Efficacy of dupilumab and risk factors for dupilumab-induced hypereosinophilia in severe asthma: a preliminary study from China

Abstract

Objective

Dupilumab has been approved for the treatment of severe asthma with type 2 inflammation by inhibiting interleukin (IL)-4 and IL-13 signaling. However, dupilumab-induced hypereosinophilia (HE) has been reported and should not be ignored. The aim of this study was to investigate the efficacy of dupilumab in Chinese patients with severe asthma, whether HE affects its efficacy, and the possible risk factors for HE.

Methods

20 patients with severe asthma who received dupilumab treatment for at least 12 months in the First Affiliated Hospital of Guangzhou Medical University from 2019 to 2022 were included. We compared clinical data and laboratory tests results before dupilumab treatment and at 4 and 12 months after treatment. Based on whether dupilumab treatment triggers HE defined as blood eosinophil count (BEC) ≥ 1.5 × 10⁹ cells/L, the patients were allocated into non-HE and HE groups.

Results

The patients showed a significant increase in asthma control test (ACT) scores, a decrease in the number of exacerbations, a decrease in the proportion of patients taking an oral corticosteroid (OCS) and in the dose, and a significant improvement in the pulmonary function parameters FEV1/FVC (%) and FEV1 (% predicted) after 4 and 12 months of treatment with dupilumab. For type 2 inflammatory biomarkers, the levels of fractional concentration of exhaled nitric oxide (FeNO), sputum eosinophil count percentage (SEC%) and total immunoglobulin E (TIgE) decreased significantly, whereas BEC were higher after 4 months of treatment, but returned to baseline levels after 12 months. 8 patients (40%) developed asymptomatic HE after dupilumab, and the efficacy was not significantly different between the HE and non-HE groups. The earliest BEC elevation appeared at 1 month after treatment, but most of them declined after 6 months, and basically returned to the baseline level around 12 months of treatment. In addition, we further found that when patients had FeNO ≥ 60 ppb, food allergens positive and combined eosinophilic otitis media (EOM), their BEC increased significantly more than that of the control group after 4 months as well as 12 months of treatment.

Conclusions

This study demonstrated that dupilumab was efficacious in Chinese patients with severe asthma, and some patients developed asymptomatic, self-limited HE, which did not affect its efficacy. Additionally, FeNO ≥60 ppb, food allergens positive, and co-morbidities with EOM may be the risk factors for developing HE.

Keywords:

• Dupilumab
• severe asthma
• efficacy
• eosinophils
• hypereosinophilia

Introduction

Bronchial asthma affects approximately 300 million people worldwide, with 3–10% of patients suffering from severe and uncontrolled asthma. Many patients with severe asthma require long-term OCS treatment or hospitalization, which results in poor quality of life, high healthcare costs, and many side effects [1,2]. Based on the major immune-inflammatory pathways involved, the most common endotypes of severe asthma are now categorized as T2-high and T2-low. A multicenter study of adults with severe asthma in China found that about 75% of patients were classified as T2-high endotype [3]. T2-high asthma is characterized by type 2 inflammation, which is driven by T helper 2 cells (Th2) or group 2 innate lymphoid cells (ILC2) and is characterized by high levels of cytokines such as IL-4, IL-5 and IL-13, accompanied by accumulation of inflammatory cells such as eosinophils and mast cells in the lung tissues, and mucus production as the main pathophysiological manifestations [4].

