TY - JOUR
T1 - Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity
T2 - a cross-sectional analysis of two cohorts
AU - Peters, Michael C.
AU - McGrath, Kelly Wong
AU - Hawkins, Gregory A.
AU - Hastie, Annette T.
AU - Levy, Bruce D.
AU - Israel, Elliot
AU - Phillips, Brenda R.
AU - Mauger, David T.
AU - Comhair, Suzy A.
AU - Erzurum, Serpil C.
AU - Johansson, Mats W.
AU - Jarjour, Nizar N.
AU - Coverstone, Andrea M.
AU - Castro, Mario
AU - Holguin, Fernando
AU - Wenzel, Sally E.
AU - Woodruff, Prescott G.
AU - Bleecker, Eugene R.
AU - Fahy, John V.
N1 - Funding Information:
The funding source was research grants awarded by the US National Institutes of Health Heart, Lung, and Blood Institute (NHLBI) and the Parker B Francis Foundation. The NHLBI provided funding for the Severe Asthma Research Program (SARP) and programme officers from NHLBI designed the structure of the SARP. An NHLBI programme officer is also a member of the SARP steering committee. The NHLBI was not involved in patient recruitment, data collection, data analysis, data interpretation, or manuscript preparation. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit the report for publication with the permission of all coauthors.
Funding Information:
This study was funded by the NIH (PO1 HL107201, R01 HL080414, U19 AI077439, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10HL109257, and U10 HL109152); and by grants from the Parker B Francis Foundation. We thank Patricia Noel and Robert Smith (Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, MD, USA) for their support and leadership of the Severe Asthma Research Program; the following coordinators, research assistants, and clinicians at the UCSF and SARP centres for their work in making our study possible: UCSF: Jennifer Soh, Zesemayat Mekonnen, Kelly Norsworthy, Sheena Kerr, Eleanor Dunican, and Charles McCulloch; Brigham and Women's Hospital and Harvard Medical School: Nawal Ali, Carrie Nettles, and Gabriela Sauza; Cleveland Clinic: Elise Baldarelli, Marybeth Boyle, John Escano, and Michelle Koo; Wake Forest University: Regina Smith, Deborah Meyers, and Wendy Moore, Washington University: Rebecca Schutz and Rachel Weaver; University of Pittsburgh: Louise Martin and Jenelle Mock; University of Wisconsin: Gina Crisafi, Holly Eversoll, Evelyne Falbene, Michele Wolf, Ronald Sorkness, and Loren Denlinger; Pennsylvania State University: Gail Snyder, Sara Marlin, Jennifer Zeller, Kelly Bixler-Nye, and Brenda Kline; Gabriella Sanchez and Carlos Iribarren (Kaiser Permanente Division of Research) for assistance in subject recruitment at the UCSF centre; and all the volunteers who participated in these studies.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/7/1
Y1 - 2016/7/1
N2 - Background Severe asthma is a complex heterogeneous disease associated with older age and obesity. The presence of eosinophilic (type 2) inflammation in some but not all patients with severe asthma predicts responsiveness to current treatments, but new treatment approaches will require a better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation, which arises in subgroups of obese and older patients, increases the severity of asthma. Interleukin-6 (IL-6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the association between IL-6 concentrations, metabolic dysfunction, and asthma severity. Methods In this cross-sectional analysis, patients were recruited from two cohorts: mainly non-severe asthmatics from the University of California San Francisco (UCSF) and mainly severe asthmatics from the Severe Asthma Research Program (SARP). We generated a reference range for plasma IL-6 in a cohort of healthy control patients. We compared the clinical characteristics of asthmatics with plasma IL-6 concentrations above (IL-6 high) and below (IL-6 low) the upper 95% centile value for plasma IL-6 concentration in the healthy cohort. We also compared how pulmonary function, frequency of asthma exacerbations, and frequency of severe asthma differed between IL-6 low and IL-6 high asthma populations in the two asthma cohorts. Findings Between Jan 1, 2005, and Dec 31, 2014, we recruited 249 patients from UCSF and between Nov 1, 2012, and Oct 1, 2014, we recruited 387 patients from SARP. The upper 95th centile value for plasma IL-6 concentration in the healthy cohort (n=93) was 3·1 pg/mL, and 14% (36/249) of UCSF cohort and 26% (102/387) of the SARP cohort had plasma IL-6 concentrations above this upper limit. The IL-6 high patients in both asthma cohorts had a significantly higher average BMI (p<0·0001) and a higher prevalence of hypertension (p<0·0001) and diabetes (p=0·04) than the IL-6 low patients. IL-6 high patients also had significantly worse lung function and more frequent asthma exacerbations than IL-6 low patients (all p values <0·0001). Although 80% (111/138) of IL-6 high asthmatic patients were obese, 62% (178/289) of obese asthmatic patients were IL-6 low. Among obese patients, the forced expiratory volume in 1 s (FEV1) was significantly lower in IL-6 high than in IL-6 low patients (mean percent predicted FEV1=70·8% [SD 19·5] vs 78·3% [19·7]; p=0·002), and the percentage of patients reporting an asthma exacerbation in the past 1–2 years was higher in IL-6 high than in IL-6 low patients (66% [73/111] vs 48% [85/178]; p=0·003). Among non-obese asthmatics, FEV1 values and the frequency of asthma exacerbations within the past 1–2 years were also significantly worse in IL-6 high than in IL-6 low patients (mean FEV1 66·4% [SD 23·1] vs 83·2% [20·4] predicted; p<0·0001; 59% [16/27] vs 34% [108/320]; p=0·01). Interpretation Systemic IL-6 inflammation and clinical features of metabolic dysfunction, which occur most commonly in a subset of obese asthma patients but also in a small subset of non-obese patients, are associated with more severe asthma. These data provide strong rationale to undertake clinical trials of IL-6 inhibitors or treatments that reduce metabolic dysfunction in a subset of patients with severe asthma. Plasma IL-6 is a biomarker that could guide patient stratification in these trials. Funding NIH and the Parker B Francis Foundation.
