Sputum Biomarkers Research Articles

Integrative Biomarker Panel for Improved Lung Cancer Diagnosis Using Plasma microRNAs and Sputum Bacterial DNA.

This study aimed to evaluate if integrating diverse molecular biomarkers in plasma and sputum could improve the diagnosis of lung cancer. The study analyzed miRNAs in plasma and bacterial DNA in sputum from 58 lung cancer patients and 62 cancer-free smokers using droplet digital PCR. The individual plasma miRNA and sputum bacterial biomarkers had sensitivities of 62-71% and specificities of 61-79% for diagnosing lung cancer. A panel of plasma miRNA or sputum bacterial biomarkers produced sensitivities of 79-85% and specificities of 74-82%. An integromic signature consisting of two miRNAs in plasma and three bacterial biomarkers in sputum had a higher sensitivity (87%) and specificity (89%) compared to individual biomarkers. The signature's diagnostic value was confirmed in a validation cohort of 56 lung cancer patients and 59 controls, independent of tumor stage, histological type, and demographic factors. Integrating diverse molecular biomarkers in plasma and sputum could improve the diagnosis of lung cancer.

Correlation of sputum inflammatory markers with severity and blood inflammatory markers in bronchiectasis.

As a disease characterized by chronic neutrophilic inflammation, various sputum biomarkers have been investigated in the association with the severity and prognosis of bronchiectasis. However, there is lack of data on the association between sputum interleukin-1beta (IL-1β), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) levels at clinical stable state and the clinical, spirometric and blood inflammatory parameters, as well as prognostic scores. The purpose of the study is to assess the association between sputum IL-1β, IL-8 and TNF-α levels at clinical stable state and various clinical and laboratory parameters in bronchiectasis. A prospective study was conducted in a major regional hospital and tertiary respiratory referral centre in Hong Kong, including 44 Chinese patients with bronchiectasis. The correlation between stable state sputum IL-1β, IL-8 and TNF-α levels with various clinical, laboratory and spirometric parameters in bronchiectasis, as well as FACED [forced expiratory volume in one second (FEV1), age, chronic colonisation by Pseudomonas aeruginosa, radiological extension and dyspnoea]/E-FACED (FACED plus exacerbations) scores were assessed. Baseline sputum IL-1β level was found to have significant moderate positive correlation with baseline blood high sensitivity C-reactive protein (hs-CRP) level with Pearson correlation coefficient (r) of 0.529 (P=0.001). Baseline sputum IL-8 level was found to have significant moderate positive correlation with baseline FACED and E-FACED score with r of 0.574 (P<0.001) and 0.539 (P<0.001) respectively. Baseline sputum TNF-α level was found to have significant moderate positive correlation with baseline FACED score with r of 0.520 (P<0.001). Sputum IL-1β and, IL-8 and TNF-α levels were shown to have significant correlation with various clinical, laboratory and spirometry parameters in bronchiectasis, as well as more severe disease as measured by FACED and E-FACED scores.

Severe Eosinophilic Asthma or Eosinophilic Granulomatosis With Polyangiitis: Potential Biomarkers for Novel Diagnostic Strategies

BackgroundSevere Eosinophilic Asthma (SEA) may be the prodromal phase of Eosinophilic Granulomatosis with Polyangiitis (EGPA). Nevertheless, few studies have tried to recognize EGPA in the early stages of the disease. ObjectivesTo identify a panel of clinical and biological markers to detect which severe asthmatic patient might be considered in a prodromal phase of EGPA and crafting a strategy for diagnostic decision-making. Methods30 patients with EGPA and 49 with SEA were enrolled. A complete pulmonary, ear, nose and Throat (ENT) and rheumatologic assessment were made. Blood (eosinophil count, eosinophilic cationic protein-ECP, IL5, IL4, total-IgE, IgG4, anti-neutrophil cytoplasmic antibody (ANCA), sputum (eosinophils count, periostin, IL8 and GMCSF) and nasal smear (eosinophilia) biomarkers were assessed. Asthma Control Test, Short Form-36, SinoNasalOutcome Test-22, and Asthma Quality of Life Questionnaire were also used. ResultsSEA patients had poorer asthma control (p<0.001) and higher level of sputum eosinophils (p<0.002) while EGPA patients reported higher levels of blood eosinophils in the past. Sputum GMCSF was the only biomarker significantly increased in EGPA patients compared with SEA (p<0.0001). Among SEA patients, those with some suggestive but not diagnostic criteria of EGPA, particularly tissue eosinophilic infiltrates, presented higher levels of sputum GMCSF (p<0.0005), blood and sputum eosinophils (p<0.0006, p<0.011) in comparison with the other patients. ConclusionSputum GMCSF and eosinophils might be useful biomarkers to support early diagnosis and treatment choices in SEA patients, suspected of having EGPA