In recent years, novel monoclonal antibody therapies targeting Th2 inflammatory receptors and mediators have emerged [5]. Dupilumab is a human monoclonal antibody that binds to the IL-4 receptor alpha subunit (IL-4Rα) and inhibits IL-4 and IL-13 signaling [6]. Multiple randomized, placebo-controlled trials have demonstrated the efficacy of dupilumab in patients with type 2-mediated inflammatory diseases such as chronic rhinosinusitis with nasal polyps (CRSwNP), severe asthma, prurigo nodularis, atopic dermatitis (AD) and eosinophilic esophagitis [7–13]. The LIBERTY ASTHMA QUEST phase III clinical trial demonstrated that dupilumab significantly reduced the exacerbations rate and improved lung function and asthma control in patients with severe asthma [14]. However, hypereosinophilia (HE), defined as BEC ≥ 1.5 × 10⁹ cells/L, occurs in approximately 4%–25% of patients during dupilumab treatment [15]. HE caused by dupilumab treatment is usually transient and does not cause clinical symptoms. However, there are occasional cases of severe complications after dupilumab treatment such as eosinophilic pneumonia and eosinophilic granulomatosis with polyangiitis (EGPA) [16–18]. HE caused by dupilumab typically begins in the 4th week of treatment and returns to baseline around the 24th week, but approximately 14% of patients experience HE lasting for 6 months or more [8,19].

It is currently unclear which patients are at risk for HE after the use of dupilumab and whether HE reduces the efficacy of dupilumab. In this study, we reviewed 20 patients with severe asthma treated with dupilumab. Firstly, the patients were divided into HE and non-HE groups according to whether HE occurred during treatment, and the clinical data and laboratory test results of the two groups were compared before dupilumab treatment and at 4 and 12 months after treatment, so as to determine whether HE affects its efficacy. Next, subgroup analyses were performed based on the different clinical characteristics of the patients at baseline to compare the post-treatment BEC levels of the patients between the different subgroups in order to identify risk factors that may lead to elevated BEC in the patients.

Materials and methods

Study design

This is a single-center, retrospective study. 20 patients with severe asthma were enrolled. All the patients completed at least 12 months of dupilumab treatment at the First Affiliated Hospital of Guangzhou Medical University between January 2019 and May 2022. All patients were > 18 years of age and all were diagnosed with asthma according to the Chinese Guidelines for the Diagnosis and Treatment of Asthma or the Global Initiative of Asthma guidelines. Severe asthma is defined as the need to add one or more of the following control medications despite daily inhaled high-dose ICS: long-acting beta-agonists, long-acting muscarinic antagonists, leukotriene receptor antagonists, or daily systemic glucocorticoids.

Study methods

Dupilumab was subcutaneously injected at an initial dose of 600 mg (two 300 mg injections), with a maintenance dose of 300 mg once every 2 weeks. HE appearing during treatment has been ruled out as a secondary factor that may lead to HE in patients, such as parasites and fungal infections, and myeloid or spray neoplasms with platelet derived growth factor receptor alpha and beta (PDGFRA and PDGFRB, respectively).

The percentage of sputum eosinophil count (SEC%), BEC, FeNO, percentage of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) (FEV1/FVC%), percentage of forced expiratory volume in the first second to the expected value (FEV1pred%), asthma control test scores, TIgE, asthma exacerbations, and OCS indicators before dupilumab treatment (baseline), and after 4 and 12 months of treatment were recorded. Patients were divided into HE and non-HE groups according to whether HE occurred during treatment. These groups were divided into subgroups according to baseline characteristics of gender, age (≥45 or < 45 years), history of treatment with biological agents, laboratory indicators (baseline BEC, baseline FeNO, baseline pulmonary function level), allergen index including foodborne (eggs, milk, fish, wheat, and shrimp), fungal (Aspergillus fumigatus, Penioillum notatum, and Cladosporium) and inhalation allergenicity (Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blattella germanica, and dander), and concomitant type 2 inflammatory diseases that included CRSwNP, EOM, AD, and aspirin exacerbated respiratory disease (AERD). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. All patients who participated in this clinical observation were aware of the content of the study and signed a consent form. This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University.

Data analyses

Continuous variables were expressed as mean (± standard deviation) or median (quartile). Categorical variables were expressed as cases (n) and percentage (%). Pairwise comparisons were performed using a paired t-test or nonparametric Wilcoxon test. The Mann-Whitney U test was used to assess whether the efficacy of dupilumab (number of acute episodes and lung function) was significantly different between the two groups. The Mann-Whitney U test was used to assess whether the median BEC changed at the month 4 and 12 of treatment (including absolute value and percentage change). The median BEC count and percentage change at the month 4 and 12 were tested based on the difference between patient BEC and baseline. p < .05 was statistically significant. All analyses were performed using SPSS version 25.0.

