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

Dongxing Zhao1,2 ,* Asghar Abbasi2 ,* Harry B Rossiter,2,3 Xiaofen Su,1 Heng Liu,1 Yuhong Pi,1 Li Sang,1 Weiyong Zhong,1 Qifeng Yang,1 Xiongtian Guo,1 Yanyan Zhou,1 Tianyang Li,1 Richard Casaburi,2 Nuofu Zhang1 1State 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; 2Rehabilitation Clinical Trials Center, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA; 3Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK*These authors contributed equally to this workCorrespondence: Nuofu ZhangState 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 ChinaEmail nfzhanggird@163.comBackground: 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 (FENO); 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 FEV1%predicted or FVC %predicted. After adjusting for sex, age, BMI, FEV1/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.Keywords: inflammation, surfactant protein D, interleukin-4