Burkholderia cepacia in cystic fibrosis children and adolescents: overall survival and immune alterations.

In current literature there are only scarce data on the host inflammatory response during Burkholderia cepacia complex (Bcc) persistence. The primary objective of the present research was to carry out cross-sectional analyses of biomarkers and evaluate disease progression in cystic fibrosis (CF) patients with chronic Bcc infection and pathogen-free ones. The secondary aim was to assess prospectively overall survival of the study participants during up to 8 years of follow-up. The study included 116 paediatric patients with CF; 47 CF patients were chronically infected with Bcc, and 69 individuals were Bcc free. Plasma and sputum biomarkers (neutrophil elastase, MMP-8, MMP-9, MMP-12, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IL-22, IL-23, IL-17, IFN-γ, TGFβ1, TNF-α) were analysed using commercially available kits. Besides, inhibitory effect of dexamethasone on proliferative response of PHA-stimulated peripheral blood lymphocytes had been assessed. Bcc infected patients did not differ from Bcc free ones in demographic and clinical parameters, but demonstrated an increased rate of glucose metabolism disturbances and survival disadvantage during prolong follow-up period. Biomarkers analyses revealed elevated TNF-α and reduced IL-17F levels in sputum samples of Bcc infected patients. These patients also demonstrated improvement of peripheral blood lymphocyte sensitivity to steroid treatment and reduction in plasma pro-inflammatory (IL-17F and IL-18) and anti-inflammatory (TGFβ1 and IL-10) cytokine concentrations. Reduction in IL-17F levels may have several important consequences including increase in steroid sensitivity and glycemic control disturbances. Further investigations are needed to clarify the role of IL-17 cytokines in CF complication development. Low plasma TGFβ1 and IL-10 levels in Bcc infected group may be a sign of subverted activity of regulatory T cells. Such immune alterations may be one of the factors contributing to the development of the cepacia syndrome.

Country-specific differences in the lung tumour microbiome.

e20044 Background: Sputum examination for the early detection of lung cancer continues to be explored ( Thunnissen 2003 ), however has so far resulted in a low diagnostic yield. An increasing number of studies have evidenced a mechanistic role of the lung microbiome in the induction of lung cancer ( Liu et al., 2020 ), and the presence of bacterial biomarkers in bronchoalveolar lavage and sputum have been proposed ( Cheng et al., 2020 ). It is currently unknown whether the sputum microbiome can appropriately capture the lung tumour microbiome. Given that the lung microbiome may vary by geography, this analysis was considered over two populations: China and Italy. Methods: Microbiome analysis was performed using BioCorteX’s industry-leading knowledge graph and integrated proprietary engines v20240126_153156. Data from 9 studies was used. In total, 461 samples from lung cancer patients in China (250 sputum, 211 tumour) and 60 from Italy (34 sputum, 26 tumour) were considered. Shannon’s diversity was used to consider within-sample diversity, and dimensional scaling based (MDS) on Bray-Curtis diversity was used to consider between-sample diversity. Results: All sample were checked to have a library size greater than 100, and more than 10 unique species. Only those species present in over 1% of samples were considered to reduce noise. In both China and Italy, tumour samples had a lower diversity than sputum samples (p = 0.00016 and p &lt; 2.2e-16, respectively). Samples from Italy had a lower diversity than samples from China (p &lt; 2.22e-16). In the MDS analysis, the tumour samples from China and Italy formed two distinct, non-overlapping clusters. A third cluster was formed from the union of sputum samples from both countries. These results were independent of any study-specific effects. Conclusions: These results indicate that the sputum microbiome is not representative of the tumour microbiome, and that the divergence of the tumour microbiome away from the sputum microbiome is country specific. The results of this analysis highlight that further work into differences in the lung tumour microbiome by country is warranted, especially in light of the growing body of evidence suggesting a causative role of the microbiome in lung cancer. It is also possible that lung cancer treatments may be impacted by the country-specific nature of the lung tumour microbiome.

