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.

Marked deterioration in rheumatoid arthritis associated bronchiectasis following treatment with Rituximab.

We report a 67 year old lady with Rheumatoid Arthritis (RA) and mild bronchiectasis (BE) whose treatment was escalated to Rituximab. Nine months after commencing Rituximab her lung sepsis worsened dramatically with repeated hospitalization, new sputum isolation of Stenotrophomonas maltophilia and Pseudomonas aeruginosa and marked radiological deterioration in BE. She was found to have a low serum IgG and IgM levels almost certainly as a complication of Rituximab. Immunoglobulin replacement therapy was instituted and her clinical status has slowly improved.

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.

Agronomic evaluation and molecular characterisation of the acetolactate synthase gene in imazapyr tolerant sugarcane (Saccharum hybrid) genotypes.

KEY MESSAGE: Mutagenesis had no effect on number of stalks/plot, stalk height, fibre and sucrose content of mutants. Imazapyr tolerance is likely due to a S622N mutation in the acetolactate synthase gene. The herbicidal compound imazapyr is effective against weeds such as Cynodon and Rottboellia species that constrain sugarcane production. This study aimed to compare agronomic characteristics of three imazapyr tolerant mutants (Mut 1, Mut 6 and Mut 7) with the non-mutated N12 control after 18 months of growth, and to sequence the acetolactate synthase (ALS) gene to identify any point mutations conferring imazapyr tolerance. There were no significant differences in the number of stalks/plot, stalk height, fibre and sucrose contents of the mutants compared with the N12 control. However, Mut 1 genotype was more susceptible to the Lepidopteran stalk borer, Eldana saccharina when compared with the non-mutated N12 (11.14 ± 1.37 and 3.89 ± 0.52% internodes bored, respectively), making Mut 1 less desirable for commercial cultivation. Molecular characterisation of the ALS gene revealed non-synonymous mutations in Mut 6. An A to G change at nucleotide position 1857 resulted in a N513D mutation, while a G to A change at nucleotide position 2184 imposed a S622N mutation. Molecular dynamics simulations revealed that the S622N mutation renders an asparagine side chain clash with imazapyr, hence this mutation is effective in conferring imazapyr tolerance.

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.

Predictive value of C-reactive protein and clinically relevant baseline variables in sarcoidosis.

BACKGROUND: This study aims to examine the predictive and prognostic implications of C-reactive protein (CRP) and clinically relevant baseline variables in determining treatment indication and disease progression in a large clinical cohort of patients with stable sarcoidosis. METHODS: A retrospective observational study of 328 sarcoidosis patients attending a regional tertiary referral centre over a 26-year period was performed. Clinical, biochemical, radiological and physiological data were analysed according to a clinically relevant dichotomous cutpoint of CRP. Multiple models of logistic regression were used to determine independent predictors of outcome as defined by indication for treatment with corticosteroids, radiological deterioration and physiological progression. RESULTS: 328/409 (80.2%) sarcoidosis patients had baseline serum CRP measured and were suitable for inclusion. Baseline CRP was elevated in 154 (47%). 178 (54.3%) were prescribed corticosteroid treatment during the disease course. Physiological deterioration was demonstrated in 48 (14.6%) patients and radiological progression in 59 (17.9%) patients. High baseline CRP was strongly associated with Lofgren's syndrome (p=<0.001) and reduced FVC% predicted (p=0.012). High CRP was found to be a negative predictor of radiological progression (p=0.046). In a sub-analyses of patients without Lofgren's syndrome (n=223), patients with high baseline CRP were almost twice as likely to receive corticosteroid treatment, OR 1.89 (95% CI 1.04-3.55). Low baseline DLCO% independently predicted the need for corticosteroid treatment (p=<0.001) and physiological decline (p=0.045). CONCLUSIONS: Elevated baseline CRP in sarcoidosis is associated with a good prognosis and is a negative predictive indicator of radiological progression. In patients without Lofgren's syndrome, high CRP and low DLCO% at presentation may identify a subset of patients more likely to develop physiological progression who may benefit from early systemic treatment.

