolerance and its plasticity, something which does not, however, apply to Deronectes diving beetles, where these traits are instead positively correlated. Here we revisit the relationship between thermal tolerance and plasticity in these beetles, paying attention to a recently discovered morphological adaptation supporting under water respiration - setal tracheal gills. Hollow setae on the elytra interconnect with the beetle's tracheal system, providing a gas exchange surface that allows oxygen to be extracted directly from the water. This enables individuals to stay submerged for longer than their subelytral air stores would allow. We show that hypoxia reduced heat tolerance, especially when individuals were denied access to air, forcing them to rely solely on aquatic gas exchange. Species with higher densities of these gas-exchanging setae exhibited improved cold tolerance, but reduced heat tolerance and lower plasticity of heat tolerance. Differences in setal tracheal gill density across species were also related to habitat use: species with low gill density were found mainly in intermittent, warmer rivers, where underwater gas exchange is more problematic and risks of surfacing may be smaller. Moreover, when controlling for differences in gill density we no longer found a significant relationship between heat tolerance and its plasticity, suggesting that the previously reported positive relationship between these variables may be driven by differences in gill density. Differences in environmental conditions between the preferred habitats could simultaneously select for characteristic differences in both thermal tolerance and gill density. Such simultaneous selection may have resulted in a non-causal association between cold tolerance and gill density. For heat tolerance, the correlations with gill density could reflect a causal relationship. Species relying strongly on diffusive oxygen uptake via setal tracheal gills may have a reduced oxygen supply capacity and may be left with fewer options for matching oxygen uptake to oxygen demand during acclimation, which could explain their reduced heat tolerance and limited plasticity. Our study helps shed light on the mechanisms that underpin thermal tolerance and plasticity in diving air-breathing ectotherms, and explores how differences in thermal tolerance across species are linked to their selected habitat, morphological adaptations and evolutionary history.

Variability of sweat chloride concentration in subjects with cystic fibrosis and G551D mutations.

INTRODUCTION: Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial. METHODS: In subjects with G551D at least 12years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48weeks. We explored 1062 pilocarpine sweat test values obtained in 78 placebo patients of the VX08-770-102 trial. RESULTS: Mean overall sweat chloride value (all patients, all tests, n=1062) was 100.8mmol/L (SD 12.7mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9mmol/L (95% CI 7.4-10.6) and within-subject SD was 8.1mmol/L (95% CI 7.5-8.7). Limits of repeatability for repeat measurements were -19.7 to +21.6mmol/L using values from one arm, and -13.3 to 11.8mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial. CONCLUSION: Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter.