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 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.

Fig. 1. Increases in plasma IL6 in a subset of asthmatics that is not related to airway measures of IL6

(A) Log transformed plasma IL6 measurements shown as kernel density plots to illustrate the distribution of the IL6 concentrations in plasma in the three cohorts. (B) Plasma IL6 values in UCSF healthy subjects, UCSF asthma patients, and SARP asthma patients. The horizontal dashed line indicates the upper 95% centile value for plasma IL6 in the healthy subjects. The shaded areas highlight the 36 (14%) UCSF asthma patients and the 102 (26%) SARP asthma patients who had plasma IL6 levels above the upper reference limit. *p<0·05 from ANOVA comparison. (C) Lack of correlation between plasma IL6 protein levels and log2 normalized gene expression levels for IL6 in sputum cells (n=210, in the SARP asthma cohort , black best-fit line). (D) Lack of correlation between plasma IL6 protein levels and sputum IL6 protein in sputum (n=109, UCSF asthma cohort , black best-fit line). (E) Plasma IL6 levels are positively and significantly correlated with plasma CRP (n= 123, UCSF asthma cohort, black best-fit line). (F) Plasma IL6 protein levels are positively and significantly correlated with blood neutrophils in the UCSF asthma cohort (black symbols and black best-fit line) and the SARP cohort (red symbols and red best-fit line). Best-fit lines were created in each cohort separately and the pearson's coefficient was calculated with the cohorts combined.

Fig 2. Increased metabolic dysfunction in IL6-high asthma

(A) A history of hypertension was significantly more common in IL6 high than in IL6 low asthma in both the UCSF and SARP cohorts, Data represented as % of subjects ± SE. (B) Total blood leukocytes number was higher in IL6 high asthma than in IL6 low asthma in the UCSF and SARP cohorts, mean, ± SE (C) A history of diabetes was significantly more common in IL6 high than in IL6 low asthma in the SARP cohort. *p<0·05 from chi-square test †p<0·05 from t-test. Data represented as % of subjects ± SE.

Fig. 3. More frequent asthma exacerbations in IL6-high asthma

(A) The percentage of asthma patients that required systemic corticosteroid treatment in the past 2 years was higher in IL6 high asthma compared to IL6 low asthma in the UCSF cohort (B) The percentage of asthma patients that required systemic corticosteroid treatment, emergency department treatment, or hospitalization for an asthma exacerbation in the past year in IL6 high asthma was higher than in IL6 low asthma in the SARP cohort. *p<0·05 from chi-square test. Data represented as % of subjects ± SE.

Fig. 4. Increased plasma IL6 is associated with metabolic dysfunction and more severe asthma in both obese and non-obese patients

(A) Plasma IL6 levels are positively and significantly correlated with body mass index (BMI) in UCSF asthma patients (black symbols) and SARP asthma patients (red symbols) pearson's coefficient was calculated with the cohorts combined. (B) The proportion of asthma patients with high plasma IL6 levels was much higher in obese asthmatics (BMI >30) than in non-obese asthmatics (BMI <30). (C) Compared to IL6-low asthma, IL6-high asthma is characterized by increased metabolic dysfunction in both obese and non-obese subgroups, as demonstrated by a higher frequency of hypertension and leukocytosis. (D) Asthma severity in IL6-high asthma is worse than in IL6-low asthma in both obese and non-obese subgroups, as demonstrated by lower FEV1 values and a higher percentage of subjects with a history of an asthma exacerbation. The exacerbation history is defined as a prednisone requiring asthma exacerbation in either the past 2 years (UCSF cohort) or the past in past year (SARP cohort).*p<0·05 from Wilcoxon rank sum test †p<0·05 from chi square test. Data represented as % of subjects ± SE, for binary variables and mean ± SEM for continuous variables.

Fig. 5. Plasma IL6 measures are unrelated to measures of type 2 inflammation in asthma

(A) Plasma IL6 levels are not related to blood eosinophil cell counts. (B) Plasma IL6 levels are not related to serum IgE levels, (C) Plasma IL6 levels are not related to exhaled nitric oxide levels. (D) Plasma IL6 levels are not related to sputum eosinophil cell percentages. UCSF asthma cohort is represented by black symbols and black best-fit lines and the SARP cohort is represented by red symbols and red best-fit lines. Best-fit lines were created in each cohort separately and the pearson's coefficient was calculated with the cohorts combined.