Successful clinical remission of severe asthma with small airway dysfunction and eosinophilic gastrointestinal disease using dupilumab after benralizumab failure

Abstract

Background

Small airway dysfunction (SAD) is an underrecognized but important feature of severe asthma, contributing to persistent symptoms and treatment resistance. Biologics targeting type 2 inflammation vary in their efficacy for SAD, and comorbid eosinophilic gastrointestinal disease (EGID) may further complicate management.

Case presentation

A 65-year-old woman with severe, type 2–high asthma and eosinophilic esophagitis had uncontrollable symptoms despite inhaled triple therapy and benralizumab. She exhibited impaired ventilatory parameters, with markedly reduced maximum mid-expiratory flow (%MMF), elevated difference in respiratory resistance between 5 Hz and 20 Hz (R5–R20), and area of reactance (AX), and mucus plugs on chest CT, along with gastrointestinal symptoms that required long-term corticosteroid therapy.

Intervention and outcomes

Given her insufficient response and comorbid gastrointestinal symptoms, therapy was switched to dupilumab. Following treatment initiation, the patient demonstrated marked improvements in SAD parameters with markedly elevated %MMF (50 to 79%), reduced R5–R20 (1.20 to 0.53 kPa/L/s), AX (4.06 to 0.81 kPa/L) and resolution of mucus plugging. Her dyspnea and gastrointestinal symptoms also improved, allowing discontinuation of oral corticosteroids within one year.

Conclusions

Dupilumab effectively improved both SAD and EGID in a patient with severe asthma refractory to benralizumab likely due to its effects on IL-4/IL-13 signaling, leading to reduction of mucus hypersecretion and eosinophilic mucosal inflammation. This case highlights the importance of considering small airway involvement and comorbid EGID when selecting biologics, and supports the use of dupilumab in type 2–high, SAD-dominant asthma with concomitant EGID.

Highlights

• •Dupilumab improved small airway dysfunction (SAD) refractory to benralizumab in severe asthma.
• •Oscillometry detected SAD improvement undetected by spirometry alone.
• •Dupilumab improved symptoms in eosinophilic gastrointestinal disease concurrent with asthma.
• •IL-4/IL-13 blockade may outperform IL-5Rα blockade in SAD-dominant asthma.

1. Introduction

Small airway dysfunction (SAD) is recognized as one of the key components of severe asthma, contributing to symptom burden, disease severity, and treatment resistance [1]. Although SAD can cause substantial morbidity even when forced expiratory volume in 1 s (FEV₁) appears within normal limits, it remains underrecognized in clinical practice [2].

Oscillometry, which measures the frequency dependence of respiratory resistance, is a useful tool for detecting SAD [3]. Proposed cut-offs for oscillometry-defined SAD include respiratory resistance between 5 Hz and 20 Hz (R5–R20) > 0.07 kPa/L/s, area of reactance (AX) > 0.44 kPa/L, and resonant frequency (Fres) > 14.14 Hz [4].

Recently, biologics targeting type 2 inflammation have transformed the management of severe asthma. Nevertheless, their effects on SAD appear heterogeneous. In a head-to-head evaluation, benralizumab effectively depleted eosinophils, but demonstrated limited impact on peripheral airway resistance and reactance, suggesting limited effects on mucus hypersecretion and small airway remodeling. In contrast, dupilumab, through inhibition of IL-4 and IL-13 signaling—key pathways in mucus production and subepithelial fibrosis—resulted in greater improvements in peripheral airway function, supporting potential advantages in SAD-dominant asthma [5,6].

We report a case of severe asthma with SAD, complicated by eosinophilic esophagitis (EoE), where switching from benralizumab to dupilumab led to marked improvement in small airway parameters and clinical symptoms. This case provides valuable insight into therapeutic strategies for SAD-dominant severe asthma, particularly in patients with concomitant eosinophilic gastrointestinal disorders (EGID).

2. Case report

A 65-year-old woman, former smoker (15 cigarettes/day for 30 years), who is a nurse by profession, was referred to our hospital in September 2022 for evaluation of uncontrolled asthma symptoms, including wheezing and cough. She had been diagnosed with EoE and gastroenteritis at another hospital in June 2021, presenting with heartburn and postprandial abdominal pain. Oral prednisolone (PSL) at 30 mg/day was initiated and tapered over time, but, by July 2022, she developed recurrent wheezing, cough, and nasal congestion. At her presentation to our hospital, she was taking PSL 4 mg daily, and the anti-histamines epinastine and roxatidine. Physical examination revealed normal vital signs and no remarkable findings other than wheezing. Laboratory investigations showed a blood eosinophil count of 30/μL (previously 1650/μL before PSL initiation) and total serum IgE of 366 IU/mL (previously 176 IU/mL). Pulmonary function tests demonstrated a vital capacity (VC) of 2.86 L (114.4% predicted), forced vital capacity (FVC) of 2.83 L (106.9%), and forced expiratory volume in 1 s (FEV₁) of 2.19 L (112.9%), with an FEV₁/FVC ratio of 77.4%. Her maximum mid-expiratory flow (MMF) was markedly reduced to 50.4% of predicted values. Oscillometry revealed elevated resistance at 5 Hz (R5: 4.9 kPa/L/s), resistance at 20 Hz (R20: 3.7 kPa/L/s), difference in R5–R20 of 1.2 kPa/L/s, AX of 4.06 kPa/L, and Fres of 9.86 Hz. Her exhaled nitric oxide (FeNO) level was elevated to 64 ppb. Chest computed tomography (CT) showed mucus plugs in the peripheral bronchi of the left upper lobe, and bronchial wall thickening in both upper lobes, with no evidence of COPD.

