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Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are debilitating events and spur disease progression. Infectious causes are frequent; however, it is unknown to what extent exacerbations are caused by larger shifts in the airways' microbiota. The aim of the current study was to analyse the changes in microbial composition between stable state and during exacerbations, and the corresponding immune response., Methods: The study sample included 36 COPD patients examined at stable state and exacerbation from the Bergen COPD Cohort and Exacerbations studies, and one patient who delivered sputum on 13 different occasions during the three-year study period. A physician examined the patients at all time points, and sputum induction was performed by stringent protocol. Only induced sputum samples were used in the current study, not spontaneously expectorated sputum. Sputum inflammatory markers (IL-6, IL-8, IL-18, IP-10, MIG, TNF-α) and antimicrobial peptides (AMPs, i.e. LL-37/hCAP-18, SLPI) were measured in supernatants, whereas target gene sequencing (16S rRNA) was performed on corresponding cell pellets. The microbiome bioinformatics platform QIIME2TM and the statistics environment R were applied for bioinformatics analyses., Results: Levels of IP-10, MIG, TNF-α and AMPs were significantly different between the two disease states. Of 36 sample pairs, 24 had significant differences in the 12 most abundant genera between disease states. The diversity was significantly different in several individuals, but not when data was analysed on a group level. The one patient case study showed longitudinal dynamics in microbiota unrelated to disease state., Conclusion: Changes in the sputum microbiota with changing COPD disease states are common, and are accompanied by changes in inflammatory markers. However, the changes are highly individual and heterogeneous events., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Tangedal, Dr. Nielsen, Dr. Aanerud, Dr. Persson and Dr. Wiker have nothing to disclose. Dr. Bakke reports personal fees from Novartis, personal fees from AstraZeneca, personal fees from Chiesi, personal fees from Boehringer-Ingelheim, outside the submitted work. Dr. Hiemstra reports grants from Boehringer Ingelheim, grants from Galapagos, outside the submitted work. Dr. Eagan reports grants from Bergen Medical Research Foundation, during the conduct of the study; personal fees from Boehringer Ingelheim, outside the submitted work. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

BackgroundThere is still limited information on systemic inflammation in alpha-1-antitrypsin-deficient (AATD) COPD patients and what effect alpha-1-antitrypsin augmentation therapy and/or exercise might have on circulating inflammatory cytokines. We hypothesized that AATD COPD patients on augmentation therapy (AATD + AUG) would have lower circulating and skeletal muscle inflammatory cytokines compared to AATD COPD patients not receiving augmentation therapy (AATD-AUG) and/or the typical non-AATD (COPD) patient. We also hypothesized that cytokine response to exercise would be lower in AATD + AUG compared to AATD-AUG or COPD subjects.MethodsArterial and femoral venous concentration and skeletal muscle expression of TNFα, IL-6, IL-1β and CRP were measured at rest, during and up to 4-hours after 50% maximal 1-hour knee extensor exercise in all COPD patient groups, including 2 additional groups (i.e. AATD with normal lung function, and healthy age-/activity-matched controls).ResultsCirculating CRP was higher in AATD + AUG (4.7 ± 1.6 mg/dL) and AATD-AUG (3.3 ± 1.2 mg/dL) compared to healthy controls (1.5 ± 0.3 mg/dL, p < 0.05), but lower in AATD compared to non-AATD-COPD patients (6.1 ± 2.6 mg/dL, p < 0.05). TNFα, IL-6 and IL-1β were significantly increased by 1.7-, 1.7-, and 4.7-fold, respectively, in non-AATD COPD compared to AATD COPD (p < 0.05), and 1.3-, 1.7-, and 2.2-fold, respectively, compared to healthy subjects (p < 0.05). Skeletal muscle TNFα was on average 3-4 fold greater in AATD-AUG compared to the other groups (p < 0.05). Exercise showed no effect on these cytokines in any of our patient groups.ConclusionThese data show that AATD COPD patients do not experience the same chronic systemic inflammation and exhibit reduced inflammation compared to non-AATD COPD patients. Augmentation therapy may help to improve muscle efflux of TNFα and reduce muscle TNFα concentration, but showed no effect on IL-6, IL-1β or CRP.

Abstract Background Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years. Methods The patients, aged 40–76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV1, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models. Results At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p 1, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry. Conclusion This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients.

