Antimicrobial therapies for prevention of recurrent acute exacerbations of COPD (AECOPD): beyond the guidelines.

BACKGROUND: Unfortunately, many COPD patients continue to exacerbate despite good adherence to GOLD Class D recommended therapy. Acute exacerbations lead to an increase in symptoms, decline in lung function and increased mortality rate. The purpose of this review is to do a literature search for any prophylactic anti-microbial treatment trials in GOLD class D patients who 'failed' recommended therapy and discuss the role of COPD phenotypes, lung and gut microbiota and co-morbidities in developing a tailored approach to anti-microbial therapies for high frequency exacerbators. MAIN TEXT: There is a paucity of large, well-conducted studies in the published literature to date. Factors such as single-centre, study design, lack of well-defined controls, insufficient patient numbers enrolled and short follow-up periods were significant limiting factors in numerous studies. One placebo-controlled study involving more than 1000 patients, who had 2 or more moderate exacerbations in the previous year, demonstrated a non-significant reduction in exacerbations of 19% with 5 day course of moxifloxacillin repeated at 8 week intervals. In Pseudomonas aeruginosa (Pa) colonised COPD patients, inhaled antimicrobial therapy using tobramycin, colistin and gentamicin resulted in significant reductions in exacerbation frequency. Viruses were found to frequently cause acute exacerbations in COPD (AECOPD), either as the primary infecting agent or as a co-factor. However, other, than the influenza vaccination, there were no trials of anti-viral therapies that resulted in a positive effect on reducing AECOPD. Identifying clinical phenotypes and co-existing conditions that impact on exacerbation frequency and severity is essential to provide individualised treatment with targeted therapies. The role of the lung and gut microbiome is increasingly recognised and identification of pathogenic bacteria will likely play an important role in personalised antimicrobial therapies. CONCLUSION: Antimicrobial therapeutic options in patients who continue to exacerbate despite adherence to guidelines-directed therapy are limited. Phenotyping patients, identification of co-existing conditions and assessment of the microbiome is key to individualising antimicrobial therapy. Given the impact of viruses on AECOPD, anti-viral therapeutic agents and targeted anti-viral vaccinations should be the focus of future research studies.

The use of cough peak flow in the assessment of respiratory function in clinical practice- A narrative literature review.

Cough peak flow (CPF) is a useful clinical measurement to assess neuromuscular activity and effective coordination, yet it is rarely used in clinical practice outside of the management of patients with neuromuscular disorders. A CPF of above 160 L/min is required for an effective cough and less than 270 L/min is associated with increased secretion retention and risk of infection. Reduced CPF can be due to a number of mechanisms including reduced respiratory muscle strength, lack of co-ordination of glottic closure and opening, airway obstruction and, age and activity related changes. CPF has been shown to be correlated with other measures of pulmonary function in neuromuscular disorders and in predicting extubation failure. Patients with Parkinson's disease have a reduced CPF even at early stages and dedicated expiratory muscle strength training (EMST) has been shown to be beneficial. Sequential studies in patient with stroke-associated dysphagia reported CPF was correlated with risk of respiratory infection and results of formal swallow assessments. Age-related changes in expiratory muscle strength and lung physiology contribute to increased risk of aspiration and pneumonia. EMST may have a role in healthy adults to improve muscle strength and effective cough, potentially reducing risk of respiratory tract infections even in the absence of disease. CPF has potential to be extremely useful in clinical practice in a wide spectrum of diseases. In particular, studies in patients with frequent exacerbations of COPD and recurrent pneumonia are currently lacking and would be of benefit to explore the relationship between ineffective cough and recurrent infection.

Review of the prevalence, pathogenesis and management of OSA-COPD overlap.

PURPOSE: OSA-COPD overlap is an important and prevalent condition yet remains under-recognised among the vast majority of respiratory health professionals. Patients with OSA-COPD overlap experience more severe respiratory symptoms and worse quality of life, and the relative risk of exacerbations, hospitalisations, and mortality is higher than in either disease state alone. METHODS: Electronic databases PUBMED and Google Scholar were searched for studies and academic papers that discussed OSA-COPD overlap. Relevant papers that discussed prevalence, pathophysiology, microbiome studies, treatment regimens and outcomes were included in this paper. RESULTS: High-risk patients with either COPD or OSA should be screened for overlap syndrome as part of routine clinical practice. Screening questionnaires can identify high-risk patients with COPD who may benefit from formal polysomnography. Patients with OSA who are aged over 40 with a significant smoking history or environmental exposures have an increased pre-test probability of obstructive airway disease. The potential roles of gastro-oesophageal reflux disease and lung-gut microbiome are evolving and merit further investigation. A tailored approach to reach a timely diagnosis and thus optimisation of both conditions are key to management. CPAP is the primary therapy for OSA; however, patients with more advanced COPD, with daytime hypercapnia or severe nocturnal desaturations, may benefit from bilevel positive airway pressure. CONCLUSION: Increased awareness, access to timely investigations and initiation of therapy will improve overall outcomes in OSA-COPD overlap by reducing hospitalisations for exacerbations of COPD and improve mortality rates.