Results

Patients general information

As shown in Table 1, twenty patients (14 males, 70%) with severe asthma were included in the study. The mean age of patients was 46.63 years. 8 patients tested positive for specific IgE, of which 4 and 6 were positive for food allergens and inhaled allergens, respectively. Regarding comorbidities, 11 (55%), 5 (25%), 2 (10%), and 5 (25%) patients had CRSwNP, AD, AERD, and EOM, respectively. In terms of treatment, 10 (50%) patients had been treated with other biologics and 15 (75%) were on OCS, while the median dose was 12.50 mg. Furthermore, the baseline BEC level of patients treated with dupilumab was predominantly in the (0.5–1.0) × 10⁹cells/L range in 9 patients (45%). None of the patients had a baseline BEC level higher than 1.5 × 10⁹cells/L. The mean baseline BEC in 20 patients was (0.54 ± 0.35) × 10⁹cells/L. In addition, there were more patients with type 2 inflammatory diseases such as CRSwNP, AD, and EOM in the HE group than in the non-HE group, as well as higher use of OCS than in the non-HE group.

Table 1. Baseline demographic and clinical characteristics of the patients.

	All (n = 20)	HE(n = 8)	Non-HE(n = 12)
Age, years, mean ± SD	46.63 ± 7.08	47.13 ± 8.63	48.08 ± 8.50
Male, n (%)	14(70)	5(62.5)	9(75.0)
Atopy, n, (%)	8(40)	4(50)	2(16.7)
Food allergens positive	4(20)	4(50)	0(0)
Fungal allergens positive	0(0)	0(0)	0(0)
Inhaled allergens positive	6(30)	4(50)	2(16.7)
CRSwNP, n, (%)	11(55)	7(87.5)	4(33.3)
AD, n, (%)	5(25)	4(50)	1(8.3)
AERD, n, (%)	2(10)	1(12.5)	1(8.3)
EOM, n, (%)	5(25)	4(50)	1(8.3)
Previous biologics, n, (%)	10(50)	4(50)	6(50.0)
Patients on OCS, n, (%)	15(75)	7(87.5)	8(66.7)
OCS, mg/day, median (IQR)	12.50(1.88,20.00)	17.50(10.00,27.50)	10.0(0.00,20.00)
BEC, ×10^9cells/L, mean ± SD	0.54 ± 0.35	0.44 ± 0.22	0.61 ± 0.41
Patients with different BEC, n (%)
< 0.3 × 10^9 cells/L	3(15)	1(12.5)	2(16.7)
0.3–0.5 × 10^9 cells/L	6(30)	2(25.0)	4(33.3)
0.5–1.0 × 10^9 cells/L	9(45)	5(62.5)	4(33.3)
1.0–1.5 × 10^9 cells/L	2(10)	0(0)	2(16.7)
Patients with FeNO > 60 ppb, n, (%)	10(50)	5(62.5)	5(41.7)

CRSwNP: chronic rhinosinusitis with nasal polyps; AD: atopic dermatitis; AERD: aspirin-exacerbated respiratory disease; EOM: Eosinophilic otitis media; OCS: oral corticosteroid; BEC: blood eosinophil counts; HE: hypereosinophilia.

