Chronic obstructive pulmonary disease (COPD) exacerbations are critical events that markedly accelerate the decline in lung function and worsen quality of life.1 However, they remain inadequately addressed by conventional treatment (including bronchodilators, corticosteroids and antibiotics), particularly in severe cases. This underscores an urgent need for innovative strategies. Dupilumab, a fully human monoclonal antibody that dually blocks IL-4 and IL-13 signaling, offering a novel therapeutic option in multiple diseases characterized with type 2 (T2) inflammation.2,3 Recent phase III trials demonstrated its potential in reducing moderate or severe exacerbations in patients with stable COPD exhibiting T2 inflammation features (blood eosinophils ≥300/μL).4,5 Nevertheless, clinical data supporting dupilumab use during COPD exacerbation is lacking. Herein, we reported the first use of dupilumab in elderly patients with COPD exhibiting T2 phenotype and corticosteroid dependence during severe exacerbations.

We presented the first case of an 80-year-old male with a ten-year history of COPD who experienced recurrent dyspnea and wheezes triggered by Pseudomonas aeruginosa pneumonia, leading to hypercapnic respiratory failure (Table 1). Although pneumonia significantly improved after invasive mechanical ventilation, effective antibiotics, and systemic methylprednisolone, his symptoms persisted, accompanied with irreducible intravenous corticosteroids and elevated eosinophils (560/μL). The second case, a 79-year-old male presented with worsening dyspnea and disturbance of consciousness, requiring intubation and invasive mechanical ventilation. After receiving antibiotics against Klebsiella pneumoniae pneumonia, triple inhalation therapy and methylprednisolone, his condition improved but then deteriorated again during corticosteroid tapering. The hematology showed IgE 340IU/mL and eosinophils rebounded from 80/μL to 760/μL. Our third case, a 71-year-old male was diagnosed with ever asthma and current COPD based on spirometry. He had been suffering from episodes of chest tightness and dyspnea, with cough and expectoration, after non-invasive ventilation and treatment against invasive pulmonary aspergillosis and pneumocystis pneumonia. He was identified as asthma-COPD overlap (ACO), relied on large doses of systemic corticosteroids and presented with elevated IgE level of 91IU/mL and positive Aspergillus fumigatus-specific IgE. Although severe pneumonia improved, their hypoxic dyspnea persisted and failed to achieve a stable condition.

At diagnosis, the three elderly patients with severe COPD exacerbations were characterized with T2 phenotypes – one with elevated blood eosinophils, one with high serum IgE and rebounded eosinophils, and another with ACO and atopy (Table 1). There is a growing recognition that 20–40% of patients with COPD exhibit eosinophilic inflammation, indicating a T2 phenotype. This patient subset constantly experiences frequent exacerbations and responds favorably to corticosteroids.6,7 At the onset of the exacerbations, defining their phenotypes was challenging due to the inhibitory effect of corticosteroid use on blood eosinophils. Expectedly, new biomarkers are emerging, such as atopy and fractional exhaled nitric oxide, beyond eosinophils.8 Upon the corticosteroid withdrawal, all three patients were affiliated with episodic dyspnea, with eosinophil counts rebounded in cases 1 and 2, high levels of IgE found in cases 2 and 3. Due to their corticosteroid dependence and characteristics of T2 phenotypes, we firstly introduced dupilumab treatment after the peak of their severe exacerbations, to facilitate the rapid control of their symptoms and withdrawal of systemic corticosteroids, finally leading to successful outcomes. And no significant adverse effects were observed.

The mechanism of T2 inflammation in COPD has not been incompletely understood. While sharing certain similarities with asthma, anti-IL-5 (mepolizumab) or anti-IL-5 receptor (benralizumab) therapies targeting eosinophils have shown limited efficacy in COPD population, with no significant lung function improvement.9,10 This therapeutic discrepancy highlights the involvement of other components in T2 inflammatory cascade. Preclinical studies implicated IL-4 and IL-13, key divers of T2 inflammation, contributed to airway remodeling and lung parenchyma destruction in COPD, and also promoted the activation and trafficking of eosinophils to airways.11 By suppressing T2 inflammation in a broader way, anti-IL-4 receptor α antibody – dupilumab demonstrates superior clinical outcomes, including reduced exacerbations and improved lung function in COPD population with elevated blood eosinophils. As a fact, eosinophilic inflammation has been also observed in approximately 30% of exacerbations.12 Although the role of dupilumab in the acute management of exacerbation has not been evaluated, its efficacy in the maintenance phase suggests potential benefits. The use of dupilumab at severe exacerbations could help corticosteroid tapering in these elderly patients, thereby avoiding adverse effects like hyperglycemia, secondary infections, osteoporosis, and adrenal insufficiency.13

To our knowledge, our cases represented the first attempt to dupilumab use during COPD exacerbation, based on the comprehensive evaluation of T2 characteristics and clinical features. Dupilumab, as an add-on treatment, should be considered earlier, particularly in severe cases, rather than postpone to the stable phase, to manage symptoms better.