A qualitative synthesis of gastro-oesophageal reflux in bronchiectasis: Current understanding and future risk.

Gastro-oesophageal reflux disease (GORD) is a common comorbidity in bronchiectasis, and is often associated with poorer outcomes. The cause and effect relationship between GORD and bronchiectasis has not yet been fully elucidated and a greater understanding of the pathophysiology of the interaction and potential therapies is required. This review explores the underlying pathophysiology of GORD, its clinical presentation, risk factors, commonly applied diagnostic tools, and a detailed synthesis of original articles evaluating the prevalence of GORD, its influence on disease severity and current management strategies within the context of bronchiectasis. The prevalence of GORD in bronchiectasis ranges from 26% to 75%. Patients with co-existing bronchiectasis and GORD were found to have an increased mortality and increased bronchiectasis severity, manifest by increased symptoms, exacerbations, hospitalisations, radiological extent and chronic infection, with reduced pulmonary function and quality of life. The pathogenic role of Helicobacter pylori infection in bronchiectasis, perhaps via aspiration of gastric contents, also warrants further investigation. Our index of suspicion for GORD should remain high across the spectrum of disease severity in bronchiectasis. Identifying GORD in bronchiectasis patients may have important therapeutic and prognostic implications, although clinical trial evidence that treatment targeted at GORD can improve outcomes in bronchiectasis is currently lacking.

Gastrointestinal stromal tumours (GISTs): an insight into clinical practice with review of literature.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are rare mesenchymal tumours of the gastrointestinal tract. We retrospectively reviewed the clinical management of all patients with GIST presenting to a regional multidisciplinary upper gastrointestinal cancer group in the north of England. METHODS: Clinical, pathological, immunohistochemical treatment strategies, follow-up and outcome data on all patients with GIST between 2007 and 2012 were reviewed. Tumours were categorised by risk according to the National Institutes of Health (NIH) and AFIP models. RESULTS: 36 (85.7%) of 42 tumours were located in the stomach, 5 (11.9%) in the small intestine and 1 (2.4%) in the oesophagus. Median age of patients was 68 (range 43-91) years. 24 patients (57.1%) were female. Tumour size ranged from 1.0  to 12.7 cm with mean size of 5.46 cm. Metastasis was present in 19 (45.2%) patients at diagnosis with distant metastases in 12 patients. Liver was the most common site of metastases. Histology and immunohistochemical analysis was available in 32 (76.2%) patients. Most common histology was spindle cell morphology 17/32 (53.1%) followed by epithelioid 9/32 (28.1%) and mixed morphology 5/32 (15.6%). The positive rate for KIT protein (CD117) was 90.6%, while that for CD34 was 75.0%. 12/25 (48.0%) and 8/23 (34.8%) patients were categorised as high risk as per NIH and AFIP risk scores, respectively. 23/42 (54.8%) patients underwent surgical resection, after which 5/23 (21.7%) had adjuvant imatinib therapy. Imatinib was given as primary therapy in 14/42 (33.3%) patients. CONCLUSIONS: Surgery alone may not be a curative treatment for GISTs. Targeted therapy with imatinib may play an important role in the treatment of GISTs. Further risk categorisation models may be needed to evaluate GIST behaviour and prognosis.

Seaweed extracts and galacto-oligosaccharides improve intestinal health in pigs following Salmonella Typhimurium challenge.