Evaluation of therapeutic efficacy

Dupilumab significantly reduced the number of exacerbations and reduced and/or eliminated the use of OCS. After 4 and 12 months of treatment, ACT scores improved from 17.90 ± 2.77 at baseline to 21.35 ± 1.95 and 22.53 ± 1.87, respectively, and the number of exacerbations decreased from 0.85 ± 0.67 times/4 months to 0.30 ± 0.47 times/4 months and 0.11 ± 0.32 times/4 months, respectively. Meanwhile, the mean OCS dosage decreased from 13.63 ± 11.28 mg/d at baseline to 5.25 ± 8.15 mg/d and 2.37 ± 4.45 mg/d. The number of patients dependent on OCS was reduced from 15 to 9 and 6 after 4 and 12 months of treatment, respectively. In addition, dupilumab treatment improved lung function and reduced type 2 inflammatory biomarkers as well. However, we found that after 4 months of treatment, patients had a significant increase in BEC levels, from 0.54 ± 0.35 × 10⁹cell/L to 1.07 ± 0.92 × 10⁹cell/L. In contrast, the SEC (%) was significantly lower than at baseline. However, the BEC levels roughly returned to baseline levels at the end of 12 months of treatment (Table 2).

Table 2. Comparison of curative effect before and after treatment with dupilumab.

	Baseline	4th month			12th month
	mean ± SD	mean ± SD	t-value	p-value	mean ± SD	t-value	p-value
ACT score	17.90 ± 2.77	21.35 ± 1.95	−6.9	0	22.53 ± 1.87	−8.41	0
Exacerbations (/4 months)	0.85 ± 0.67	0.30 ± 0.47	4.07	.001	0.11 ± 0.32	5.72	0
Patients on OCS, n, (%)	15(75%)	9(45%)	–	.014	6(30%)	–	.008
OCS (mg/d)	13.63 ± 11.28	5.25 ± 8.15	2.66	.003	2.37 ± 4.45	4.43	0
FEV1/FVC (%)	57.75 ± 10.01	67.67 ± 11.30	−4.17	.001	74.01 ± 11.26	−4.56	0
FEV1 (% predicted)	60.16 ± 19.35	79.42 ± 19.64	−4.09	0	85.95 ± 18.47	−6.16	0
FeNO (ppb)	57.85 ± 26.42	32.10 ± 16.71	3.3	.003	22.90 ± 18.30	4.29	.001
BEC,10^9 cell/L	0.54 ± 0.35	1.07 ± 0.92	−2.24	.037	0.53 ± 0.38	0.02	.981
SEC (%)	37.64 ± 20.36	14.12 ± 22.60	3.54	.008	5.54 ± 6.09	6.33	0
TIgE, kU/L	564.16 ± 469.46	110.50 ± 104.71	4.11	.001	51.68 ± 46.77	4.07	.001

FeNO: fractional exhaled nitric oxide; TIgE: total immunoglobulin E; FEV1: forced expiratory volume in 1 s, FVC: forced vital capacity; ACT: asthma control test; OCS: oral corticosteroid; BEC: blood eosinophil counts; SEC (%): the percentage of sputum eosinophil count.

Dupilumab did not become less efficacious in asthma patients because of the presence of HE in patients. A total of 8 patients who developed BEC ≥1.5 × 10⁹cell/L during follow-up were defined as the HE group and the rest as the non-HE group. Our results revealed that the number of exacerbations, ACT scores, and pulmonary function parameters in the HE group were not significantly different from those in the non-HE group, and there was also no significant difference between the two groups in terms of the reduction of FeNO, TIgE, and sputum eosinophils induced by dupilumab (Table 3).

Table 3. Comparison of curative effect before and after treatment with dupilumab between HE and non-HE group.

