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. 2025 Feb;211(2):194-204.
doi: 10.1164/rccm.202402-0403OC.

Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma

John V Fahy  1 , Nathan D Jackson  2 , Satria P Sajuthi  2 , Elmar Pruesse  2 , Camille M Moore  2 , Jamie L Everman  2 , Cydney Rios  2 , Monica Tang  1 , Marc Gauthier  3 , Sally E Wenzel  3   4 , Eugene R Bleecker  5 , Mario Castro  6 , Suzy A Comhair  7 , Serpil C Erzurum  7 , Annette T Hastie  8 , Wendy Moore  8 , Elliot Israel  9 , Bruce D Levy  9 , Loren Denlinger  10 , Nizar N Jarjour  10 , Mats W Johansson  10 , David T Mauger  11 , Brenda R Phillips  11 , Kaharu Sumino  12 , Prescott G Woodruff  1 , Michael C Peters  1 , Max A Seibold  2   13   14
Affiliations

Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma

John V Fahy et al. Am J Respir Crit Care Med. 2025 Feb.

Abstract

Rationale: Corticosteroid-responsive type 2 (T2) inflammation underlies the T2-high asthma endotype. However, we hypothesized that type 1 (T1) inflammation, possibly related to viral infection, may also influence corticosteroid response. Objectives: To determine the frequency and within-patient variability of T1-high, T2-high, and T1/T2-high asthma endotypes and whether virally influenced T1-high disease influences corticosteroid response in asthma. Methods: Patients in SARP-3 (Severe Asthma Research Program-3) had sputum collected at baseline, after intramuscular (triamcinolone acetonide) corticosteroid treatment, and at 1- and 3-year follow-ups. Sputum cell RNA was used for whole-transcriptome gene network and viral metagenomic analyses. We then profiled patients as highly expressing T1 and/or T2 gene networks and established the influence of these endotypes on corticosteroid responsiveness and the likelihood of viral transcript detection in the airways. Measurements and Main Results: We found that 22% and 35% of patients with asthma highly expressed T1 and T2 network genes, respectively, and that 8.5% highly expressed both networks. Asthma severity outcomes were worse in T2-high compared with T1-high asthma and most severe in the T1-high/T2-high subgroup. Corticosteroid treatment strongly suppressed T2 but poorly suppressed T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-low/T2-high disease and not in patients with T1-high/T2-high disease. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a respiratory virus, and high viral carriage was associated with 14-fold increased risk of T1-high disease. Conclusions: Airway T1 immune responses are relatively common in asthma, are largely corticosteroid resistant, and are associated with subclinical viral infection.

Keywords: sputum; transcriptomics; type 1 asthma; type 2 asthma; viral metagenomics.

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Comment in

  • In Asthma, Change Is the Only Constant.
    Staples KJ. Staples KJ. Am J Respir Crit Care Med. 2025 Feb;211(2):141-142. doi: 10.1164/rccm.202411-2290ED. Am J Respir Crit Care Med. 2025. PMID: 39700529 Free PMC article. No abstract available.

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