Bingham K, Zahrani YA, Stewart I, Portelli MA, Fogarty A, McKeever TM, Singapuri A, Heaney LG, Mansur AH, Chaudhuri R, Thomson NC, Holloway JW, Howarth PH, Djukanovic R, Blakey JD, Chauhan A, Brightling CE, Pogson ZEK, Hall IP, Martinez-Pomares L, Shaw D, Sayers I. Immun Inflamm Dis. 2025 Mar;13(3):e70116. doi: 10.1002/iid3.70116.
ABSTRACT
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 (R2 = 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 × 10−4 and 2.20 × 10−7; 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.
Summary
- A large proportion of asthma patients showed a complex systemic inflammation with multiple overlapping inflammatory profiles suggesting several disease mechanisms spanning Type 1, 2 and 17 inflammation.
- Nearly half of asthma patients showed elevated levels of mediators that are current biological drug targets suggesting these patients may be amenable to these drugs or even combination monoclonal antibody therapy.
- Our data also confirms and extends previous findings on childhood versus adult onset, exacerbation prone asthma and eosinophilic driven asthma subgroups.