Human Sputum Proteomics: Advancing Non-Invasive Diagnosis of Respiratory Diseases with Enhanced Biomarker Analysis Methods

Many ailments can be diagnosed while they are asymptomatic, meaning that the patient has no signs or symptoms of a progressing disease. If caught in their initial stage of formation, these disorders can be effectively treated, leading to successful outcomes; curative therapies can halt illnesses from advancing, thus improving the quality of life and long-term survival of the patient. Still, cutting-edge upgrades in precision technologies are necessary for early, reliable, affordable, and rapid disease detection, but also vital for the well-being of people and the future of global public health. The emerging role and utility of non-invasive and repeatable diagnostic test approaches for the detection of health conditions have been exemplified by liquid biopsies based on genomic biomarkers. As such, biological fluids permit any measurable molecular indicator or signature (e.g., proteins) to provide valuable information on an individual’s wellness and/or disease. Among the bodily secretions used for non-invasive diagnostics is sputum, a complex viscous gel-like biopolymeric network that has gained growing recognition as a rich source of biomarkers of airway infections and pulmonary diseases, and serves as a determinant to reveal other illnesses. As per the World Health Organization, the burden of respiratory conditions is exacerbated by factors ranging from considerable subjection to air pollution and occupational contaminants to tobacco smoking and second-hand smoke, in addition to poor socio-economic status. Due to the likely increase in these determinants, respiratory tract ailments are on the rise, affecting the health of many individuals, in addition to putting stress on healthcare facilities and services worldwide. The aim of this study was to perform a narrative review of sputum constituents with an emphasis on proteins and glycoproteins assessed as possible biomarkers of lung and other organ diseases. A search was conducted using mucus, sputum proteomics, sputum biomarkers, and point-of-care testing as keywords employing Google, PubMed (MEDLINE), and Web of Science, selecting the most referenced and related papers of the last decade. We, therefore, highlight the need to use expectorated or induced sputum specimens as a routine sample source for testing valuable protein biomarkers to diagnose these chronic disorders, predict inflammation and disease progression, as well as monitor the effectiveness of treatments. Further, we discuss the urgent need for fast and reliable point-of-care methods to detect and quantify crucial protein biomarkers in sputum specimens, and the limitations faced when dealing with their complex matrices.

Nebulised interferon beta-1a (SNG001) in the treatment of viral exacerbations of COPD

BackgroundRespiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-β is naturally produced in response to viral infection, limiting replication. This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-β1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance.MethodsIn Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation [i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids]).ResultsIn Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001–placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments.ConclusionsOverall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study.Trial registrationEU clinical trials register (2017-003679-75), 6 October 2017.

Mucus Structure, Viscoelastic Properties, and Composition in Chronic Respiratory Diseases.

The respiratory mucus, a viscoelastic gel, effectuates a primary line of the airway defense when operated by the mucociliary clearance. In chronic respiratory diseases (CRDs), such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), the mucus is overproduced and its solid content augments, changing its structure and viscoelastic properties and determining a derangement of essential defense mechanisms against opportunistic microbial (virus and bacteria) pathogens. This ensues in damaging of the airways, leading to a vicious cycle of obstruction and infection responsible for the harsh clinical evolution of these CRDs. Here, we review the essential features of normal and pathological mucus (i.e., sputum in CF, COPD, and asthma), i.e., mucin content, structure (mesh size), micro/macro-rheology, pH, and osmotic pressure, ending with the awareness that sputum biomarkers (mucins, inflammatory proteins and peptides, and metabolites) might serve to indicate acute exacerbation and response to therapies. There are some indications that old and novel treatments may change the structure, viscoelastic properties, and biomarker content of sputum; however, a wealth of work is still needed to embrace these measures as correlates of disease severity in association with (or even as substitutes of) pulmonary functional tests.

