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

Abstract

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 better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation - which occurs in subgroups of obese and older patients - modifies asthma to make it worse. Interleukin 6 (IL6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the relationship between IL6, metabolic dysfunction, and asthma severity. Methods We generated a reference range in health for plasma IL6 in a cohort of healthy controls (n=93). We compared the clinical characteristics of asthmatics with plasma IL6 levels below and above the upper limit of normal (“IL6 low” and “IL-high” asthma) in two asthma cohorts - predominantly non-severe asthmatics recruited at the University of California San Francisco (UCSF)(n=249) and predominantly severe asthmatics recruited by the Severe Asthma Research Program (SARP)(n=387). Findings The upper 95th centile value for plasma IL6 in the healthy cohort was 3·1pg/mL, and 14% of UCSF cohort and 26% of the SARP cohort had plasma IL6 levels above this upper limit. The “IL6-high” patients in both asthma cohorts had a significantly higher body mass index and a higher prevalence of metabolic disease than the IL6-low patients (all p values < 0.01). IL6-high patients also had significantly lower lung function and more frequent asthma exacerbations than IL6-low patients (all p values < 0·01). Although 75% of IL6-high asthmatics were obese, 63% of obese patients were IL6-low. Among obese patients, the forced expired volume in one second (FEV1) was significantly lower in IL6-high than in IL6-low patients (mean FEV1 70·8 [S.D. 19·5] vs. 78·1 [19·7] % predicted, p = 0·002), and the percentage of patients reporting an asthma exacerbation in the past 1-2 years was higher in IL6-high than in IL6-low patients (66 vs. 48%, p = 0·003). Among non-obese asthmatics, FEV1% and asthma exacerbation outcomes were also significantly worse in IL6-high than in IL6-low patients (mean FEV1 66·4 [SD 23·1] vs. 83·2 [20·4] % predicted, p< 0·01; 59 vs. 34 %, p=0·008). Interpretation Systemic IL6 inflammation and clinical features of metabolic dysfunction - occurring most commonly among a subset of obese asthmatics but also in a small subset of non-obese patients - is associated with more severe asthma. IL6 inhibitors or treatments that improve metabolic dysfunction represent rational clinical trials to pursue for a subset of patients with severe asthma, and plasma IL6 is a biomarker that could guide patient stratification.

Severe asthma in children

“…44 Recently, the novel hypothesis that the airway may be the target of systemic inflammation has been proposed. 45 In a study of two adult cohorts comprising more than 600 patients, asthma outcomes were related to serum IL-6 (a marker of systemic inflammation). A total of 111/138 of the IL-6 high asthmatic patients were obese, but 178/289 of obese asthma patients were IL-6 low.…”

Mechanisms by which obesity impacts upon asthma

“…Finally, examination of the bronchoalveolar lavage fluid from a small group of patients with severe asthma demonstrated the presence of ILC3s,31 suggesting that ILC3s producing IL-17 may play an important role in human asthma. M1 macrophages are known to produce IL-1β and IL-6, which is important, since increased production of IL-6 is another feature of metabolic dysfunction in obesity, and is associated with severe asthma in obese individuals 34. Together these studies suggest that the NLRP3 inflammasome, IL-1β and IL-17-producing ILC3s, all activated by the metabolic dysfunction in obesity, may comprise a non-type 2 mechanism that explains obesity-associated asthma, although additional mechanisms may be involved as well.…”

ALX receptor ligands define a biochemical endotype for severe asthma

“…Asthmatic and healthy subjects were recruited and completed baseline characterization with some subjects agreeing to bronchoscopy. Details regarding SARP methods, subject enrollment, and study procedures can be found in Peters et al (45).…”