Pork and pork products are recognised as vehicles of Salmonella Typhimurium infection in humans. Seaweed-derived polysaccharides (SWE) and galacto-oligosaccharides (GOS) have shown to exhibit antimicrobial, prebiotic and immunomodulatory activity. The objective of this study was to assess the effects of dietary GOS and SWE supplementation on reducing S. Typhimurium numbers and intestinal inflammation in vivo. In total, 30 pigs (n=10/treatment, BW 30.9 kg) were randomly assigned to three dietary treatments: (1) basal diet; (2) basal diet+2.5 g GOS/kg diet; (3) basal diet+SWE (containing 180 mg laminarin/kg diet+340 mg fucoidan/kg diet). Following an 11-day dietary adaptation period, pigs were orally challenged with 108 colony-forming units/ml S. Typhimurium (day 0). Pigs remained on their diets for a further 17 days and were then sacrificed for sample collection. The SWE supplementation did not affect S. Typhimurium numbers on days 2 and 4 post-challenge but reduced S. Typhimurium numbers in faecal samples collected day 7 post-challenge (-0.80 log gene copy numbers (GCN)/g faeces) and in caecal and colonic digesta (-0.62 and -0.98 log GCN/g digesta, respectively; P<0.05) compared with the control treatment. Lactobacillus numbers were increased in caecal and colonic digesta after GOS supplementation (+0.70 and +0.35 log GCN/g digesta, respectively; P<0.05). In colonic tissue, both GOS and SWE supplementation resulted in reduced messenger RNA expression levels of interleukin (IL)-6, IL-22, tumour necrosis factor-α and regenerating islet-derived protein 3-γ (P<0.05). It can be concluded that dietary supplementation of SWE reduced faecal and intestinal S. Typhimurium numbers compared with the basal diet, whereas dietary GOS supplementation increased Lactobacillus numbers in caecal and colonic digesta but did not affect S. Typhimurium numbers. Supplementation of GOS and SWE reduced the gene expression of pro-inflammatory cytokines in colonic tissue of pigs after the experimental S. Typhimurium challenge.

High prevalence of stress urinary incontinence in adult patients with bronchiectasis.

Stress urinary incontinence (SUI) is frequently under-reported in patients with chronic lung disease and may have negative psychosocial consequences. We conducted a prospective study to determine the prevalence, severity and treatment outcomes of SUI in female bronchiectasis patients referred for airway clearance techniques. Nineteen out of 40 (48%) patients reported SUI symptoms. Of these, 14 (74%) reported a reduced quality of life secondary to SUI. Following personalised intervention, symptom improvement was observed in 13/19 (68%). Five out of 19 (26%) required specialist referral for further continence care. No associations with lung disease severity and SUI were noted. SUI is common in adult female bronchiectasis patients and should be routinely screened for to improve patients' overall quality of life.

Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts.

INTRODUCTION: Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality. METHODS: We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies. RESULTS: The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in 'severe' patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline. CONCLUSION: The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.

Lack of association between KIR and HLA-C type and susceptibility to idiopathic bronchiectasis.

INTRODUCTION: Idiopathic bronchiectasis is a poorly defined disease characterised by persistent inflammation, infection and progressive lung damage. Natural killer (NK) cells provide a major defense against infection, through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIR), and human leukocyte antigens (HLA) class I molecules. Homozygosity for HLA-C has been shown in a single study to confer increased genetic susceptibility to idiopathic bronchiectasis. We aimed to assess whether the KIR and HLA repertoire, alone or in combination, may influence the risk of developing idiopathic bronchiectasis, in an independent replication study. METHODS: In this prospective, observational, case-control association study, 79 idiopathic bronchiectasis patients diagnosed following extensive aetiological investigation were compared with 98 anonymous, healthy, age, sex and ethnically-matched controls attending blood donor sessions in the same geographical location. DNA extraction was performed according to standardised techniques. Determination of presence or absence of KIR genes was performed by a sequence specific oligonucleotide probe method. Allele frequencies for the proposed KIR, HLA-B and HLA-C risk alleles both individually and in combinations were compared. RESULTS: We found no significant differences in allele frequency between the idiopathic bronchiectasis and control samples, whether considering HLA-C group homozygosity alone or in combination with the KIR type. DISCUSSION: Our results do not show an association between HLA-C and KIR and therefore do not confirm previous positive findings. This may be explained by the lower frequency of HLA-C1 group homozygosity in the control population of the previous study (27.2%), compared to 42.3% in our study, which is consistent with the genetic profiling of control groups across the UK. The previous positive association study may therefore have been driven by an anomalous control group. Further larger prospective multicentre replication studies are needed to determine if an association exists.