Sputum Biomarkers in Wood and Tobacco Smoke Etiotypes of Chronic Obstructive Pulmonary Disease.

There is a need to better understand the etiotypes of chronic obstructive pulmonary disease (COPD) beyond the tobacco-smoke (TS-COPD). Wood smoke COPD (WS-COPD) is characterized by greater airway compromise, milder emphysema, and slower rate of lung function decline than TS-COPD. However, it is unclear if these two etiotypes of COPD have differences in sputum biomarker concentrations. Objective was to compare sputum levels of selected sputum biomarkers between WS-COPD and TS-COPD, and healthy controls. Eighty-eight women (69±12 years) were recruited and classified into: WS-COPD (n=31), TS-COPD (n=29) and controls (n=28). Using ELISA, we determined induced sputum levels of metalloproteinase 9 (MMP-9), chemokine ligand 5 (CCL5), interleukin-8 (IL-8), chemokine ligand 16 (CCL16/HCC-4) and vascular endothelial growth factor (VEGF-1). Differences were analyzed by Kruskal-Wallis and Mann-Whitney-U tests and correlation between airflow limitation and biomarkers by Spearman's test. At similar degree of airflow obstruction, anthropometrics and medications use, the level of sputum CCL5 was higher in TS-COPD than WS-COPD (p=0.03) without differences in MMP-9, IL-8, CCL16/HCC-4, and VEGF-1. Women with WS-COPD and TS-COPD showed significantly higher sputum levels of MMP-9, IL-8 and CCL5 compared with controls (p<0.001). FEV1% predicted correlated negatively with levels of MMP-9 (rho:-0.26; P=0.016), CCL5 (rho:-0.37; P=0.001), IL-8 (rho:-0.42; P<0.001) and VEGF (rho:-0.22; P=0.04). While sputum concentrations of MMP-9, IL-8, and CCL5 were higher in COPD women compared with controls, women with TS-COPD had higher levels of CCL5 compared with those with WS-COPD. Whether this finding relates to differences in pathobiological pathways remains to be determined.

Survey of Inflammatory Biomarkers in Blood and Sputum in Pulmonary Tuberculosis Patients

Write / type abstract in this section. Abstract written using Times New Roman 11, structured (150 - 200 words), consisting of 1 paragraph. Abstract in Indonesian and English. The authors must follow the instructions given in this guide. This document can be used as a reference in writing your manuscript. Be sure not to change the style in this template, including the type and size of the font, the size of the space, the indent distance, and so on. The abstract component consists of Background, Objectives, Methods, Results, and Conclusions. Excludes tables, ref-erences, abbreviations and acronyms that are not explained, do not contain infor-mation or conclusions that are not in the text.

Engineering a Point-of-Care Paper-Microfluidic Electrochemical Device Applied to the Multiplexed Quantitative Detection of Biomarkers in Sputum.

Health initiatives worldwide demand affordable point-of-care devices to aid in the reduction of morbidity and mortality rates of high-incidence infectious and noncommunicable diseases. However, the production of robust and reliable easy-to-use diagnostic platforms showing the ability to quantitatively measure several biomarkers in physiological fluids and that could in turn be decentralized to reach any relevant environment remains a challenge. Here, we show the particular combination of paper-microfluidic technology, electrochemical transduction, and magnetic nanoparticle-based immunoassay approaches to produce a unique, compact, and easily deployable multiplex device to simultaneously measure interleukin-8, tumor necrosis factor-α, and myeloperoxidase biomarkers in sputum, developed with the aim of facilitating the timely detection of acute exacerbations of chronic obstructive pulmonary disease. The device incorporates an on-chip electrochemical cell array and a multichannel paper component, engineered to be easily aligned into a polymeric cartridge and exchanged if necessary. Calibration curves at clinically relevant biomarker concentration ranges are produced in buffer and artificial sputum. The analysis of sputum samples of healthy individuals and acutely exacerbated patients produces statistically significant biomarker concentration differences between the two studied groups. The device can be mass-produced at a low cost, being an easily adaptable platform for measuring other disease-related target biomarkers.

