Chronic rhinosinusitis (CRS) has a strong association with asthma, with a prevalence of asthma among CRS patients of about 25%, a sharp contrast to the 5% observed within the general population (1, 2). The classification of CRS includes primary or secondary CRS, further stratified into localized or diffuse disease based on anatomical distribution, with additional categorization into type 2 or non-type 2 disease (1, 3). Approximately 5%–10% of asthmatic patients suffer from severe asthma, which can be divided into type 2-high asthma, characterized by eosinophilic airway inflammation, and type 2-low asthma, defined by neutrophilic and paucigranulocytic features (4). Monoclonal antibody therapies are currently used as part of the medical treatment for a selection of patients with severe asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP). These monoclonal antibodies target the underlying type 2 inflammation and have shown their efficacy resulting in a significant decrease in asthma exacerbations, nasal polyp size, sinus opacification, severity of symptoms, the need for oral corticosteroids and for sinus surgeries (5–7). Despite advancements, some individuals remain uncontrolled in terms of upper and/or lower airway symptoms.

Our case report offers a unique contribution to the Global Airway Research field as it presents comprehensive clinical findings alongside the collection and analysis of nasal polyp tissue, nasal secretions, and blood samples spanning an 8-year period in a patient undergoing dual monoclonal antibody therapy for CRSwNP and severe eosinophilic asthma. Additionally, a proteome analysis offers valuable insights into the underlying mechanisms associated with this therapeutic approach.

In 2014, a 47-year-old patient was referred to pulmonology after an anaphylactic reaction to a nonsteroidal anti-inflammatory drug (NSAID) and 6 months of persistent upper and lower airway complaints. The patient was on medium dose inhaled therapy (ICS/LABA) and Montelukast 10 mg daily, started by the general practitioner. At presentation, he had increased type 2 biomarkers with high blood eosinophilia (1,520/µl or 18.3%), IgE (192.5 kU/L), and FeNO (90 ppb), without systemic manifestations. Lung function test showed an obstructive pattern with a prebronchodilator FEV₁ value of 2.74 L (68% predicted) and 3.11 L (77% predicted) after bronchodilatation. The patient was diagnosed with a severe, late-onset eosinophilic asthma. Asthma medication was changed to high-dose inhaled therapy (ICS/LABA) with additional low-dose inhaled therapy as needed. Loss of smell and bilateral nasal obstruction led to referral to the ear, nose and throat (ENT) department. Nasal endoscopy showed bilateral small polyps in the middle meatus, with a total nasal polyp score (TNPS) of 2. A diagnosis was made of chronic rhinosinusitis with nasal polyps (CRSwNP), severe eosinophilic asthma, aspirin sensitivity and hypereosinophilia, for which a course of systemic corticosteroids, nasal irrigations with corticosteroids twice daily, and doxycycline 100 mg once daily for 3 weeks, were initiated.

Uncontrolled upper airway symptoms necessitated a complete functional endoscopic sinus surgery (FESS) in January 2015. Due to persistent cystic mucus at the level of the frontal sinus, an additional DRAF III procedure was performed. Histological examination of the polyp tissue demonstrated the presence of eosinophils and Charcot Leyden crystals, indicating high eosinophilic activity. By late 2015, high blood eosinophilia (1,290/µl or 12.1%) and uncontrolled symptoms with rapid polyp recurrence persisted. In February 2016, the patient was eligible to participate in a clinical study assessing the efficacy and safety of reslizumab, an anti-IL-5 treatment, given intravenously (3 mg/kg every 4 weeks) (8). Since mepolizumab, another IL-5 targeting agent, became reimbursable in Belgium, the therapy was switched to mepolizumab (100 mg every 4 weeks) after two years, while systemic corticosteroids were continued at a dose of 4 mg every other day. Lung function tests improved, showing a pre-bronchodilator FEV1 of 4.03 L (98% predicted) and 4.07 L (99% predicted) post-bronchodilator after six months of treatment. A good asthma control with mepolizumab and high-dose ICS/LABA was achieved by the end of 2018 and led to the tapering and eventually discontinuation of the systemic corticosteroids. Despite 8 years of treatment and relatively well-controlled asthma, severe upper airway symptoms persisted, requiring 4 additional complete sinus surgeries, antibiotics and a cumulative dose of 8,390 mg of oral corticosteroids (Figure 1a).

