Evidence for Exacerbation-Prone Asthma and Predictive Biomarkers of Exacerbation Frequency

Abstract

Rationale: Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers.Objectives: To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers.Methods: Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers.Measurements and Main Results: Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV₁ and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/μl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/μl increase in baseline eosinophil number.Conclusions: Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.

Keywords: IL-6; exacerbation-prone asthma; metabolic dysfunction; obesity; type-2 inflammation.

Figure 1.

(A) Schematic of the SARP (Severe Asthma Research Program) clinical protocol. Asthma exacerbations were assessed at 6-month intervals using alternating phone interviews (gray boxes) and in-person visits (black boxes). Plasma IL-6 measurements and blood eosinophil cell counts were made at a baseline visit (arrow). (B) Number of asthma exacerbations that occurred over the SARP 3-year protocol. Baseline asthma exacerbations were recorded based upon subject recall for the year preceding the baseline visit. BL = baseline.

Figure 2.

(A) Longitudinal change of annual exacerbation frequency categories over time using a Sankey diagram: each blue rectangular node represents the number of subjects in each annual exacerbation frequency category. Subjects with zero exacerbations are represented in light blue, subjects with one or two exacerbations in blue, and subjects with three or more exacerbations in dark blue. The size of the rectangular nodes represents the percentage of subjects at each annual exacerbation frequency category at each year of the study. Horizontal bar lines connect the nodes and depict the number of subjects that transition to and from each node the subsequent year. These horizontal bar lines are color coded based on the longitudinal exacerbation phenotype the subjects fall into over the 3 years of follow-up. The size of the horizontal bar lines represents the number of subjects at each transition: green = exacerbation-resistant asthma (ERA), orange = exacerbation-intermittent asthma, and red = exacerbation-prone asthma (EPA). (B) Percentage of subjects in each exacerbation phenotype. ERA was the most common phenotype (41%), whereas the smallest number of subjects demonstrated EPA (21%). (C) Exacerbation burden by exacerbation phenotype. The overall exacerbation burden was highly skewed, and EPA subjects experienced a significantly higher number of asthma exacerbations and asthma-related hospitalizations per subject over 3 years of follow-up. EPA subjects were more likely to experience an emergency department visit for asthma over 3 years of follow-up. Error bars denote SEs. ED = emergency department; EIA = exacerbation-intermittent asthma.

Figure 3.

Second order transition modeling; shown are the probabilities of at least one exacerbation occurring in the third year of follow-up, corresponding to different states of knowledge about exacerbation frequency in the prior years. No prior knowledge reflects the observed probability of having an exacerbation at Year 3 (40%). One year of prior knowledge reflects the probability of having an exacerbation at Year 3 with 1 year prior knowledge of exacerbation frequency (0 exacerbation or >0 exacerbations); 2 years of prior knowledge reflects the probability of having an exacerbation at Year 3 with 2 years of prior knowledge of exacerbation history (both years 0, 1 yr of 0 and 1 yr >0, both years >0). Error bars denote 95% confidence intervals.

Figure 4.

Negative binomial regression models predicting the development of asthma exacerbations over 3 years of follow-up. (A) Directed acyclic graph demonstrating the hypothesized relationship between plasma IL-6 and blood eosinophil cell counts on the outcome variable of asthma exacerbations. Body mass index (BMI), age, and depression are the minimal sufficient adjustment set of covariates for estimating the total effect of eosinophils and IL-6 on the primary outcome of exacerbations. Marginal effect of primary predictor variables of (B) plasma IL-6 and (C) blood eosinophil cell counts are controlled for BMI, age, and history of depression. Marginal effect of plasma IL-6 and blood eosinophils are also controlled for each other. GERD = gastroesophageal reflux disease.