Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts.
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.



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.



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).



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.



NIH and the Parker B Francis Foundation.
Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Michael C
MC
Peters
Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Kelly Wong
KW
McGrath
Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University Winston-Salem, NC, USA.
Gregory A
GA
Hawkins
Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University Winston-Salem, NC, USA.
Annette T
AT
Hastie
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Bruce D
BD
Levy
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Elliot
E
Israel
Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, PA, USA.
Brenda R
BR
Phillips
Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, PA, USA.
David T
DT
Mauger
Department of Pathobiology, Cleveland Clinic, Cleveland, OH, USA.
Suzy A
SA
Comhair
Department of Pathobiology, Cleveland Clinic, Cleveland, OH, USA.
Serpil C
SC
Erzurum
Department of Biomolecular Chemistry, University of Wisconsin School of Medicine, Madison, WI, USA.
Mats W
MW
Johansson
Section of Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, WI, USA.
Nizar N
NN
Jarjour
Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
Andrea M
AM
Coverstone
Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Pediatrics, Washington University, St Louis, MO, USA.
Mario
M
Castro
Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Fernando
F
Holguin
Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Sally E
SE
Wenzel
Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Prescott G
PG
Woodruff
Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University Winston-Salem, NC, USA.
Eugene R
ER
Bleecker
Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA. Electronic address: John.Fahy@ucsf.edu.
John V
JV
Fahy
D000328:Adult; D001249:Asthma / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood*; D008168:Lung / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D012720:Severity of Illness Index
C508600:IL6 protein, human; D015850:Interleukin-6