Based on her clinical findings, she was diagnosed with bronchial asthma complicated by SAD, and treatment with inhaled triple therapy containing indacaterol, glycopyrronium, and mometasone was initiated. However, since her asthma remained poorly controlled, benralizumab was commenced. Shortly after initiation, the patient experienced abdominal pain and diarrhea, requiring an increase in PSL to 12.5 mg/day. Attempts to taper PSL to below 5 mg/day led to recurrent gastrointestinal symptoms, significantly impacting her quality of life. Evaluation indicated that her ACT score remained unchanged at 20 following benralizumab treatment. Spirometric indices, including %FVC and %FEV₁, were within normal limits at baseline and showed modest improvement after benralizumab. However, %MMF was reduced at 50% prior to treatment, consistent with small airway dysfunction, and improved to 64% following initiation of benralizumab (Fig. 1).

Fig. 1.

Changes in small airway parameters following treatment with biologics

Impulse oscillometry before biologic treatment (A), after 8 months of benralizumab (B), and after 12 months of dupilumab therapy (C). Dupilumab markedly improved R5–R20, AX, Fres, and %MMF compared with benralizumab, indicating resolution of small airway dysfunction. AX: area of reactance, FEV₁: forced expiratory volume in 1 s, Fres: resonant frequency, FVC: forced vital capacity, MMF: maximum mid-expiratory flow, R5: respiratory resistance at 5 Hz, R20: respiratory resistance at 20 Hz, R5–R20: difference in respiratory resistance between 5 Hz and 20 Hz.

Although EoE had been confirmed histologically, the diagnosis of eosinophilic gastroenteritis remained uncertain. Double-balloon enteroscopy and small intestinal biopsies revealed only mild eosinophilic infiltration, insufficient for a definitive diagnosis. Because her clinical response remained unclear at 4-6 months of benralizumab treatment—with an unchanged ACT score and only modest improvement in %MMF—observation was extended to 8 months, consistent with GINA guidance to extend the trial period to 6-12 months in cases of unclear response, and with CHEST consensus recommendations [7,8]. Given the persistent lack of improvement and based on reports of dupilumab efficacy in EoE, we switched her biologic to dupilumab [9].

Following dupilumab initiation, both her asthma control and gastrointestinal symptoms improved dramatically, enabling gradual PSL tapering and complete discontinuation within approximately one year. When comparing SAD-related markers before initiation of biologics, 8 months after benralizumab treatment initiation, and 12 months after dupilumab treatment initiation, dupilumab resulted in improvement across all indices associated with SAD (R5–R20, AX, Fres and %MMF) (Fig. 1). Furthermore, following dupilumab therapy, chest CT scans demonstrated resolution of the mucus plugs in the upper lobe bronchi and marked improvement of the bronchial wall thickening, which had been evident prior to dupilumab initiation (Fig. 2A–D). Dupilumab treatment has been continued for over 24 months, and she remains well controlled without oral corticosteroids or relapse of asthma or gastrointestinal symptoms. This clinical course fulfills the criteria for clinical remission according to Japan Asthma Society's Practical Guidelines for Asthma Management (PGAM) [10].

Fig. 2.

Improvement in bronchial abnormalities on chest CT

(A, C) Baseline images showed mucus plugs (yellow arrows) and bronchial wall thickening (red arrows).

(B, D) Follow-up images after 12 months of dupilumab demonstrated disappearance of the mucus plugs (white arrows) and improvement of bronchial wall thickening (blue arrows).

3. Discussion

This case highlights the clinical value of dupilumab in severe SAD refractory to benralizumab. Although the patient had preserved FEV₁, she exhibited pronounced small airway impairment, as indicated by dyspnea, markedly reduced %MMF, elevated R5–R20, AX and Fres, and mucus plugs on chest CT, which are characteristic features of SAD-dominant asthma.

Small airways contribute substantially to airway resistance in asthma, and are closely associated with disease severity, frequency of exacerbation, and therapeutic responsiveness [11]. SAD is observed in approximately 75–90% of patients with severe asthma, and is linked to reduced physical activity [12]. Mucus plugs contribute to airflow obstruction and are associated with SAD [13]. Recent reports have shown that dupilumab can improve SAD parameters, such as R5–R20 and Fres, likely through suppression of type 2 inflammation and reduction of mucus hypersecretion in moderate to severe asthma [14].

