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      Serum Amyloid A in Stable COPD Patients is Associated with the Frequent Exacerbator Phenotype

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          Abstract

          Background

          We sought to determine whether circulating inflammatory biomarkers were associated with the frequent exacerbator phenotype in stable COPD patients ie, those with two or more exacerbations in the previous year.

          Methods

          Eighty-eight stable, severe, COPD patients (4 females) were assessed for exacerbation frequency, pulmonary function, fraction of expired nitric oxide (F ENO); inflammatory variables were measured in venous blood. Logistic regression assessed associations between the frequent exacerbator phenotype and systemic inflammation.

          Results

          Compared with infrequent exacerbators, frequent exacerbators (n=10; 11.4%) had greater serum concentration (median (25th-75th quartile)) of serum amyloid A (SAA; 134 (84–178) vs 71 (38–116) ng/mL; P=0.024), surfactant protein D (SP-D; 15.6 (9.0–19.3) vs 8.5 (3.6–14.9) ng/mL; P=0.049) and interleukin-4 (IL-4; 0.12 (0.08–1.44) vs 0.03 (0.01–0.10) pg/mL; P=0.001). SAA, SP-D and IL-4 were not significantly correlated with FEV 1%predicted or FVC %predicted. After adjusting for sex, age, BMI, FEV 1/FVC and smoking pack-years, only SAA remained independently associated with the frequent exacerbator phenotype (OR 1.49[1.09–2.04]; P=0.012). The odds of being a frequent exacerbator was 18-times greater in the highest SAA quartile (≥124.1 ng/mL) than the lowest SAA quartile (≤44.1 ng/mL) (OR 18.34[1.30–258.81]; P=0.031), and there was a significant positive trend of increasing OR with increasing SAA quartile (P=0.008). For SAA, the area under the receiver operating characteristic curve was 0.721 for identification of frequent exacerbators; an SAA cut-off of 87.0 ng/mL yielded an 80% sensitivity and 61.5% specificity.

          Conclusion

          In stable COPD patients, SAA was independently associated with the frequent exacerbator phenotype, suggesting that SAA may be a useful serum biomarker to inform progression or management in COPD.

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          Most cited references 40

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          Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations.

          Patients with chronic obstructive pulmonary disease (COPD) are prone to frequent exacerbations which are a significant cause of morbidity and mortality. Stable COPD patients often have lower airway bacterial colonisation which may be an important stimulus to airway inflammation and thereby modulate exacerbation frequency. Twenty nine patients with COPD (21 men, 16 current smokers) of mean (SD) age 65.9 (7.84) years, forced expiratory volume in 1 second (FEV(1)) 1.06 (0.41) l, FEV(1) % predicted 38.7 (15.2)%, FEV(1)/FVC 43.7 (14.1)%, inhaled steroid dosage 1.20 (0.66) mg/day completed daily diary cards for symptoms and peak flow over 18 months. Exacerbation frequency rates were determined from diary card data. Induced sputum was obtained from patients in the stable state, quantitative bacterial culture was performed, and cytokine levels were measured. Fifteen of the 29 patients (51.7%) were colonised by a possible pathogen: Haemophilus influenzae (53.3%), Streptococcus pneumoniae (33.3%), Haemophilus parainfluenzae (20%), Branhamella catarrhalis (20%), Pseudomonas aeruginosa (20%). The presence of lower airway bacterial colonisation in the stable state was related to exacerbation frequency (p=0.023). Patients colonised by H influenzae in the stable state reported more symptoms and increased sputum purulence at exacerbation than those not colonised. The median (IQR) symptom count at exacerbation in those colonised by H influenzae was 2.00 (2.00-2.65) compared with 2.00 (1.00-2.00) in those not colonised (p=0.03). The occurrence of increased sputum purulence at exacerbation per patient was 0.92 (0.56-1.00) in those colonised with H influenzae and 0.33 (0.00-0.60) in those not colonised (p=0.02). Sputum interleukin (IL)-8 levels correlated with the total bacterial count (rho=0.459, p=0.02). Lower airway bacterial colonisation in the stable state modulates the character and frequency of COPD exacerbations.
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            Immunoregulatory functions of surfactant proteins.

