Concomitant or sequential pulmonary infection with non-tuberculous mycobacteria and Aspergillus.

Non-tuberculous mycobacteria (NTM) and Aspergillus are ubiquitous organisms that have the potential to cause significant pulmonary disease in certain clinical contexts. An association is known to exist between NTM and Aspergillus lung infections. However, it is unclear if NTM infection predisposes to Aspergillus infection or vice versa. It is also unclear whether treatment for one results in a favourable ecological niche that facilitates the growth of the other and promotes subsequent clinical disease. An improved understanding of the link between these two pulmonary pathogens is critical to guide improvements in clinical practice, and ultimately, enhance outcomes among patients who are at risk of experiencing these infections, either concomitantly or sequentially. Here, we discuss the association between pulmonary NTM and Aspergillus infections. We address the frequency with which coinfection or sequential infections are reported to occur, predisposing risk factors that have been identified and the impact on clinical outcomes. Current data on the mechanistic links between NTM and Aspergillus lung infections are also considered. The potential implications for routine clinical practice are explored.

The cost of Mycobacterium avium complex lung disease in Canada, France, Germany, and the United Kingdom: a nationally representative observational study.

BACKGROUND: Management of nontuberculous mycobacterial lung disease (NTMLD) consists of a long-term multi-drug antibiotic regimen, yet many patients do not achieve culture conversion. We estimated the NTMLD-related direct medical costs in Canada, France, Germany, and the United Kingdom (UK) among refractory patients who were infected with Mycobacterium avium complex (MAC), without concomitant cystic fibrosis, tuberculosis, or HIV. METHODS: We conducted a retrospective observational physician survey of nationally representative samples. The survey captured anonymized information about patients' treatment histories for NTMLD-related health care resource utilization over a 24-month period. We summarized NTMLD-related resource use and estimated the total economic burden, from each country's health care payer perspective. RESULTS: In total, 59 physicians provided data on 157 patients. The average person time observed during the 24-month period was 1.7 years (SD: 0.4); 17% of patients died by the end of the study period. The major components of NTMLD-related direct medical costs among refractory patients were hospitalizations (varying from 29% of total annual costs in the UK to 69% in France), outpatient visits (8% in Canada to 51% in the UK), and outpatient testing such as post-diagnostic sputum testing, bronchial wash/lavage, spirometry, biopsies, imaging, and electrocardiograms (5% in France to 35% in Canada). In this patient cohort, the average direct medical costs per person-year, in local currencies, were approximately $16,200 (Canada), €11,600 (Germany), €17,900 (France) and £9,700 (UK). CONCLUSIONS: Based on this study's findings, we conclude that managing patients with refractory NTMLD caused by MAC is associated with a substantial economic burden.

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.

Primary Ciliary Dyskinesia Due to Microtubular Defects is Associated with Worse Lung Clearance Index.

PURPOSE: Primary ciliary dyskinesia (PCD) is characterised by repeated upper and lower respiratory tract infections, neutrophilic airway inflammation and obstructive airway disease. Different ultrastructural ciliary defects may affect lung function decline to different degrees. Lung clearance index (LCI) is a marker of ventilation inhomogeneity that is raised in some but not all patients with PCD. We hypothesised that PCD patients with microtubular defects would have worse (higher) LCI than other PCD patients. METHODS: Spirometry and LCI were measured in 69 stable patients with PCD. Age at testing, age at diagnosis, ethnicity, ciliary ultrastructure, genetic screening result and any growth of Pseudomonas aeruginosa was recorded. RESULTS: Lung clearance index was more abnormal in PCD patients with microtubular defects (median 10.24) than those with dynein arm defects (median 8.3, p = 0.004) or normal ultrastructure (median 7.63, p = 0.0004). Age is correlated with LCI, with older patients having worse LCI values (p = 0.03, r = 0.3). CONCLUSION: This study shows that cilia microtubular defects are associated with worse LCI in PCD than dynein arm defects or normal ultrastructure. The patient's age at testing is also associated with a higher LCI. Patients at greater risk of obstructive lung disease should be considered for more aggressive management. Differences between patient groups may potentially open avenues for novel treatments.