Provision of nitrogen as ammonium rather than nitrate increases silicon uptake in sugarcane.

Silicon (Si) is important in mitigating abiotic and biotic plant stresses, yet many agricultural soils, such as those of the rainfed production areas of the South African sugar industry, are deficient in plant-available Si, making Si supplementation necessary. However, Si uptake by sugarcane (Saccharum spp. hybrids) is limited even where silicate amendments improve soil Si status. Rhizosphere pH, which can affect Si uptake, can be manipulated using different N-form fertilizers. We tested whether (i) fertilization with [Formula: see text] (rhizosphere acidification) increased Si uptake compared with [Formula: see text] (rhizosphere alkalinization); and (ii) uptake differed between an N-efficient, more acid-tolerant cultivar (N12) and an N-inefficient, less acid-tolerant cultivar (N14). Two pot trials with low-Si soil were fertilized with calcium silicate (Ca2SiO4) slag, plus N from ammonium sulphate [(NH4)2SO4], ammonium thiosulphate [(NH4)2S2O3] and calcium nitrate [Ca(NO3)2] (Trial 1) or N from (NH4)2S2O3 and Ca(NO3)2 only (Trial 2). Trial 2 included cultivars N12 and N14. Nitrate treatments significantly increased soil pH and soil Si compared with [Formula: see text] However, [Formula: see text] treatments significantly increased leaf and stalk Si content compared with [Formula: see text] reflected in a significant negative relationship between soil pH and leaf Si. Acid-extracted soil Si was negatively related to leaf and stalk Si, likely due to adsorption of silicic acid to soil surfaces under higher pH of the [Formula: see text] treatment and its reduced availability for plant uptake. We conclude that [Formula: see text] increased Si uptake into leaf and stalk, and propose that reduced rhizosphere pH solubilized Si from Ca2SiO4 and increased silicic acid availability for plant uptake. By contrast, [Formula: see text] may have reduced Si uptake due to adsorption of Si to soil surfaces at higher pH. Our results indicate that ammoniacal fertilizers, such as (NH4)2SO4 and urea, have potential for promoting dissolution of applied Ca2SiO4 and subsequent uptake of Si by sugarcane.

A rapid and visual loop-mediated isothermal amplification assay to detect Leifsonia xyli subsp. xyli targeting a transposase gene.

UNLABELLED: Leifsonia xyli subsp. xyli (Lxx), causal organism of ratoon stunt (RSD), does not produce any reliable internal or external symptoms on sugarcane. Its detection on a large scale is solely based on microscopic and serological methods. These methods require well-equipped laboratories, are time consuming and are not feasible for near-field detection of Lxx. In this study, we developed a loop-mediated isothermal amplification (LAMP) assay for rapid and sensitive detection of Lxx without the use of sophisticated equipment. To the best of our knowledge, this is the first report on the detection of Lxx in 30 min via an isothermal amplification method at 65°C. A transposase gene, ISLxx5, was used to design a set of six primers specifically targeting eight genomic sequences. The xylem sap was used as template, thus circumventing the need to isolate pure genomic DNA. The positive reactions were visually detected through a colour change of hydroxynaphthol blue (HNB) from violet to light blue, thus, eliminating the need for gel electrophoresis. The LAMP method was 10 times more sensitive than serological detection and as sensitive as immunofluorescence microscopy (IFM). The simplicity and sensitivity of the ISLxx5 LAMP assay makes it suitable for near-field diagnosis of RSD. SIGNIFICANCE AND IMPACT OF THE STUDY: Detection of Leifsonia xyli subsp. xyli (Lxx) on a large scale is based on serological assays such as evaporative-binding enzyme-linked immunoassay (EB-EIA). These methods are time consuming and require well-equipped laboratories. This study presents the development of a loop-mediated isothermal amplification (LAMP) assay which allows detection of Lxx in 30 min at 65°C, using xylem sap as the template. The assay requires minimal laboratory equipment and could be used at near farm conditions, thus saving time and money required to transfer samples from remote areas to diagnostic laboratories. The LAMP method shows potential as an alternative detection method for RSD.

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.