	Baseline			4th month			12th month
	Non-HE (n = 12)	HE (n = 8)	p	Non-HE (n = 12)	HE (n = 8)	p	Non-HE (n = 12)	HE (n = 8)	p
SEC (%)	31.15 (23.38, 49.43)	43.5 (11.50, 62.50)	.728	2.40 (1.50, 7.50)	4.75 (0.75, 18.13)	.724	3.50 (1.50, 6.00)	3.57 (0.50, 16.66)	.902
FeNO (ppb)	55.50 (27.75, 72.25)	62.00 (50.00, 92.00)	.353	21.00 (18.00, 22.00)	41.83 (22.50, 52.00)	.085	20.00 (11.00, 31.00)	14.00 (8.02, 33.00)	.57
TIgE (kU/L)	457.50 (124.88, 554.25)	450.50 (402.75, 727.50)	.44	55.90 (36.60, 117.25)	122 (59.98, 127.73)	.211	42.10 (23.30, 69.40)	33.30 (26.30, 93.36)	.641
FEV1/FVC (%)	57.66 (51.12, 71.51)	60.49 (50.49, 64.66)	.939	70.26 (60.08, 82.00)	63.10 (56.90, 70.52)	.28	77.41 (64.56, 84.20)	71.20 (64.42, 78.00)	.448
FEV1 (% predicted)	65.90 (43.43, 78.93)	62.87 (52.91, 78.03)	.817	80.80 (64.25, 102.01)	76.73 (72.99, 88.58)	.28	84.32 (69.45, 96.45)	89.30 (79.40, 101.50)	.386
Exacerbations (/4 months)	1.00 (0.25, 1.00)	1.00 (0.25, 1.00)	.665	0.00 (0.00, 1.00)	0.00 (0.00, 0.75)	.758	0.00 (0.00, 0.00)	0.00 (0.00, 1.00)	.068
ACT scores	18.00 (17.00, 18.75)	18.00 (16.00, 20.50)	.844	21.50 (21.00, 23.75)	20.50 (19.00, 22.50)	.084	24.00 (22.00, 24.00)	22.00 (19.00, 23.00)	.078
OCS (mg/d)	10.00 (0.00, 20.00)	15.00 (10.00, 27.5)	.272	0.00 (0.00, 2.50)	7.5 (0.00, 13.75)	.15	0.00 (0.00, 0.00)	2.50 (0.00, 10.00)	.117

HE: hypereosinophilia; EOS: eosinophils; FeNO: fractional exhaled nitric oxide; TIgE: total immunoglobulin-E; FEV1: forced expiratory volume in 1s; FVC: forced vital capacity; AE: asthma exacerbation; ACT: asthma control test; OCS: oral corticosteroid.

Analysis of HE-related events during dupilumab treatment

Temporal distribution of HE

As shown in Figure 1, BEC increased in the first month of dupilumab treatment, peaked after 4 to 5 months of treatment in the HE group, and gradually decreased after approximately 6 months of treatment. BEC tended to return to baseline levels after 12 months of dupilumab treatment.

Figure 1. Trends in blood eosinophil counts in HE and non-HE groups after dupilumab treatment. Note: EOS: eosinophils; HE: hypereosinophilia.

Possible risk factors of HE

We next performed subgroup analyses based on the different clinical characteristics of the patients at baseline, comparing the BEC levels of the different subgroups after treatment to look for risk factors that might have led to an increase in the BEC of patients. As shown in Figure 2 and Supplementary Table S1, after 4 months of dupilumab treatment, the median increase in BEC was significantly higher in the food allergy positive group than in the food allergy negative group, and this significant difference persisted until 12 months after treatment. Similarly, patients with EOM exhibited a median increase in BEC after 4 months of treatment compared to baseline and after 12 months. Interestingly, patients with baseline FeNO ≥ 60 ppb also exhibited a significantly higher increase in median BEC after 4 months of treatment compared with baseline, whereas this difference disappeared after 12 months of treatment.

Figure 2. Subgroup analysis according to different conditions at baseline to compare changes in BEC after 4 and 12 months of dupilumab treatment. *p < .05, **p < .01, ***p < .001. BEC: blood eosinophil counts; FeNO: fractional exhaled nitric oxide; CRSwNP: chronic rhinosinusitis with nasal polyps; AD: atopic dermatitis; EOM: Eosinophilic otitis media.