Lung Clearance Index (LCI) is Stable in Most Primary Ciliary Dyskinesia (PCD) Patients Managed in a Specialist Centre: a Pilot Study.

Primary ciliary dyskinesia is a condition in which abnormal cilia structure or function leads to reduced mucociliary clearance and obstructive lung disease. Twenty-nine patients had lung clearance index (LCI) measured in 2009 and we attempted to perform a 5-year follow-up. Only 12 patients could be re-recruited, but in this small group LCI was stable over the 5 years, which confirms previous data showing that spirometry is also stable in these patients over the medium term. The two patients with the highest LCI in 2009 had since died, despite one having relatively preserved spirometry at the time. These data may be used to inform sample size calculations of future studies.

Long-term antibiotic treatment for non-cystic fibrosis bronchiectasis in adults: evidence, current practice and future use.

INTRODUCTION: Bronchiectasis is defined pathologically by the permanent dilation of the bronchi and bronchioles and chronic airway inflammation. This is the outcome of a number of different aetiologies but up to half of bronchiectasis cases are labelled idiopathic. It is characterised by a chronic productive cough, haemoptysis, shortness of breath and recurrent infective exacerbations. Long-term antibiotics are used with the aim of reducing symptom severity and exacerbation frequency, improving quality of life and preventing disease progression. Areas covered: This perspective provides an overview of evidence and current practice for long-term oral, inhaled and pulsed intravenous antibiotic therapy in adults with non-cystic fibrosis bronchiectasis. Evidence was drawn from a recent systemic literature review. Expert commentary: An approach to long-term antibiotic treatment is provided. Side effects of treatment, methods of monitoring treatment success and actions to be considered if treatment fails are discussed. Emerging long-term antibiotic treatments and strategies are considered.

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.

The antimicrobial susceptibility of non-tuberculous mycobacteria.

OBJECTIVES: Pulmonary non-tuberculous mycobacterial infection (NTM) is a challenging and increasingly prevalent infection. Antimicrobial resistance is common and may be associated with poor outcomes. This retrospective study aimed to report longitudinal trends in mycobacterial isolation and NTM drug susceptibility. METHODS: Mycobacterial culture and drug sensitivity testing results were obtained over a 13 year period. Drug sensitivity testing was performed by broth macrodilution for slow-growing mycobacteria and disc diffusion for rapidly growing mycobacteria. RESULTS: Culture results were obtained from 109,311 samples (31,758 subjects) of which 5960 samples (1209 subjects) isolated NTM over 13 years. Drug susceptibility results were obtained for 2637 NTM isolates (898 subjects). NTM isolation increased over time, driven by the Mycobacterium avium complex and Mycobacterium abscessus. Amongst most species, resistance to the key agents clarithromycin and amikacin was rare. The highest rate of resistance was found in M. abscessus and Mycobacterium simiae. Most M. abscessus isolates were sensitive to macrolides, aminoglycosides and tigecycline; M. simiae isolates were only consistently sensitive to clofazimine, amikacin and cycloserine. CONCLUSIONS: NTM isolation is increasingly common in our centre. Reassuringly, resistance to clarithromycin and amikacin is rare in most species. Tigecycline, cycloserine and clofazimine may be useful in the treatment of the most resistant species, M. abscessus and M. simiae.

TRAIL-expressing mesenchymal stem cells kill the putative cancer stem cell population.

