Multi-omics in Severe Asthma From Olive Pollen Allergy (DUPITEOLE)

Multi-omics Study (Biological Therapy Followed by Immunotherapy) in Patients With Severe Asthma Due to Olive Pollen Allergy

Patients with severe olive pollen allergy exhibit characteristic sensitization profiles, marked by strong recognition of minor allergens like Ole e 7, and, more importantly, show poor clinical responses to pharmacological treatments and immunotherapy. Previous studies have revealed that these patients experience a permanent immunological dysfunction (notably, dysregulated effector T-cell function) leading to a systemic inflammatory state that persists beyond the pollen season.

The hypothesis is that short-term treatment (6 months) with Dupilumab can stabilize and reverse the inflammatory state in patients with severe olive pollen allergy (Project PI22/01737), enabling them to transition to conventional allergen immunotherapy.

This study aims to deepen our understanding of the mechanisms underlying this immunological stabilization through multi-omics profiling (metabolomics, proteomics, transcriptomics) to explain the resolution of inflammation. Specifically, the goal is to restore an effective regulatory T-cell response, allowing for allergen-specific immunotherapy, which can be administered for three years in routine clinical practice as the only treatment capable of altering the disease's progression.

Since immunotherapy relies on functional regulatory T-cell responses, this approach could validate a therapeutic strategy for these patients that modifies the disease long-term, breaking the cycle of chronic inflammation. This would reduce dependency on costly biologic treatments and significantly improve the quality of life.

Study Overview

• Status: Active, not recruiting
• Conditions: Severe Asthma; Allergy and Asthma; Pollen; Allergy, Asthma

Detailed Description

Olive pollen (Olea europaea) is one of the leading causes of respiratory allergy in Mediterranean countries. Among the 14 olive pollen allergens identified to date, Ole e 1 is the major sensitizing allergen, whereas sensitization to Ole e 7 is strongly associated with a severe clinical phenotype in regions with intense olive cultivation, such as Córdoba (Spain). This phenotype is characterized by persistent airway inflammation, poor asthma control, and reduced response to allergen immunotherapy despite standard treatment.

Previous studies have demonstrated that severe olive pollen allergy is associated with a predominant type 2 inflammatory response, including increased frequencies of Th2 cells and type 2 innate lymphoid cells (ILC2), together with an imbalance between Th2 and Th1 immune responses. These immunological alterations are considered major contributors to persistent airway inflammation and reduced clinical efficacy of allergen immunotherapy.

Dupilumab, a fully human monoclonal antibody targeting the interleukin-4 receptor alpha (IL-4Rα), inhibits signaling mediated by both IL-4 and IL-13 and has demonstrated efficacy in several type 2 inflammatory diseases, including severe asthma, chronic rhinosinusitis with nasal polyps, and atopic dermatitis. Short-term treatment with biological agents has also been shown to restore immune homeostasis and improve subsequent responses to allergen immunotherapy in selected allergic populations.

This observational study is conducted within the framework of the ISCIII-funded competitive research project PI22/01737. The objective is to characterize longitudinal immunological and molecular changes associated with allergen immunotherapy in severe olive pollen-induced allergic asthma and to evaluate the influence of previous short-term dupilumab treatment on these responses under routine clinical practice conditions.

Clinical follow-up will be complemented by comprehensive multi-omics analyses, including targeted serum metabolomics, serum proteomics, transcriptomic profiling, and peripheral T-cell immunophenotyping. These complementary approaches are intended to identify biological pathways associated with immune regulation, inflammatory activity, and the development of long-term immune tolerance during allergen immunotherapy.

Comparisons will be performed between individuals previously treated with a short course of dupilumab before initiation of allergen immunotherapy and individuals receiving conventional treatment without previous biological therapy. The integration of clinical, immunological, and multi-omics data is expected to improve the understanding of mechanisms associated with successful allergen immunotherapy and to identify candidate biomarkers related to treatment response and immune stabilization.

Because of the exploratory nature of the study and the complexity of the molecular analyses, the findings will primarily generate biological hypotheses and candidate biomarkers for validation in larger prospective cohorts. Identification of reproducible molecular signatures associated with successful immune modulation may contribute to the development of more personalized therapeutic strategies for severe olive pollen allergy and optimize the use of allergen immunotherapy in this population.

• Study Type: Observational
• Enrollment (Estimated): 18

Contacts and Locations

Study Locations

• Spain
  • Cordoba
    • Córdoba, Cordoba, Spain, 14004
      • Hospital Universitario Reina Sofia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

study with prospective follow-up medication , aimed at analyzing the inflammatory status of a group of asthmatic patients allergic to olive pollen with a severe phenotype during treatment with immunotherapy under routine clinical practice conditions and following the technical data sheet, in a group of patients who have previously received a short cycle of dupilumab and another group who have not received this treatment. The initiation and maintenance phase of immunotherapy is administered in our Immunotherapy Unit.

Description

Inclusion Criteria:

• Patients ≥ 18 years old, residing in areas with high olive pollen exposure (exceeding 10,000 grains/m³ during the past five pollen seasons).
• Proven allergy to olive pollen with predominant or isolated sensitization to Ole e 7.
• Diagnosis of asthma that remains uncontrolled despite completing steps 5-6 of the GEMA guidelines during the olive pollen season.
• Controlled asthma with a forced expiratory volume in 1 second (FEV1) > 80% of the predicted normal value before starting subcutaneous immunotherapy (SCIT).