In May 2022, a multidisciplinary team of ENT specialists and pulmonologists decided to add dupilumab, an anti-IL-4Rα antibody, because discontinuing mepolizumab was considered unsafe due to the patient's initially high eosinophil levels and the associated risks of elevated eosinophilia with dupilumab in monotherapy. This decision was driven by the patient's very poorly controlled upper airway symptoms, characterized by persistent purulent secretions and significant symptoms, with a SNOT-22 score of 68 (Figure 2a). The patient started dual therapy (mepolizumab 100 mg every 4 weeks and dupilumab 300 mg every 2 weeks) while continuing high-dose ICS/LABA.

Our patient with CRSwNP, severe eosinophilic asthma, and uncontrolled upper airway symptoms, experienced substantial improvement with dual monoclonal antibody therapy without major complications or side effects. Adding dupilumab improved upper airway symptoms and decreased both eosinophilic and neutrophilic inflammation, despite prior anti-IL-5 therapy. The effects were consistently observed in polyp tissue and nasal secretions. Since dupilumab is known to induce hypereosinophilia when initiated, the treatment with mepolizumab could not be terminated (9, 10). Attempts to reduce mepolizumab led to the recurrence of upper and lower airway symptoms.

The mechanism by which dupilumab reduces neutrophilic inflammation is not well understood. Some studies suggest that IL-4 and IL-13 signaling via IL-4 receptor influences neutrophilic inflammation by affecting neutrophil recruitment, chemotaxis, and function. Blocking this pathway may reduce neutrophilic inflammation (11). However, none of the studies involving anti-IL4Rα specifically examined neutrophil activity before, during, or after treatment. Further research is needed to clarify this.

There is limited research on the efficacy of dual monoclonal antibody therapy in CRSwNP. While some case studies discuss the rationale and safety in asthma, few present clinical outcomes and the effect on local nasal inflammation in CRSwNP (12–14). Non-responders to biologicals among patients with a clear type 2 inflammation highlight the complexity of CRSwNP pathophysiology and the need for further understanding. Research by Van Nevel et al. showed increased concentrations of granulocyte-colony stimulating factor (G-CSF), a cytokine regulating neutrophils, in patients treated with an anti-IgE monoclonal antibody compared to before treatment (15). There is a growing interest in understanding mixed eosinophilic-neutrophilic inflammation and its association to disease outcomes (16, 17). Further research is essential to elucidate underlying mechanisms of treatment resistance and advance personalized CRSwNP management.

Recognizing the limitations of a single case study, such as its uniqueness, underscores the need for further clinical research. Future studies should aim to establish proper patient selection criteria and evaluate the effectiveness of dual monoclonal antibody therapy in CRS patients. Additionally, it is important to investigate the specific types of inflammation both before and during monoclonal antibody treatment in a larger population. A systematic approach to selecting the appropriate drug for specific endotypes is essential, with nasal secretions potentially serving as a non-invasive tool for monitoring endotypes before and during therapy.

In conclusion, this case report highlights the complexities of treating type 2 inflammatory airway disease and demonstrates the benefits of combined monoclonal antibody therapy. The positive outcomes underline the importance of a multidisciplinary approach and the need to target multiple inflammatory pathways.

From the patient's perspective, the introduction of dual monoclonal antibody therapy was life-changing. For the first time in 8 years, he experienced significant relief from his upper airway symptoms, which had previously been a constant burden. The return of his sense of smell was particularly exciting, as it reconnected him to simple pleasures he had long missed. The improvements in his breathing and overall quality of life were profound. He is determined to continue the dual therapy, which has restored his quality of life.