Predicting Lung Function Using Biomarkers in Alpha-1 Antitrypsin Deficiency.

Lung disease progression in alpha-1 antitrypsin deficiency (AATD) is heterogenous and manifests in different ways. Blood biomarkers are an attractive method of monitoring diseases as they are easy to obtain and repeatable. In non-AATD COPD, blood biomarker panels have predicted disease severity, progression, and mortality. We measured a panel of seven serum biomarkers in 200 AATD patients and compared levels between those with COPD and those without. We assessed whether biomarkers were associated with baseline lung function parameters (FEV1 and TLco) or absolute change in these parameters. In total, 111 patients with a severely deficient genotype of AATD (PiZZ) and COPD were included in the analyses. Pearson's correlation coefficient was measured for biomarker correlations and models were compared using ANOVA. CRP and CCL18 were significantly higher in the serum of AATD COPD versus AATD with no COPD. Biomarkers were not predictive of cross-sectional lung function measurements, however, CC16 was significantly associated with an absolute change in TLco (p = 0.018). An addition of biomarkers to the predictive model for TLco added significant value over covariates alone (R2 0.13 vs. 0.02, p = 0.028). Our findings suggest that CC16 is predictive of emphysema progression in AATD COPD. Proteomics data may reveal alternative candidate biomarkers and further work should include the use of longitudinal biomarker measurements.

New Pharmacological Tools to Target Leukocyte Trafficking in Lung Disease.

Infection and inflammation of the lung results in the recruitment of non-resident immune cells, including neutrophils, eosinophils and monocytes. This swift response should ensure clearance of the threat and resolution of stimuli which drive inflammation. However, once the threat is subdued this influx of immune cells should be followed by clearance of recruited cells through apoptosis and subsequent efferocytosis, expectoration or retrograde migration back into the circulation. This cycle of cell recruitment, containment of threat and then clearance of immune cells and repair is held in exquisite balance to limit host damage. Advanced age is often associated with detrimental changes to the balance described above. Cellular functions are altered including a reduced ability to traffic accurately towards inflammation, a reduced ability to clear pathogens and sustained inflammation. These changes, seen with age, are heightened in lung disease, and most chronic and acute lung diseases are associated with an exaggerated influx of immune cells, such as neutrophils, to the airways as well as considerable inflammation. Indeed, across many lung diseases, pathogenesis and progression has been associated with the sustained presence of trafficking cells, with examples including chronic diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis and acute infections such as Pneumonia and Pneumonitis. In these instances, there is evidence that dysfunctional and sustained recruitment of cells to the airways not only increases host damage but impairs the hosts ability to effectively respond to microbial invasion. Targeting leukocyte migration in these instances, to normalise cellular responses, has therapeutic promise. In this review we discuss the current evidence to support the trafficking cell as an immunotherapeutic target in lung disease, and which potential mechanisms or pathways have shown promise in early drug trials, with a focus on the neutrophil, as the quintessential trafficking immune cell.

Small Airways Disease, Biomarkers and COPD: Where are We?

The response to treatment and progression of Chronic Obstructive Pulmonary Disease (COPD) varies significantly. Small airways disease (SAD) is being increasingly recognized as a key pathological feature of COPD. Studies have brought forward pathological evidence of small airway damage preceding the development of emphysema and the detection of obstruction using traditional spirometry. In recent years, there has been a renewed interest in the early detection of SAD and this has brought along an increased demand for physiological tests able to identify and quantify SAD. Early detection of SAD allows early targeted therapy and this suggests the potential for altering the course of disease. The aim of this article is to review the evidence available on the physiological testing of small airways. The first half will focus on the role of lung function tests such as maximum mid-expiratory flow, impulse oscillometry and lung clearance index in detecting and quantifying SAD. The role of Computed Tomography (CT) as a radiological biomarker will be discussed as well as the potential of recent CT analysis software to differentiate normal aging of the lungs to pathology. The evidence behind SAD biomarkers sourced from blood as well as biomarkers sourced from sputum and broncho-alveolar lavage (BAL) will be reviewed. This paper focuses on CC-16, sRAGE, PAI-1, MMP-9 and MMP-12.

COVID-19, immunothrombosis and venous thromboembolism: biological mechanisms.

