Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma
<b>Rationale:</b> 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. <b>Objectives:</b> 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. <b>Methods:</b> 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. <b>Measurements and Main Results:</b> 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 FEV<sub>1</sub> 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. <b>Conclusions:</b> Airway T1 immune responses are relatively common in asthma, are largely corticosteroid resistant, and are associated with subclinical viral infection.
Authors
- Loren C. Denlinger (ORCID: https://orcid.org/0009-0008-1299-1186)
- Elmar Pruesse (ORCID: https://orcid.org/0000-0002-1656-6020)
- Nizar N. Jarjour (ORCID: https://orcid.org/0000-0003-0170-8927)
- Max A. Seibold (ORCID: https://orcid.org/0000-0002-8685-4263)
- Wendy C. Moore (ORCID: https://orcid.org/0000-0001-6869-3059)
- SUZY A. A. COMHAIR (ORCID: https://orcid.org/0000-0003-1918-9002)
- Jamie L. Everman (ORCID: https://orcid.org/0000-0002-1935-4672)
- John V. Fahy (ORCID: https://orcid.org/0000-0001-5427-9308)
- SERPIL CEM ERZURUM (ORCID: https://orcid.org/0000-0001-5202-9065)
- Cydney Rios
- Mario Castro (ORCID: https://orcid.org/0000-0001-6328-8994)
- Mats W. Johansson (ORCID: https://orcid.org/0000-0001-5699-978X)
- Kaharu Sumino (ORCID: https://orcid.org/0000-0002-6214-2966)
- Annette T. Hastie (ORCID: https://orcid.org/0000-0001-6607-7797)
- Monica Tang (ORCID: https://orcid.org/0000-0001-8847-5817)
- Nathan D. Jackson (ORCID: https://orcid.org/0009-0008-2675-021X)
- Marc Gauthier (ORCID: https://orcid.org/0000-0001-5037-2804)
- Bruce David Levy (ORCID: https://orcid.org/0000-0001-9515-5731)
- Camille M. Moore (ORCID: https://orcid.org/0000-0002-7363-8684)
- Sally E. Wenzel (ORCID: https://orcid.org/0000-0002-4242-0164)
- Prescott G. Woodruff (ORCID: https://orcid.org/0000-0003-3176-0603)
- David T. Mauger (ORCID: https://orcid.org/0000-0002-4663-5285)
- Brenda R. Phillips (ORCID: https://orcid.org/0000-0003-1351-6359)
- Satria P. Sajuthi (ORCID: https://orcid.org/0000-0001-9598-7298)
- Michael C. Peters (ORCID: https://orcid.org/0000-0003-1854-4447)
- Eugene R. Bleecker
- Elliot Israel
Institutions
- Brigham and Women's Hospital (US)
- Pennsylvania State University (US)
- Cleveland Clinic (US)
- University of Wisconsin–Madison (US)
- Harvard University (US)
- University of Arizona (US)
- University of Kansas (US)
- City College of San Francisco (US)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Cleveland Foundation (US)
- University of California System (US)
- National Jewish Health (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Mayo Clinic in Arizona (US)
- University of Kansas Medical Center (US)
- University of Pittsburgh Medical Center (US)
- Wake Forest University (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- American Journal of Respiratory and Critical Care Medicine
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1164/rccm.202402-0403oc
- Citations
- 24
- Primary Topic
- Asthma and respiratory diseases
- Type
- article
- Field-Weighted Citation Impact
- 7.84
Funders
- National Institutes of Health