Pulmonary alveolar proteinosis: report of two cases in the West of Ireland with review of current literature.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung condition characterised by the accumulation of lipoproteinaceous surfactant material within alveolar airspaces resulting in clinical manifestations ranging from asymptomatic to severe respiratory failure. Three disease subtypes are recognised: autoimmune, secondary and congenital. METHODS: We describe two presentations of PAP in the West of Ireland with a review of the current literature. RESULTS: Autoimmune PAP, associated with the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, accounts for >90 % of cases. Treatment with whole lung lavage is the current standard of care. Novel therapies targeting alveolar macrophages (recombinant GM-CSF therapy) and anti-GM-CSF antibodies (rituximab, plasmapharesis) are under investigation. CONCLUSIONS: This is a summary of available literature outlining current clinical practice in the diagnosis, management, and treatment of PAP. PAP should be considered in the differential diagnosis of any patient with a restrictive pulmonary defect. Without high clinical suspicion, this diagnosis can easily be missed.

Non-cystic fibrosis bronchiectasis.

Bronchiectasis is a chronic debilitating condition with considerable phenotypic diversity. A vicious cycle of infection and inflammation exists in damaged airways with patients suffering from persistent cough, purulent sputum production, recurrent chest infections and general malaise. The associated burden of disease in terms of increased morbidity, reduced quality of life and the socioeconomic cost of long-term management is significant. Further research is essential to improve our understanding of the development and progression of this disease. This article reviews what is currently known about bronchiectasis, its pathophysiology, aetiology and management strategies.

Phenotyping adults with non-cystic fibrosis bronchiectasis: a prospective observational cohort study.

BACKGROUND: Bronchiectasis is the outcome of a number of different airway insults. Very few studies have characterised the aetiology and utility of a dedicated screening proforma in adult patients attending a general bronchiectasis clinic. METHODS: A prospective observational study of 189 bronchiectasis patients attending two centres in the North East of England over a two-year period was performed. RESULTS: The aetiology of bronchiectasis was identified in 107/189(57%) patients. Idiopathic bronchiectasis (IB) represented the largest subgroup (43%). Post-infection bronchiectasis (PIB) constituted the largest proportion (24%) of known causes. Mean age (SD) at diagnosis was 54(20) years with a mean age at symptom onset of 37(24) years, accounting for a diagnostic delay of 17 years. Age of symptom onset was significantly younger in patients with PIB compared to IB (p < 0.0001) and in Pseudomonas sputum positive patients (p = 0.007). Screening for APBA and total immunoglobulin deficiency identified 9 (5%) patients who then had tailored treatment. Routine screening for other aetiologies was deemed unnecessary. CONCLUSION: IB and PIB accounted for two thirds of cases of bronchiectasis in a general population. We recommend routine screening for ABPA and total immunoglobulin deficiency but not for other rarer aetiologies.

Solitary fibrous tumours of the pleura: report of two cases and literature review.

BACKGROUND: Solitary fibrous tumours of the pleura (SFTPs) are rare pleural mesenchymal neoplasms with distinct clinicopathological and immunohistochemical features, accounting for less than 5 % of all neoplasms involving the pleura. METHODS: We present two cases of SFTP with a review of the current literature. RESULTS: Clinical presentation varies according to size and intrathoracic localisation. The molecular pathology of SFTPs is largely unknown. Complete surgical resection is recommended with long-term clinic and radiographic follow-up due to its malignant potential. CONCLUSIONS: This is a summary of available literature outlining current clinical practice in the diagnosis, management, and treatment of SFTPs in Ireland.

Long-lived mesoscopic entanglement outside the Lamb-Dicke regime.

We create entangled states of the spin and motion of a single 40Ca+ ion in a linear ion trap. We theoretically study and experimentally observe the behavior outside the Lamb-Dicke regime, where the trajectory in phase space is modified and the motional coherent states become squeezed. We directly observe the modification of the return time of the trajectory, and infer the squeezing. The mesoscopic entanglement is observed up to Deltaalpha=5.1 with coherence time 170 micros and mean phonon excitation n = 16.

High-efficiency detection of a single quantum of angular momentum by suppression of optical pumping.

We propose and demonstrate experimentally the discrimination between two spin states of an atom purely on the basis of their angular momentum. The discrimination relies on angular momentum selection rules and does not require magnetic effects such as a magnetic dipole moment of the atom or an applied magnetic field. The central ingredient is to prevent by coherent population trapping an optical pumping process which would otherwise relax the spin state before a detectable signal could be obtained. We detected the presence or absence of a single quantum (h) of angular momentum in a trapped calcium ion in a single observation with success probability 0.86. As a practical technique, the method can be applied to read out some types of quantum computer.

Oxford ion-trap quantum computing project.

We describe recent progress in the development of an ion-trap quantum information processor. We discuss the choice of ion species and describe recent experiments on read-out for a ground-state qubit and photoionization trap loading.