Asthma severity and corticosteroid response depend on variable type 1 and type 2 inflammation in the airway

The prevalence, inter-relationships, and longitudinal behavior of type 1 (T1) and type 2 (T2) immune responses in asthma are uncertain, as is the role of viruses as determinants of these responses. Here, we performed whole transcriptome network analysis on sputum cells collected from Severe Asthma Research Program (SARP)-3 patients before and after treatment with intramuscular corticosteroid and again at 1 and 3-year follow-up visits. We used network analysis to analyze whole-transcriptome gene expression and metagenomic analysis of these RNA-seq data to detect viruses. We identified T1 and T2 airway networks, the expression of which showed that 26% and 44% of patients had T1-high and T2-high asthma at baseline, respectively. Asthma severity outcomes were worse in T2-high asthma than in T1-high asthma and most severe in the subgroup of patients (14%) with combined T1- and T2-high disease. Corticosteroid treatment suppressed T2 but not T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-L/T2-H disease and not in T1-H/T2-H patients. Although T1 and T2 inflammation at baseline was a significant predictor of T1 and T2 inflammation at follow-up visits, most patients had variable rather than persistent expression of T1 and T2 network genes. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a virus and high viral carriage was associated with an 11-fold increased risk of T1-high disease. Together our results uncover a relatively high burden of T1-high and T1/T2-high disease subtypes in severe asthma, which are corticosteroid-resistant and manifest with sub-clinical viral infection. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT01606826 ### Funding Statement This study was funded under the following grants: National Institutes of Health grant U01 HL146002 (BDL) National Institutes of Health grant U10 HL109172 (EI) National Institutes of Health grant U10 HL109168 (NNJ) National Institutes of Health grant U10 HL109152 (SEW) National Institutes of Health grant U10 HL109257 (MC) National Institutes of Health grant U10 HL109146 (JVF) National Institutes of Health grant U10 HL109250 (SCE) National Institutes of Health grant U10 HL109164 (ERB) National Institutes of Health grant U10 109086 (DTM) National Institutes of Health grant R01 HL080414 (JVF) National Institutes of Health grant P01 HL107202 (JVF) National Institutes of Health grant P01 HL132821 (MAS) National Institutes of Health grant R01 HL135156 (MAS) Sandler Asthma Basic Research Center at UCSF (JVF) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institution Review Boards at all sites involved in the study (University of Pittsburgh, Brigham & Women's Hospital, University of California, San Francisco, The Cleveland Clinic, University of Wisconsin, Madison, Wake Forest University, University of Kansas, Penn State College of Medicine) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Participant metadata used in this study and gene lists and their enriched pathways for 42 WGCNA co-expression networks can be accessed from https://github.com/seiboldlab/SARP\_T1\_T2_inflammation. All RNA-seq data in the study will be deposited at Gene Expression Omnibus (GEO).