Defining the Blood Cytokine Profile in Asthma to Understand Asthma Heterogeneity.

Background: Asthma is a heterogeneous disease characterized by overlapping clinical and inflammatory features.

Objective: This study aimed to provide insight into the systemic inflammatory profile in asthma, greater understanding of asthma endotypes and the contribution of genetic risk factors to both.

Methods: 4205 patients with asthma aged 16-60 were recruited from UK centers; serum cytokines were quantified from 708, including cytokines associated with Type 1, 2 and 17 inflammation. 3037 patients were genotyped for 25 single nucleotide polymorphisms associated with moderate-severe asthma.

Results: Serum cytokines associated with Th2 inflammation showed high coordinated expression for example, IL-4/IL-5 (R = 0.513). The upper quartile of the serum cytokine data identified 43.7% of patients had high levels for multiple Th2 cytokines. However, the groups defined by serum cytokine profile were not clinically different. Childhood-onset asthma was characterized by elevated total IgE, allergic rhinitis and dermatitis. Exacerbation prone patients had a higher BMI, smoking pack-years, asthma control questionnaire score and reduced lung function. Patients with blood eosinophils of > 300 cells/µL had elevated total IgE and lower smoking pack-years. None of these groups had a differential serum cytokine profile. Asthma risk alleles for; rs61816764 (FLG) and rs9303277 (IKFZ3) were associated with childhood onset disease (p = 2.67 × 10 and 2.20 × 10 ; retrospectively). No genetic variant was associated with cytokine levels.

Conclusion: Systemic inflammation in asthma is complex. Patients had multiple overlapping inflammatory profiles suggesting several disease mechanisms. Genetic risk factors for moderate-severe asthma confirmed previous associations with childhood onset of asthma.