Discussion

Dupilumab is widely used in the treatment of severe asthma, moderate-to-severe AD, and CRSwNP by inhibiting IL-4 and IL-13 signaling, and thus plays a key role in suppressing type 2 inflammation. The LIBERTY ASTHMA QUEST trial confirmed the efficacy of dupilumab in asthmatics with BEC ≥ 0.15 × 10⁹ cells/L or FeNO ≥ 25 ppb, and was more pronounced at BEC ≥ 0.3 × 10⁹ cells/L [8]. One study further found that for asthma patients with a baseline BEC >0.5 × 10⁹ cell/L, they showed a favourable response to dupilumab and it appeared that as baseline type 2 inflammatory biomarkers increased, dupilumab improved patients’ lung function and level of asthma control more significantly [20]. In the present study, the mean values of type 2 inflammatory markers such as BEC (0.54 ± 0.35) × 10⁹ cell/L, FeNO (57.85 ± 26.42) ppb, and TIgE (564.16 ± 469.46 kU/L) of the patients at baseline were higher than that of the LIBERTY ASTHMA QUEST study of BEC (0.35 ± 0.37) × 10⁹ cell/L, FeNO (34.97 ± 32.85) ppb and TIgE (432.40 ± 746.46) kU/L, suggesting that they may respond better to dupilumab.

HE induced by dupilumab treatment of asthma was mostly transient and not accompanied by clinical symptoms, and the presence of HE did not affect its efficacy, and the BEC of the patients in the HE group basically recovered to the baseline level at the end of 12 months of treatment. It was found that the presence of HE during dupilumab treatment for AD may lead to a reduction in its efficacy and may cause allergy-related complications [21,22]. However, in this study, the above did not occur in dupilumab-treated asthma patients, and the results showed no significant differences in the number of exacerbations, lung function, or improvement in type 2 inflammation between the HE and non-HE groups. Meanwhile, the levels of BEC could be reduced to (0.50 ± 0.36) × 10⁹ cell/L at the full 12 months of treatment, essentially roughly the same as baseline (0.54 ± 0.35) × 10⁹ cell/L. Wechsler et al. reviewed 11 clinical trials of dupilumab and similarly found that dupilumab-induced HE was transient and usually unrelated to clinical symptoms or efficacy effects, and that the BEC declined to or below baseline over time [23].

HE induced by dupilumab rarely requires discontinuation and/or addition of systemic glucocorticoids. In their recommendations for the management of HE induced by dupilumab, Caminati et al. suggest that patients presenting with a BEC >1.5 × 10⁹ cell/L need to be followed up more frequently to once a month, and that if the patient’s BEC level is further elevated to ≥3.0 × 10⁹ cell/L, assessment of organ damage needs to be initiated, and that if evidence of organ damage occurs, discontinuation of dupilumab and systemic glucocorticoids may be attempted, and reintroduction of dupilumab may be attempted when the patient’s BEC level falls below 1.5 × 10⁹ cell/L and the patient’s condition is reassessed [24]. In this study, 2 patients developed BEC ≥3.0 × 10⁹ cell/L after dupilumab treatment. Eosinophilic pneumonia was suspected in patient 1, so dupilumab was suspended and 20 mg/d of OCS was administered, after which his BEC decreased rapidly and remained stable. Re-treatment with dupilumab was then given, and although the patient experienced subsequent fluctuations in BEC, he did not develop clinical symptoms. HE with clinical symptoms is reported to be extremely rare, mostly eosinophilic pneumonia or EGPA. Wechsler et al. found that among 4666 patients on dupilumab, the number of patients who developed HE with comorbid clinical symptoms was only 7, and all of these occurred in patients with asthma and/or CRSwNP [23]. In this study, patient 1 who developed HE with clinical symptoms was asthma combined with CRSwNP, suggesting that airway disease (asthma, CRSwNP) may be a risk factor for patients to develop HE. Elevated BEC caused by dupilumab may be due to two reasons, one of which is that blockade of the IL-4/13 pathway reduces migration of eosinophils and accumulation in blood by inhibiting eotaxin-3, VCAM-1, and TARC, but without simultaneously inhibiting eosinophilopoiesis in bone marrow [15]; secondly, because glucocorticoids inhibit eosinophils, patients may also experience elevated BEC when OCS is reduced during dupilumab administration [25]. Patient 2 had his OCS dose reduced from 40 mg to 30 mg 1 month after dupilumab treatment due to significant improvement in symptoms, which may have contributed to his elevated BEC, and when the OCS dose was re-increased, this patient’s BEC level was immediately and effectively controlled, and therefore no further elevation of BEC was observed when the OCS dose was slowly and carefully lowered in the subsequent follow up visits.