Monitoring disease progression in childhood bronchiectasis.

Bronchiectasis (not related to cystic fibrosis) is a chronic lung disease caused by a range of etiologies but characterized by abnormal airway dilatation, recurrent respiratory symptoms, impaired quality of life and reduced life expectancy. Patients typically experience episodes of chronic wet cough and recurrent pulmonary exacerbations requiring hospitalization. Early diagnosis and management of childhood bronchiectasis are essential to prevent respiratory decline, optimize quality of life, minimize pulmonary exacerbations, and potentially reverse bronchial disease. Disease monitoring potentially allows for (1) the early detection of acute exacerbations, facilitating timely intervention, (2) tracking the rate of disease progression for prognostic purposes, and (3) quantifying the response to therapies. This narrative review article will discuss methods for monitoring disease progression in children with bronchiectasis, including lung imaging, respiratory function, patient-reported outcomes, respiratory exacerbations, sputum biomarkers, and nutritional outcomes.

Validation of Sputum Biomarker Immunoassays and Cytokine Expression Profiles in COPD.

Immunoassays are commonly used to assess airway inflammation in sputum samples from chronic obstructive pulmonary disease (COPD) patients. However, assay performance and validation in this complex matrix is inconsistently reported. The aim of this study was to assess the suitability of various immunoassays for use with sputum samples, followed by use of validated immunoassays to evaluate biomarker levels in COPD patients. Assays were assessed for recombinant reference standard suitability, optimal sample dilution, standard recovery in the biological matrix and reproducibility. Validated assays were used to assess sputum supernatants in Cohort A (n = 30 COPD, n = 10 smokers, n = 10 healthy) and Cohort B (n = 81 COPD, n = 15 smokers, n = 26 healthy). Paired baseline and exacerbation samples from 14 COPD patients were assessed in cohort A, and associations with sputum cell counts and bacterial colonisation investigated in cohort B. 25/32 assays passed validation; the primary reason for validation failure was recombinant reference standard suitability and sample dilution effects. Interleukin (IL-)6 and IL-8 were significantly increased in COPD patients compared to healthy subjects and smokers for both cohorts. Tumour necrosis factor (TNF)α and IL-1β were higher in COPD compared to smokers using one immunoassay but not another, partly explained by different absolute recovery rates. IL-1β, IL-2, IL-4, IL-8, IL-17A, Granulocyte colony stimulating factor (G-CSF), Interferon (IFN-)γ, Interferon gamma induced protein (IP-)10, Macrophage inflammatory protein (MIP)-1α, MIP-1β and TNF-α levels correlated with sputum neutrophil percentage in COPD patients. IL-1β, IL-4, IL-8, G-CSF and IFN-γ levels were associated with Haemophilus influenzae colonisation in COPD patients. Current smokers had lower levels of IL-1β, IL-4, IL-8, G-CSF, IFN-γ, IP-10, Monocyte chemoattractant protein (MCP)-1, MIP-1α, MIP-1β and TNF-α. Validated immunoassays applied to sputum supernatants demonstrated differences between COPD patients and controls, the effects of current smoking and associations between Haemophilus influenzae colonisation and higher levels of selected cytokines. Immunoassay validation enabled inflammatory mediators associated with different COPD characteristics to be determined.

Cross-sectional Study of Workers Employed at a Copper Smelter-Effects of Long-term Exposures to Copper on Lung Function and Chronic Inflammation.

