Type 2 inflammation in cystic fibrosis is a predictor of mortality and targeted with <scp>CFTR</scp> modulator therapy
Authors: Daniel P. Cook, Ashley Y. Wu, Christopher M. Thomas, Robert G. Hamilton, Ray Stokes Peebles, Vern Eric Kerchberger
Journal: Allergy (2024)

Cystic fibrosis (CF) is a common autosomal recessive disease due to mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). While the main CF airway pathologic feature is severe neutrophilic inflammation, Type 2 (T2) inflammation may be augmented. Persons with CF and CFTR-deficient animal models have increased T2 inflammation defined by an elevated IgE response to fungal allergens1-4 and elevated lymphocyte production of IL-4 and IL-13.2, 3, 5, 6 To further understand the role of T2 inflammation in clinical outcomes of persons with CF, we interrogated our institution's research-enabled electronic health record (EHR). To define T2 inflammation, we focused on readily available clinical laboratory tests including blood absolute eosinophil count (AEC) and total IgE levels. The objective of this analysis was to investigate the clinical characteristics of T2 inflammation in CF, whether T2 inflammation in CF is associated with worse outcomes, and how CFTR modulator therapy influences T2 biomarker levels. Within the EHR, we identified 483 adults with diagnostic coding for CF, including 316 with at least one instance of elevated AEC (>300 cells/μL) or IgE (>100 IU/mL), termed T2 CF, and 167 individuals without T2 biomarker elevations, termed non-T2 CF (Figure S1). Despite no differences in age, sex, or race, T2 CF had significantly greater prescriptions for inhaled corticosteroids, systemic corticosteroids, and while infrequent, anti-IgE, anti-IL-5, and anti-IL-4 receptor biologic therapies compared to non-T2 CF patients (Table 1). Allergic comorbidities were significantly enriched among T2 CF subjects including asthma, bronchiectasis, and allergic bronchopulmonary aspergillosis, as were diagnosis codes for Pseudomonas aeruginosa infections and Staphylococcus aureus infections. Phenome-wide association (PheWAS) demonstrated that T2 CF subjects had significant enrichment of phecodes associated with a variety of infections including bacterial pneumonia from Pseudomonas, MRSA, MSSA, and Streptococcus pneumoniae; bronchopneumonia and lung abscess; and fungal mycoses compared to non-T2 CF (Figure 1A, Table S1). Spirometry showed significant reductions in prebronchodilator FEV1, FVC and FEV1/FVC ratio among T2 CF compared to non-T2 CF (Figure 1B; Figure S2A,B). Using a linear mixed effects regression model to account for repeat testing over time, and adjusting for demographics, mutational status, and receipt of systemic or inhaled corticosteroids, each log-fold increase in serum IgE was associated with a mean 3.3 decrease in percent predicted FEV1 (Table S3). Aligning with decreased pulmonary function and increased burden of infection and respiratory-related phenotypes, overall survival was also significantly lower in T2 CF than non-T2 CF despite both groups having similar demographics and age of first contact for CF care (Figure 1C), with an adjusted hazard ratio for death of 2.24 by Cox proportional hazards regression model (95% confidence interval [CI]: 1.34–3.75, p = .002, Table S2). Lastly, using linear mixed effects regression correlating CFTR modulator therapy with clinical laboratory test values, receipt of highly-effective CFTR modulator therapy (HEMT, Elexacaftor/Tezacaftor/Ivacaftor and Ivacaftor) was associated with a mean 30% reduction of serum IgE levels (95% CI: 23% to 37%, p < .001) and receipt of non-HEMT (Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor) was associated with a mean 13% reduction of serum IgE levels (95% CI: 1% to 24%, p = 0.37). (Figure 1D,E, Table S4). In conclusion, our study demonstrates a T2 endotype exists within CF characterized by increased obstructive pulmonary disease, and distinct phenotypic signature of increased allergic disease, infections, and burden of CF complications. Most importantly, we also demonstrate for the first time an increased risk of death among CF subjects with T2 inflammatory signatures compared to CF subjects lacking significant T2 inflammation. Concordantly, we found that CFTR modulator therapy was associated with IgE reductions, suggesting a complex relationship between CFTR function and T2 inflammation. Understanding how common CF pathogens influence the T2 signature and whether T2 inflammation contributes to bacterial or fungal colonization may provide insights into disease pathogenesis. Although IgE and AEC are commonly performed as annual laboratory tests for CF patients, these tests may not completely reflect T2 inflammation in the lung. Other markers such as TARC (thymus and activation-regulated chemokine) or periostin, or labs pertaining to atopic disease including antigen-specific IgE testing may also be important in the CF population. Further studies identifying modifiers of T2 inflammation in CF may have prognostic and therapeutic importance in this vulnerable population. DPC, RSP, and VEK contributed to conception and design of research; DPC, AYW, CMT, RGH, and VEK performed experiments and data acquisition; DPC, RSP, and VEK analyzed data; DPC, RSP, and VEK interpreted results of experiments; DPC, RSP, and VEK prepared figures; DPC, RSP, and VEK drafted manuscript; DPC, AYW, CMT, RGH, RSP, and VEK edited, reviewed, and approved final version of manuscript. The authors would like to thank the physicians, staff, and patients at the Vanderbilt University Medical Center Adult CF Clinic for their support of this study. This work was funded by the National Institutes of Health (K08 AI 181763—D.P.C., K01 HL 157755—V.E.K., R01 AI 124456—R.S.P., R01 AI 145265—R.S.P., U19 AI 095227—R.S.P., R01 AI 111820—R.S.P., R21 AI 145397), the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (101BX004299—R.S.P.), and the Cystic Fibrosis Foundation (COOK20L0—D.P.C.). Portions of the study described in this publication were supported by CTSA award no. UL1 TR002243 from the National Center for Advancing Translational Sciences. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.