Our results revealed that patients with combined EOM or food allergen positive had higher increases in BEC after dupilumab than controls at month 4 and month 12. In a single-centre retrospective study of dupilumab-treated AD patients, patients in the food allergy-positive group were found to have a 39% increase in mean BEC levels compared to baseline after 4 months of treatment with dupilumab, compared to only a 5% increase in the negative group [26]. In this study, patients in the food allergens positive group experienced a median BEC increase of 1.10 × 10⁹ cells/L from baseline with dupilumab, which was much higher than the negative group’s increase of −0.02 × 10⁹ cells/L. Similarly, patients with comorbid EOM also experienced a more significant level of BEC elevation after 4 months of dupilumab use compared with the negative group. No cohort studies of dupilumab treatment for EOM have been published. However, there are no cohort studies of dupilumab in the treatment of EOM, but case reports by Iino [27] and Shimizu [28] found that 4 patients had elevated BEC and much greater than baseline levels after treatment with dupilumab.

The present study was limited to be a retrospective study with a small number of enrolled cases, which does not exclude that the non-HE group had an elevated BEC greater than 1.5 × 10⁹ cells/L that was not recorded during the follow-up period, and prospective, large-sample studies are still needed in the future to investigate the risk factors for the emergence of an elevated BEC in patients with severe asthma using dupilumab.

Conclusions

In this single-center study we found good initial efficacy of dupilumab in the treatment of severe asthma. Although some patients may develop asymptomatic HE, the BEC of the majority of patients returned to baseline at the completion of 12 months of treatment. In addition, subgroup analysis revealed that patients with FeNO ≥60 ppb, food allergens positive, and co-morbidities with EOM were more likely to have elevated BEC after dupilumab treatment. Biologics are currently an important therapeutic measure for the control of severe asthma, and further exploration of risk factors and possible mechanisms of HE during dupilumab use is warranted in the future.

Authors contributions

QZ and JX designed the study. YL, ZD and JW completed completed subject enrollment. CO, XC and YL performed the statistical analysis. YL, ZD and JW drafted the manuscript. QZ and JX edited and revised the manuscript. All authors contributed to the critical revision of the manuscript and approved the final version.

Ethical approval

All participants or their parents provided oral and written informed consent for participating in this study, and in conformity with the ethics approval by the First Affiliated Hospital of Guangzhou Medical University ethics committee (Medical Research Ethics Review No. 35, 2018).

Consent form

The funders had no roles in study design, data collection, data analysis, interpretation and writing of the report. QZ and JX had full access to the data in the study and had final responsibility for the decision to submit it for publication.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The original data used and/or analysed during this study are available from the corresponding author JX (email: [email protected]) or QZ (email: [email protected]) on reasonable request.

Additional information

Funding

This study was supported by National Natural Science Foundation of China (82070026), Zhongnanshan Medical Foudation of Guangdong Province (ZNSA-2020013), Zhongnanshan Medical Foudation of Guangdong Province (ZNSXS-20220083), Guangzhou Science and Technology Plan Project and Zhongnanshan Medical Foudation of Guangdong Province (202102010355, ZNSA-2020003), Science and Technology Innovation Project of Guangzhou Medical University (2022A015), Undergraduate Innovation Ability Improvement Program of Guangzhou Medical University (02-408-2304-01023XM), Foundation of Featured Clinical Technique of Guangzhou (2019TS24), Construction Project of Guangzhou Demonstration Unit for Collaborative Treatment of Critical and Difficult Diseases with Traditional Chinese and Western Medicine, and Science and Technology Program of Guangzhou (202201020551).