BACKGROUND: Tumours contain stem-like, side population (SP) cells, which have increased tumorigenic potential, resistance to traditional therapies and may be responsible for treatment failures and relapse in patients. METHODS: Mesenchymal stem cells (MSCs) were engineered to express the apoptotic ligand, TNF-related apoptosis-inducing ligand (TRAIL). Squamous (H357) and lung (A549) cancer cell lines were sorted into side and non-side populations (non-SP) by Hoechst flow cytometry. The survival and growth of both SP and non-SP cancer populations, in conjunction with TRAIL-expressing MSCs and mitoxantrone chemotherapy, were assessed by flow cytometry and colony forming ability. RESULTS: Mesenchymal stem cells expressing TRAIL migrate to tumours and reduce the growth of primary cancers and metastases. This report demonstrates that these cells cause apoptosis, death and reduced colony formation of the SP of squamous and adenocarcinoma lung cancer cells and are synergistic when combined with traditional chemotherapy in apoptosis induction. CONCLUSIONS: The sensitivity of putative cancer stem cells to TRAIL-expressing MSCs, suggests their possible role in the prevention of cancer relapse.

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.

Mortality in bronchiectasis: a long-term study assessing the factors influencing survival.

There is little literature about the mortality associated with bronchiectasis. The aim of the present study was to investigate factors affecting mortality in patients with bronchiectasis. In total, 91 patients were examined for aetiology, pulmonary function tests, high-resolution computed tomography, sputum microbiology and quality of life scores and were then followed over 13 yrs. Overall, 29.7% of the patients died. On multivariate analysis, age, St George's Respiratory Questionnaire activity score, Pseudomonas aeruginosa infection, total lung capacity (TLC), residual volume/TLC and the transfer factor coefficient were all independently associated with mortality. In patients with moderate to severe bronchiectasis, mortality is associated with a degree of restrictive and obstructive disease, poor gas transfer and chronic pseudomonas infection. These features should guide future research into disease progression, and identify those patients needing intensive treatment.

Procalcitonin in stable and unstable patients with bronchiectasis.

Presently used markers of infection in bronchiectasis are inadequate to judge stability or make decisions about antibiotic treatment during bacterial exacerbations. Procalcitonin (PCT) is a new marker that has been used in community-acquired pneumonia and promises to allow much more specific and sensitive monitoring of patients with bacterial infections. This is the first study assessing its use in bronchiectasis. Thirty-eight consecutive inpatients and 63 consecutive outpatients were included in the study. All patients had PCT, other inflammatory markers, and a symptom score recorded. Inpatients had these values repeated at day 5 and 10 of their stay, while receiving intravenous antibiotics. Outpatients: PCT levels were generally low in the outpatient group. PCT was significantly correlated to C-reactive protein. Higher levels were associated with increased symptoms (P = 0.09) and an increased likelihood of antibiotic prescription (P = 0.007). Inpatients: As a group, inflammatory markers were significantly higher than in the outpatient group (P = 0.007). There was no correlation between the levels of PCT and the other inflammatory markers. PCT concentrations were generally low (as with other markers), which may reflect mucosal infection. Larger studies are needed, but PCT seems unlikely to be able to guide treatment of an exacerbation in bronchiectasis. PCT may offer more promise as a measure of stability.

Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade.

Cancers are a heterogeneous mix of cells, some of which exhibit cancer stem cell-like characteristics including ATP-dependent drug efflux and elevated tumorigenic potential. To determine whether aerodigestive squamous cell carcinomas (SCCs) contain a subpopulation of cancer stem cell-like cells, we performed Hoechst dye efflux assays using four independent cell lines. Results revealed the presence of a rare, drug effluxing stem cell-like side population (SP) of cells within all cell lines tested (SCC-SP cells). These cells resembled previously characterised epithelial stem cells, and SCC-SP cell abundance was positively correlated with overall cellular density and individual cell quiescence. Serial SCC-SP fractionation and passaging increased their relative abundance within the total cell population. Purified SCC-SP cells also exhibited increased clonogenic potential in secondary cultures and enhanced tumorigenicity in vivo. Despite this, SCC-SP cells remained chemotherapeutically sensitive upon ATP-dependent transporter inhibition. Overall, these findings suggest that the existence of ATP transporter-dependent cancer stem-like cells may be relatively common, particularly within established tumours. Future chemotherapeutic strategies should therefore consider coupling identification and targeting of this potential stem cell-like population with standard treatment methodologies.