Investigations of a combination of atopic status and age of asthma onset identify asthma subphenotypes

Abstract

Objective

Subphenotypes of asthma may be determined by age onset and atopic status. We sought to characterize early or late onset atopic asthma with fungal or non-fungal sensitization (AAFS or AANFS) and non-atopic asthma (NAA) in children and adults in the Severe Asthma Research Program (SARP). SARP is an ongoing project involving well-phenotyped patients with mild to severe asthma.

Methods

Phenotypic comparisons were performed using Kruskal-Wallis or chi-square test. Genetic association analyses were performed using logistic or linear regression.

Results

Airway hyper-responsiveness, total serum IgE levels, and T2 biomarkers showed an increasing trend from NAA to AANFS and then to AAFS. Children and adults with early onset asthma had greater % of AAFS than adults with late onset asthma (46% and 40% vs. 32%; P < 0.00001). In children, AAFS and AANFS had lower % predicted FEV₁ (86% and 91% vs. 97%) and greater % of patients with severe asthma than NAA (61% and 59% vs. 43%). In adults with early or late onset asthma, NAA had greater % of patients with severe asthma than AANFS and AAFS (61% vs. 40% and 37% or 56% vs. 44% and 49%). The G allele of rs2872507 in GSDMB had higher frequency in AAFS than AANFS and NAA (0.63 vs. 0.55 and 0.55), and associated with earlier age onset and asthma severity.

Conclusions

Early or late onset AAFS, AANFS, and NAA have shared and distinct phenotypic characteristics in children and adults. AAFS is a complex disorder involving genetic susceptibility and environmental factors.

Keywords:

• Age of asthma onset
• asthma subphenotypes
• atopic asthma with fungal sensitization
• GSDMB
• non-atopic asthma
• severe asthma

Acknowledgements

The authors acknowledge all investigators, staff, and participants in the SARP studies. The following companies provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up: AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi–Genzyme–Regeneron, and TEVA.

Disclosure statement

Dr. Castro receives University Grant Funding from NIH, American Lung Association, PCORI; he receives Pharmaceutical Grant Funding from AstraZeneca, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi; he is a consultant for Genentech, Teva, Sanofi-Aventis, Merck, Novartis; he is a speaker for Amgen, AstraZeneca, Genentech, GSK, Regeneron, Sanofi, Teva; he receives Royalties from Elsevier. Dr. Denlinger receives University Grant Funding from NHLBI; he also receives PrecISE and GRAIL grants from NHLBI and Lung Health Cohort grant from ALA-ACRC which are not related to SARP; he receives drugs for the NHLBI PrecISE trial from GlaxoSmithKline, Laurel, Sun Pharma, Vifor, Vitaeris/CSL Behring, Vitaflo and equipment contracts with the NHLBI PrecISE trial from Vyaire, Caire Diagnostics, MIR, Propeller Health, ZEPHYRx. Dr. Gaston is founder and equity owner in Respiratory Research Incorporated as well as Airbase Breathing Company, LLC; his lab is funded by the NIH, the Eli Lilly Foundation, the Harrington Discovery Institute, and the Riley Children’s Foundation. Dr. Jarjour receives University Grant Funding from NHLBI; he is a consultant for AstraZeneca, GSK. Dr. Levy reports grants from NHLBI, personal consulting fees from AstraZeneca, Bayer, Gossamer Bio, NControl, Novartis, Pieris Pharmaceuticals, Sanofi, Teva, participates on NIAID/DAIT COVID-19 DSMB board, and has stock from Entrinsic Biosciences, Nocion Therapeutics. Dr. Mauger reports grants from NHLBI and drugs for NIH-funded clinical trials from Genentech, GSK, OM Pharma, Sanofi-Regeneron. Dr. Wenzel receives Pharmaceutical Grant Funding from AstraZeneca, Knopp, Regeneron; she is a consultant for AstraZeneca, Knopp, Novartis, Sanofi, GSK; she is on scientific advisory board of Aer Therapeutics. All other authors have nothing to disclose. Dr. Bleecker reports grants from NHLBI and Pharmaceutical Grant Funding from AstraZeneca, Novartis, Regeneron, Sanofi Genzyme, and clinical trials administrated through University of Arizona; he is a consultant for AstraZeneca, Glaxo Smith Kline, Knopp Pharmaceuticals, Novartis, Regeneron, and Sanofi Genzyme; he receives payment for lectures from AstraZeneca and support for travel from AstraZeneca, Glaxo Smith Kline, Novartis, Regeneron, and Sanofi Genzyme. Dr. Meyers reports grants from NHLBI and Pharmaceutical Grant from GSK; she receives consulting fees from AstraZeneca. The rest of the authors declare that they have no relevant conflict of interest.

Additional information

Funding

This study was supported by NIH grant AI149754. SARP cross-sectional cohort (stage 1 and 2; SARP1-2) was supported by NIH grants HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174, HL69349, UL1RR024992, M01RR018390, M01RR07122, M01RR03186, HL087665, and HL091762. SARP longitudinal cohort (stage 3; SARP3) was funded by the NHLBI U10 HL109172, HL109168, HL109152, HL109257, HL109146, HL109250, HL109164, and HL109086 and the Clinical and Translational Science Awards (CTSA) Program UL1 TR001102, UL1 TR000427, UL1 TR001420, and UL1 TR002378. SARP longitudinal cohort (stage 4; SARP4) was funded by NIH HL146002. Genetic studies for SARP cross-sectional cohort were funded by NIH HL87665 and Go Grant RC2HL101487. SARP whole-genome sequencing was supported by National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) X01 grant. This work was also supported by the NIH grants HL142769. The following companies provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up: AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi–Genzyme–Regeneron, and TEVA. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.