Exclusion criteria

1. Having received allergen immunotherapy or biological treatment in the last 5 years.
2. Pregnant women.
3. Relevant comorbidity: cancer, myocardial infarction, severe immunological disorder .
4. Contraindications contained in the official technical data sheet for Dupixent® (dupilumab).
5. Contraindications of SCIT.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Dupilumab Pre-treated; Severe Phenotype Olive Pollen Allergy Patients Treated with Conventional Therapy plus Dupilumab
Conventional Treated; Severe Phenotype Olive Pollen Allergy Patients Treated with Conventional Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Targeted serum metabolomic profile	A targeted serum metabolomic profile associated with allergic inflammation will be assessed using a validated targeted metabolomics platform to evaluate changes induced by allergen immunotherapy.	Baseline T0 (March 2024) and annually during the 3-year allergen immunotherapy period T1 (October 2024), T2, and T3, with additional assessments at 1 and 2 years after treatment completion (T4 and T5).
Serum proteomic profile	Serum levels of proteins involved in allergic inflammation and immune regulation will be quantified to evaluate changes during allergen immunotherapy. Protein quantification will be performed using a validated proximity extension assay (PEA).	Baseline (T0), T1 (October 2024), annually during the 3-year allergen immunotherapy (T2-T3), and 1 and 2 years after treatment completion (T4-T5).
Transcriptomic profile	Gene expression profiles associated with allergic inflammation and immune regulation will be assessed by RNA sequencing to evaluate changes during allergen immunotherapy.	Baseline (T0), T1 (October 2024), annually during the 3-year allergen immunotherapy (T2-T3), and 1 and 2 years after treatment completion (T4-T5).
Asthma Control Test (ACT) score	Asthma control will be assessed using the validated Asthma Control Test (ACT). Changes in ACT score during allergen immunotherapy will be evaluated.	Every 4 weeks during the first 6 months (T0), annually during each olive pollen season the 3-year immunotherapy period (T1-T3), and at 1 and 2 years post-treatment (T4-T5).
Asthma symptom and medication score	Asthma symptoms and rescue medication use will be assessed using the predefined study score during each olive pollen season.	Every 2 weeks during olive pollen season at T0, annually during each olive pollen (5 assessments) season the 3-year immunotherapy period (T1-T3), and at 1 and 2 years post-treatment (T4-T5).
Peripheral T-cell immunophenotype	Peripheral effector and regulatory T-cell subsets will be quantified by multiparametric flow cytometry to evaluate immunological changes during allergen immunotherapy.	Baseline (T0), T1 (October 2024), annually during the 3-year allergen immunotherapy (T2-T3), and 1 and 2 years after treatment completion (T4-T5).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline demographic characteristics	Baseline demographic characteristics, including age and sex, will be collected.	Baseline (T0)
Body mass index (BMI)	Body mass index (BMI) will be calculated from height and weight recorded during follow-up. Weight and height will be combined to report BMI in kg/m^2.	Baseline (T0) and annually at T1-T5.
Asthma control according to GEMA	Asthma control will be classified as controlled, partially controlled, or uncontrolled according to the GEMA guideline.	Every 2 weeks during olive pollen season at T0, annually during each olive pollen (5 assessments) season the 3-year immunotherapy period (T1-T3), and at 1 and 2 years post-treatment (T4-T5).
Asthma treatment step according to GEMA	Asthma treatment will be classified according to the GEMA treatment step required to maintain disease control.	Every 2 weeks during olive pollen season at T0, annually during each olive pollen (5 assessments) season the 3-year immunotherapy period (T1-T3), and at 1 and 2 years post-treatment (T4-T5).
Rhinoconjunctivitis symptom and medication score	Rhinoconjunctivitis symptoms and rescue medication use will be assessed using a predefined study score during each olive pollen season.	Every 2 weeks during olive pollen season at T0, annually during each olive pollen (5 assessments) season the 3-year immunotherapy period (T1-T3), and at 1 and 2 years post-treatment (T4-T5).
Forced expiratory volume in one second (FEV1)	Forced expiratory volume in one second (FEV1) will be assessed by spirometry according to ATS/ERS recommendations.	Every 2 weeks during olive pollen season at T0, annually during each olive pollen (5 assessments) season the 3-year immunotherapy period (T1-T3), and at 1 and 2 years post-treatment (T4-T5).
Mini Asthma Quality of Life Questionnaire (MiniAQLQ) score	Health-related quality of life will be assessed using the Mini Asthma Quality of Life Questionnaire (MiniAQLQ). Scores range from 1 to 7, with higher scores indicating better quality of life.	Every 2 weeks during olive pollen season at T0, annually during each olive pollen (5 assessments) season the 3-year immunotherapy period (T1-T3), and at 1 and 2 years post-treatment (T4-T5).

Collaborators and Investigators

• Sponsor: Maimónides Biomedical Research Institute of Córdoba
• Collaborators: CEU San Pablo University
• Investigators: Principal Investigator: Berta Ruiz-Leon, MD., Ph.D., Hospital Universitario Reina Sofia de Cordoba

Publications and helpful links

General Publications

• Escribese MM, Gomez-Casado C, Barber D, Diaz-Perales A. Immune Polarization in Allergic Patients: Role of the Innate Immune System. J Investig Allergol Clin Immunol. 2015;25(4):251-8.

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2024
• Primary Completion (Estimated): November 30, 2029
• Study Completion (Estimated): November 30, 2029

Study Registration Dates

• First Submitted: December 30, 2024
• First Submitted That Met QC Criteria: July 20, 2026
• First Posted (Actual): July 23, 2026

Study Record Updates

• Last Update Posted (Actual): July 23, 2026
• Last Update Submitted That Met QC Criteria: July 20, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: immunotherapy; Dupilumab; Severe asthma; olive pollen allergy
• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Asthma; Hypersensitivity
• Other Study ID Numbers: FCO-DPT-2024-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No