AB - Background Severe asthma is a complex heterogeneous disease associated with older age and obesity. The presence of eosinophilic (type 2) inflammation in some but not all patients with severe asthma predicts responsiveness to current treatments, but new treatment approaches will require a better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation, which arises in subgroups of obese and older patients, increases the severity of asthma. Interleukin-6 (IL-6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the association between IL-6 concentrations, metabolic dysfunction, and asthma severity. Methods In this cross-sectional analysis, patients were recruited from two cohorts: mainly non-severe asthmatics from the University of California San Francisco (UCSF) and mainly severe asthmatics from the Severe Asthma Research Program (SARP). We generated a reference range for plasma IL-6 in a cohort of healthy control patients. We compared the clinical characteristics of asthmatics with plasma IL-6 concentrations above (IL-6 high) and below (IL-6 low) the upper 95% centile value for plasma IL-6 concentration in the healthy cohort. We also compared how pulmonary function, frequency of asthma exacerbations, and frequency of severe asthma differed between IL-6 low and IL-6 high asthma populations in the two asthma cohorts. Findings Between Jan 1, 2005, and Dec 31, 2014, we recruited 249 patients from UCSF and between Nov 1, 2012, and Oct 1, 2014, we recruited 387 patients from SARP. The upper 95th centile value for plasma IL-6 concentration in the healthy cohort (n=93) was 3·1 pg/mL, and 14% (36/249) of UCSF cohort and 26% (102/387) of the SARP cohort had plasma IL-6 concentrations above this upper limit. The IL-6 high patients in both asthma cohorts had a significantly higher average BMI (p<0·0001) and a higher prevalence of hypertension (p<0·0001) and diabetes (p=0·04) than the IL-6 low patients. IL-6 high patients also had significantly worse lung function and more frequent asthma exacerbations than IL-6 low patients (all p values <0·0001). Although 80% (111/138) of IL-6 high asthmatic patients were obese, 62% (178/289) of obese asthmatic patients were IL-6 low. Among obese patients, the forced expiratory volume in 1 s (FEV1) was significantly lower in IL-6 high than in IL-6 low patients (mean percent predicted FEV1=70·8% [SD 19·5] vs 78·3% [19·7]; p=0·002), and the percentage of patients reporting an asthma exacerbation in the past 1–2 years was higher in IL-6 high than in IL-6 low patients (66% [73/111] vs 48% [85/178]; p=0·003). Among non-obese asthmatics, FEV1 values and the frequency of asthma exacerbations within the past 1–2 years were also significantly worse in IL-6 high than in IL-6 low patients (mean FEV1 66·4% [SD 23·1] vs 83·2% [20·4] predicted; p<0·0001; 59% [16/27] vs 34% [108/320]; p=0·01). Interpretation Systemic IL-6 inflammation and clinical features of metabolic dysfunction, which occur most commonly in a subset of obese asthma patients but also in a small subset of non-obese patients, are associated with more severe asthma. These data provide strong rationale to undertake clinical trials of IL-6 inhibitors or treatments that reduce metabolic dysfunction in a subset of patients with severe asthma. Plasma IL-6 is a biomarker that could guide patient stratification in these trials. Funding NIH and the Parker B Francis Foundation.
UR - http://www.scopus.com/inward/record.url?scp=84973557274&partnerID=8YFLogxK
U2 - 10.1016/S2213-2600(16)30048-0
DO - 10.1016/S2213-2600(16)30048-0
M3 - Article
C2 - 27283230
AN - SCOPUS:84973557274
SN - 2213-2600
VL - 4
SP - 574
EP - 584
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 7
ER -