Background and objective: Activation of the blood coagulation system is a common observation in inflammatory diseases. The role of coagulation in COPD is underexplored. Methods: The study included 413 COPD patients and 49 controls from the 3‐year Bergen COPD Cohort Study (BCCS). One hundred and forty‐eight COPD patients were also examined during AECOPD. The plasma markers of coagulation activation, TAT complex, APC–PCI complex and D‐dimer, were measured at baseline and during exacerbations by enzyme immunoassays. Differences in levels of the markers between stable COPD patients and controls, and between stable COPD and AECOPD were examined. The associations between coagulation markers and later AECOPD and mortality were examined by negative binomial and Cox regression analyses. Results: TAT was significantly lower in stable COPD (1.03 ng/mL (0.76–1.44)) than in controls (1.28 (1.04–1.49), P = 0.002). During AECOPD, all markers were higher than in the stable state: TAT 2.56 versus 1.43 ng/mL, APC–PCI 489.3 versus 416.4 ng/mL and D‐dimer 763.5 versus 479.7 ng/mL (P < 0.001 for all). Higher D‐dimer in stable COPD predicted a higher mortality (HR: 1.60 (1.24–2.05), P < 0.001). Higher TAT was associated with both an increased risk of later exacerbations, with a yearly incidence rate ratio of 1.19 (1.04–1.37), and a faster time to the first exacerbation (HR: 1.25 (1.10–1.42), P = 0.001, all after adjustment). Conclusion: Activation of the coagulation system is increased during COPD exacerbations. Coagulation markers are potential predictors of later COPD exacerbations and mortality. Elevated coagulation markers are potential predictors of higher mortality and also a shorter time to the first AECOPD as well as a higher 3‐year AECOPD rate. Activation of the coagulation system is increased during COPD exacerbations. See relatedEditorial [ABSTRACT FROM AUTHOR]

Macrophage migration inhibitor factor (MIF) is a pluripotent cytokine associated with several different inflammatory conditions, but its role within lung inflammation and chronic obstructive pulmonary disease (COPD) is unclear. This study aimed to examine MIF in both stable COPD and during acute exacerbations (AECOPD). The study included 433 patients with COPD aged 41-76 and 325 individuals from the Bergen COPD cohort study who served as controls. All patients had an FEV1 of <80% predicted, FEV1/FVC ratio of <0.7, and a smoking history >10 packyears. Serum levels of MIF were compared between the two groups at baseline, and for 149 patients, measurements were also carried out during AECOPD. Linear regression models were fitted with MIF as the outcome variable and adjusted for sex, age, body composition, smoking, and Charlson Comorbidity Score (CCS). Median MIF (interquartile range) in patients with COPD was 20.1 ng/ml (13.5-30.9) compared with 14.9 ng/ml (11.1-21.6) in controls (P < 0.01). MIF was bivariately associated with sex, body composition, and CCS (P < 0.05 for all). In the regression analyses, MIF was significantly higher in patients with COPD, coefficient 1.32 (P < 0.01) and 1.30 (P < 0.01) unadjusted and adjusted, respectively. In addition, in 149 patients during episodes of AECOPD, MIF was significantly elevated, with a median of 23.2 ng/ml (14.1-42.3) compared with measurements at stable disease of 19.3 ng/ml (12.4 - 31.3, P < 0.01). Serum levels of MIF were significantly higher in patients with COPD compared with controls. We also identified an additional increase in MIF levels during episodes of AECOPD. [ABSTRACT FROM AUTHOR]

Summary: Patients with COPD are at risk for other comorbid diseases, like heart failure, coronary heart disease, and depression. However, little is known about COPD phenotypes and prevalence of sub-clinical renal failure. 433 COPD patients and 233 subjects without COPD, from Western Norway, age 40–75, GOLD stage II–IV, were examined in 2006/07 upon entry to the Bergen COPD Cohort Study. Plasma creatinine was measured in 422 of the COPD patients. The Glomerular Flow Rate (GFR) was determined with the Cockcroft Gault formula, and having a GFR < 60 was defined as renal failure. Examined explanatory factors were sex, age, smoking habits, GOLD stage, hypoxemia, exacerbation history, cachexia, use of daily inhaled steroids, Charlson comorbidity score, use of ACE inhibitors and/or ARBs, and the inflammatory plasma markers C-reactive protein (CRP), soluble tumor necrosis factor receptor 1 (sTNF-R1) and neutrophil gelatinase associated lipocalin (NGAL). Associations between explanatory variables and renal failure were examined by a logistic regression analysis. The prevalence of having GFR < 60 was 9.6% in female COPD patients and 5.1% in male COPD patients (p = 0.08). In multivariable analysis, female sex, higher age, cachexia, and the inflammatory markers sTNF-R1 and NGAL were all independently associated with a higher risk for renal failure, whereas use of inhaled steroids, Charlson score, GOLD stage, respiratory failure, and exacerbation frequency were not. Undiagnosed renal failure is a concern particularly in elderly COPD patients and COPD patients with cachexia. [ABSTRACT FROM AUTHOR]