             J. Wright (2004)
            Because the lungs function as the body's gas-exchange organ, they are inevitably exposed to air that is contaminated with pathogens, allergens and pollutants. Host-defence mechanisms within the lungs must facilitate clearance of inhaled pathogens and particles while minimizing an inflammatory response that could damage the thin, delicate gas-exchanging epithelium. Pulmonary surfactant is a complex of lipids and proteins that enhances pathogen clearance and regulates adaptive and innate immune-cell functions. In this article, I review the structure and functions of the surfactant proteins SP-A and SP-D in regulating host immune defence and in modulating inflammatory responses.
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              Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels.

              Respiratory tract infections may acutely increase risk from coronary heart disease (CHD), though the mechanisms have not been defined. Patients with chronic obstructive pulmonary disease (COPD) are prone to repeated exacerbations that are often associated with respiratory infections. These patients also have increased cardiovascular morbidity and mortality. We hypothesized that transient acute increases in plasma fibrinogen, an independent risk factor for CHD, could occur at COPD exacerbation (mediated through a rise in IL6) and thereby provide a mechanism linking respiratory infection to risk of coronary heart disease. 93 COPD patients [mean (SD) age 66.8 (8.1) years] were followed regularly over one year, with daily diary card monitoring of respiratory symptoms and peak expiratory flow rate (PEFR); 67 patients [mean FEV1 1.06 (0.44) l, FVC 2.43 (0.79) l] were seen during 120 exacerbations. At each visit spirometry was measured and blood samples taken for plasma fibrinogen and Interleukin-6 (IL-6) levels. At baseline, the mean (SD) plasma fibrinogen was elevated at 3.9 (0.67) g/l in the 67 patients with exacerbations during the study and the median (IQR) IL-6 at 4.3 (2.4 to 6.8) pg/ml. Plasma fibrinogen increased by 0.36 (0.74) g/l at exacerbation (p <0.001). with IL-6 levels rising by 1.10 (-2.73 to 6.95) pg/ml (p = 0.008). There was a relation between the changes in fibrinogen at exacerbation and IL-6 levels (r = 0.348, p <0.001). Multiple regression revealed significantly greater rises in fibrinogen when exacerbations were associated with purulent sputum (b = 0.34 g/l; p = 0.03), increased cough (b = 0.31 g/l, p = 0.019) and symptomatic colds (b = 0.228; p = 0.024). Plasma fibrinogen levels were elevated in stable patients with COPD and may contribute to the increased cardiovascular morbidity and mortality in these patients. COPD exacerbations increased serum IL-6 levels, leading to a rise in plasma fibrinogen. Thus acute rather than chronic infection may have a role in predisposing to coronary heart disease or stroke.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                copd
                copd
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove
                1176-9106
                1178-2005
                30 September 2020
                2020
                : 15
                : 2379-2388
                Affiliations
                [1 ]State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong 510120, People’s Republic of China
                [2 ]Rehabilitation Clinical Trials Center, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center , Torrance, CA, 90502, USA
                [3 ]Faculty of Biological Sciences, University of Leeds , Leeds LS2 9JT, UK
                Author notes
                Correspondence: Nuofu Zhang State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou, Guangdong510120, People’s Republic of China Email nfzhanggird@163.com
                [*]

                These authors contributed equally to this work

                Article
                266844
                10.2147/COPD.S266844
                7535123
                © 2020 Zhao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 4, Tables: 8, References: 46, Pages: 10
                Funding
                Funded by: National Key R&D Program of China;
                Funded by: Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program;
                This work was funded unconditionally by National Key R&D Program of China (2018YFC1313600 & 2016YFC0901102); Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S155). The sponsors have no role in design, conduct, data interpretation of the study, and preparation, review or approval of this manuscript.
                Categories
                Original Research

                Respiratory medicine

                surfactant protein d, inflammation, interleukin-4

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