The aim of the study was to assess the effect of exposure to copper-containing dust on lung function and inflammatory endpoints among workers of a German copper plant, effects rarely studied before. One hundred four copper-exposed smelter workers and 70 referent workers from the precious metal and lead facilities were included, with different metal exposures in both groups due to the different process materials. Body plethysmography, exhaled nitric oxide (FeNO) measurements, and blood sampling were conducted in all workers. Smoking status and the use of respiratory protective equipment were considered. In a subgroup of 40 nonsmoking volunteers (28 copper-exposed and 12 referents), sputum biomarkers were assessed. Median lung function values of both copper-exposed and the referent groups were within reference ranges of "healthy" individuals, and statistical differences between the groups were mostly not evident. Similarly, differences in blood and sputum biomarkers were too small to be biologically relevant. The results suggest the absence of the detectable effects of copper-containing dust exposure on lung function or chronic inflammation within the investigated cohort.

Potency of Various MicroRNA as Sputum Biomarker in Lung Cancer

&lt;p class="AbstractNormal"&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Lung cancer is one the deadliest cancer known. Current method using low-dose CT scan to screen lung cancer applied are proved to reduce mortality, but lack in accuracy leading to overdiagnosis. Current researches are mostly seeking for a non-invasive and cost-effective method, hence biomarkers such as microRNA has a potency to screen and diagnose lung cancer. This literature review aimed to discuss the potency of microRNA in sputum as a biomarker in screening lung cancer.&lt;/p&gt;&lt;p class="AbstractNormal"&gt;&lt;strong&gt;Methods:&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;The study is conducted by literature searching for related journals in search engines such as PubMed, Science Direct, and Google Scholar with keywords. 35 articles were included with relevance and within 10 years publication.&lt;/p&gt;&lt;p class="AbstractNormal"&gt;&lt;strong&gt;Result:&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;MicroRNA is a short non-coding RNA which regulates gene expression. It acts in an oncogene or tumor suppressor gene regulation. DNA mutations or defects occurred in cancer particularly in lung cancer causes increase or decrease of microRNA expression. Alterations of microRNA expression in sputum detected by rt-PCR may represent progressions of lung cancer from a cell cycle dysregulation and provides better sensitivity and specificity among other biomarkers. Combinations of miRNA species offer increase of sensitivity and specificity. Particular types of microRNA are able to classify the types of lung cancer in progress.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;MicroRNA has the promising potency and strong accuracy with a non-invasive and cost-effective procedure in detecting early signs of lung cancer occurrence and can be further applied as biomarker used in lung cancer.&lt;/p&gt;&lt;p&gt;Keywords: Biomarker; Lung Cancer; microRNA; Screening; Sputum&lt;/p&gt;

Serum and sputum MMP-9/TIMP-1 in winter sports athletes and swimmers: relationships with airway function

Introduction Skiers and swimmers present characteristics of airway inflammation and remodelling of the extracellular matrix similar to what is observed in mild asthma. We aimed to compare serum and sputum MMP-9/TIMP-1 levels, to assess the balance between airway fibrogenesis and inflammation process in both categories of athletes, and to observe its seasonal variations in winter sports athletes. Methods We conducted a retrospective study. Winter sports athletes (n = 41), swimmers (n = 25) and healthy nonathletes (n = 10) had blood sampling, lung function measurement, skin prick tests, eucapnic voluntary hyperpnoea challenge, methacholine inhalation test, and induced sputum analysis. Twelve winter sport athletes performed the tests during both summer and winter. Serum and sputum biomarkers were measured by ELISA. Results No significant difference in serum or sputum MMP-9/TIMP-1 ratio was observed between groups, nor relationship with airway function or responsiveness. Serum MMP-9/TIMP-1 ratio was higher during the summer in winter sport athletes compared with winter season (median [Interquartile range]: 3.65 [2.47-4.03] ng.ml−1 and 1.27 [0.97-1.62] ng.ml−1, respectively, p = 0.005). Sputum MMP-9 correlated with methacholine PC20 (r = 0.45, p = 0.019) and serum cc16/SP-D ratio (r = −0.47, p = 0.013). Conclusion MMP-9/TIMP-1 ratio in sputum or serum may fluctuate with training or environment but does not correlate with airway function or responsiveness in athletes.

Sputum biomarkers during acute severe asthma attacks in children-a case-control study.