Thrombotic events that frequently occur in COVID-19 are predominantly venous thromboemboli (VTE) and are associated with increasing disease severity and worse clinical outcomes. Distinctive microvascular abnormalities in COVID-19 include endothelial inflammation, disruption of intercellular junctions and microthrombi formation. A distinct COVID-19-associated coagulopathy along with increased cytokines and activation of platelets, endothelium and complement occur in COVID-19, which is more frequent with worsening disease severity. This proinflammatory milieu may result in immunothrombosis, a host defence mechanism that can become dysregulated, leading to excess formation of immunologically mediated thrombi which predominantly affect the microvasculature. The haemostatic and immune systems are intricately linked, and multifactorial processes are likely to contribute to VTE and immunothrombosis in COVID-19. This state-of-the-art review will explore the pathobiological mechanisms of immunothrombosis and VTE in COVID-19 focusing on: COVID-19-associated coagulopathy, pathology, endothelial dysfunction and haemostasis, the immune system and thrombosis, genetic associations and additional thrombotic mechanisms. An understanding of the complex interplay between these processes is necessary for developing and assessing how new treatments affect VTE and immunothrombosis in COVID-19.

A Systematic Review and Meta-Analysis of the Prevalence and Impact of Pulmonary Bacterial Colonisation in Stable State Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: Half of acute exacerbations of COPD are due to bacterial infection, and the other half are likely influenced by microbial colonisation. The same organisms commonly cultured during acute exacerbations are often found in the sputum of patients during stability. A robust assessment of the prevalence of potentially pathogenic microorganisms (PPMs) in the sputum of stable COPD patients may help to inform the targeted prevention of exacerbation by these organisms. METHODS: A systematic review and meta-analysis was carried out to determine the prevalence of PPMs in patients with COPD in the stable state. Meta-analysis of prevalence was carried out using the Freeman-Tukey double arcsine transformation random effects model, and sub-group analysis was performed for sputum modality. Prevalence of total and individual PPMs was calculated from patient-level data from individual studies. RESULTS: Pooled prevalence of PPMs identified by sputum culture was found to be 41% (95% CI 36-47%). Significant heterogeneity was found across all studies, which can likely be attributed to inconsistent measuring and reporting of PPMs. The most commonly reported organisms were H. influenzae, M catarrhalis, S. pneumoniae, S. aureus, and P. aeruginosa. Declining lung function was weakly correlated with prevalence of PPMs. CONCLUSION: The airways of patients with COPD are colonised with PPMs during the stable state in almost half of patients. A complex relationship likely exists between the microbiome in the stable state and the phenotype of COPD patients. Targeted microbial therapy for preventing exacerbations of COPD should carefully consider the stable microbiome as well as the exacerbated.

Mitigating Health Risks to Reopen a Clinical Research Laboratory During the COVID-19 Pandemic: A Framework.

BACKGROUND: The COVID-19 pandemic has led to many countries implementing lockdown procedures, resulting in the suspension of laboratory research. With lockdown measures now easing in some areas, many laboratories are preparing to reopen. This is particularly challenging for clinical research laboratories due to the dual risk of patient samples carrying the virus that causes COVID-19, SARS-CoV-2, and the risk to patients being exposed to research staff during clinical sampling. To date, no confirmed transmission of the virus has been confirmed within a laboratory setting; however, operating processes and procedures should be adapted to ensure safe working of samples of positive, negative, or unknown COVID-19 status. OBJECTIVE: In this paper, we propose a framework for reopening a clinical research laboratory and resuming operations with the aim to maximize research capacity while minimizing the risk to research participants and staff. METHODS: This framework was developed by consensus among experienced laboratory staff who have prepared to reopen a clinical research laboratory. RESULTS: Multiple aspects need to be considered to reopen a clinical laboratory. We describe our process to stratify projects by risk, including assessment of donor risk and COVID-19 clinical status, the COVID-19 status of the specific sample type, and how to safely process each sample type. We describe methods to prepare the laboratory for safe working including maintaining social distancing through signage, one-way systems and access arrangements for staff and patients, limiting staff numbers on site and encouraging home working for all nonlaboratory tasks including data analysis and writing. Shared equipment usage was made safe by adapting booking systems to allow for the deployment of cleaning protocols. All risk assessments and standard operating procedures were rewritten and approved by local committees, and staff training was initiated to ensure compliance. CONCLUSIONS: Laboratories can adopt and adapt this framework to expedite reopening a clinical laboratory during the current COVID-19 pandemic while mitigating the risk to research participants and staff.