Dupilumab, a monoclonal antibody targeting IL-4 and IL-13 signaling [15], may exert broader anti-inflammatory effects on peripheral airways compared to benralizumab, which primarily depletes eosinophils via IL-5Rα blockade [16]. Basophils, which are not the primary target of anti-IL-5Rα agents, provide an early source of IL-4 that primes Th2 responses upon allergen exposure and drives group 2 innate lymphoid cell-mediated eosinophil recruitment [17,18]; because dupilumab blocks IL-4Rα signaling, it may additionally attenuate this basophil-driven pathway, a mechanism not addressed by eosinophil-depleting therapies. IL-4 and IL-13 have been shown to induce airway smooth muscle contraction in the small airways in humans, whereas IL-5 does not elicit such an effect. Furthermore, dupilumab has been demonstrated to inhibit airway smooth muscle contraction in the small airways, suggesting that it may exert superior efficacy in targeting small airway pathology [19].

Post hoc analyses of phase IV studies have further indicated that dupilumab may provide greater improvements in small airway function than benralizumab in patients with type 2–high asthma [5]. In this patient, dupilumab improved SAD parameters that had not responded to benralizumab, and also achieved clinical remission as defined by the PGAM criteria [10]. Although a definitive minimal clinically important difference (MCID) for impulse oscillometry measurements of SAD parameters has not been established, MCIDs of ≥0.06 kPa/L/s for R5–R20 and ≥ 0.65 kPa/L/Hz for AX over a one-year follow-up period have been reported [20]. In our patient, R5–R20 improved from 1.20 kPa/L/s at baseline to 0.82 kPa/L/s after benralizumab treatment, and subsequently to 0.53 kPa/L/s after switching to dupilumab. AX also progressively improved from 4.06 to 2.15 kPa/L after benralizumab, and further to 0.81 kPa/L after dupilumab treatment. Although direct comparison with the MCID values reported in the aforementioned study [20] should be interpreted with caution because of potential differences in oscillometry devices and measurement systems, the observed changes in both R5–R20 and AX exceeded the reported MCID thresholds. Similarly, %MMF improved from 50% at baseline to 64% after benralizumab treatment, and further to 79% after switching to dupilumab. Although the patient's baseline Fres (9.86 Hz) did not exceed previously reported cut-offs for SAD, it nonetheless showed a clear and consistent reduction following dupilumab treatment (9.9 to 6.5 Hz), in contrast to the negligible change observed with benralizumab (9.8 to 9.9 Hz). It should be noted that no validated MCID currently exists for %MMF or Fres, and these changes should be interpreted descriptively rather than as evidence of a clinically established minimally important difference. Furthermore, the ACT score remained unchanged at 20 during benralizumab treatment but improved by 5 points to 25 after switching to dupilumab, suggesting meaningful clinical benefit [21].

In addition to its respiratory benefits, dupilumab has demonstrated efficacy in EoE, improving both clinical symptoms and histologic markers of inflammation [9], whereas benralizumab has shown limited clinical effect in this setting [22]. Although the patient's elevated total IgE (366 IU/mL) could suggest omalizumab as an alternative, a placebo-controlled trial of omalizumab in EoE failed to demonstrate improvement in esophageal eosinophil counts or symptoms [23].

In this patient, switching from benralizumab to dupilumab led to marked improvement in both asthma control and gastrointestinal symptoms, supporting the rationale for targeting shared type 2 inflammatory pathways across organ systems. The challenge of controlling asthma that is complicated by comorbid conditions has been demonstrated in the QUEST trial for asthma with concomitant chronic rhinosinusitis, and a similar difficulty may be present in asthma complicated by EGID [24]. This case underscores the importance of considering comorbid EGID when selecting biologics for the treatment of patients with severe asthma.

This case report has several limitations. Allergen-specific sensitization (specific IgE or skin-prick testing) and sputum eosinophil counts beyond peripheral blood were not assessed in this patient, which limits full characterization of her type 2-high phenotype. The diagnosis of eosinophilic gastroenteritis remained histologically inconclusive, likely reflecting patchy mucosal involvement and the low sensitivity of biopsy sampling in non-EoE EGID [25].

4. Conclusion

Dupilumab successfully improved small airway dysfunction and induced remission of eosinophilic gastrointestinal symptoms in a patient with severe asthma refractory to benralizumab. This case underscores the importance of evaluating small airway involvement and considering dupilumab as a therapeutic option in selected patients with type 2–driven, SAD-predominant asthma complicated by EGID.

CRediT authorship contribution statement

Yu Nakatani: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Kimiko Tsuji: Writing – review & editing, Supervision, Conceptualization. Akari Ito: Writing – review & editing. Takehiko Ito: Writing – review & editing. Akihito Yokoyama: Writing – review & editing, Supervision. Toshiyuki Kozuki: Supervision.

Ethical approval

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Data statement

Data sharing is not applicable to this article as it contains patient information that cannot be disclosed to protect patient privacy.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

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 paper.