To study sputum mediator profiles pattern in children with acute severe asthma, compared with stable asthma and healthy controls. The mechanisms of acute severe asthma attacks, such as biomarkers cascades and immunological responses, are poorly understood. We conducted a prospective observational case-control study of children aged 5 to 17years, who presented to hospital with an asthma attack. Children with stable asthma were recruited during outpatient asthma clinic visits. Control children without an asthma diagnosis were recruited from surgical wards. Sputum mediator profiles were measured, and sputum leukocyte differential cell counts were generated. Sputum data were available in 48 children (acute asthma; n=18, stable asthma; n=17, healthy controls; n=13). Acute-phase biomarkers and neutrophil attractants such as IL-6 and its receptor, IL-8 and cytokines linked with bacterial signals, including TNF-R1 and TNF-R2, were elevated in asthma attacks versus stable asthma and healthy controls. T-cell attractant cytokines, associated with viral infections, such as CCL-5, CXCL-10 and CXCL-11, and CXCL-9 (secreted from eosinophils after a viral trigger) were also raised. Mediator profiles consistent with bacterial and viral respiratory infections, and T2 inflammation markers co-exist in the sputum of children with acute severe asthma attacks.

Identification of Sputum Biomarkers Predictive of Pulmonary Exacerbations in COPD

Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. ClinicalTrials.gov; No.: NCT01969344; URL: www. gov.

Inflammation biomarkers in sputum for clinical trials in cystic fibrosis: current understanding and gaps in knowledge

RationaleSputum biomarkers hold promise as a direct measure of inflammation within the cystic fibrosis (CF) lung, but variability in study design and sampling methodology have limited their use. A full evaluation of the reliability, validity and clinical relevance of individual biomarkers is required to optimise their use within CF clinical research. ObjectivesA biomarker Special Interest Working Group was established within the European Cystic Fibrosis Society-Clinical Trials Network Standardisation Committee, to perform a review of the evidence regarding sputum biomarkers in CF. MethodsFrom the 139 included articles, we identified 71 sputum biomarkers to undergo evaluation of their clinimetric properties, responsiveness, discriminant, concurrent and convergent validity. ResultsCurrent evidence confirms the potential of sputum biomarkers as outcome measures in clinical trials. Inconsistency in responsiveness, concurrent and convergent validity require further research into these markers and processing standardisation before translation into wider use. Of the 71 biomarkers identified, Neutrophil Elastase (NE), IL-8, TNF-α and IL-1β, demonstrated validity and responsiveness to be currently considered for use in clinical trials. Other biomarkers show future promise, including IL-6, calprotectin, HMGB-1 and YKL-40. ConclusionA concerted international effort across the cystic fibrosis community is needed to promote high quality biomarker trial design, establish large population-based biomarker studies, and work together to create standards for collection, storage and analysis of sputum biomarkers.

Chronic obstructive pulmonary disease risk assessment tools: is one better than the others?

Purpose of reviewRisk assessment tools are essential in COPD care to help clinicians identify patients at higher risk of accelerated lung function decline, respiratory exacerbations, hospitalizations, and death.Recent findingsConventional methods of assessing risk have focused on spirometry, patient-reported symptoms, functional status, and a combination of these tools in composite indices. More recently, qualitatively and quantitatively assessed chest imaging findings, such as emphysema, large and small airways disease, and pulmonary vascular abnormalities have been associated with poor long-term outcomes in COPD patients. Although several blood and sputum biomarkers have been investigated for risk assessment in COPD, most still warrant further validation. Finally, novel remote digital monitoring technologies may be valuable to predict exacerbations but their large-scale performance, ease of implementation, and cost effectiveness remain to be determined.SummaryGiven the complex heterogeneity of COPD, any single metric is unlikely to fully capture the risk of poor long-term outcomes. Therefore, clinicians should review all available clinical data, including spirometry, symptom severity, functional status, chest imaging, and bloodwork, to guide personalized preventive care of COPD patients. The potential of machine learning tools and remote monitoring technologies to refine COPD risk assessment is promising but remains largely untapped pending further investigation.