Detection and Management of Eosinophilia in Asthmatic Adults and Children Receiving Dupilumab Treatment: A Focused Review

Introduction

Dupilumab is a fully humanized monoclonal antibody that selectively binding IL-4 receptor alpha subunit, which is a shared receptor for both IL-4 and IL-13.¹ This kind of action places dupilumab as a major compound in interfering with T2 inflammation pathways underlying a broad spectrum of different conditions. This is reflected in the several indications for which dupilumab is approved, including asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), eosinophilic esophagitis and prurigo nodularis.² More recently, dupilumab license has been extended to COPD patients.³ As part of dupilumab mechanisms of action, the expression of VCAM-1 and Eotaxin-3, respectively, mediating eosinophils adhesion and their migration from endothelium, is downregulated, preventing eosinophils trafficking to tissues and possibly accounting for their transient increase in the blood stream of treated subjects.⁴ That occurrence has been mostly reported for respiratory (asthma, CRSwNP) and to a lesser extent for atopic dermatitis indications, and in a minority of patients when considering hypereosinophilia threshold.⁵ Eosinophilia is generally defined as a blood eosinophil count (BEC) ranging between 500/mm³ and 1500/mm³, moderate hypereosinophilia between 1500/mm³ and 5000/mm³ and severe hypereosinophilia >5000/mm³.⁶ Overall, BEC increase in dupilumab treated patients usually presents short duration and spontaneous remission without clinical relevance, as supported by the fully comparable safety profile of dupilumab vs other compounds of the same drug class (including benralizumab, mepolizumab, omalizumab and tezepelumab).^7–9 However, on a clinical ground the phenomenon needs to be considered and properly managed/followed-up in order to prevent or early detect potential eosinophil-related adverse events but on the other side to avoid unnecessary treatment exclusion or discontinuation.

So far, some operational algorithms have been proposed addressing the issue in adult populations, including either CRSwNP patients or patients with respiratory impairment more in general.^5,10,11

In the present narrative and focused review, the authors aimed to provide a state of the art related to eosinophils increase occurring in asthma children and adults prescribed with dupilumab by including Randomized Controlled Trials (RCTs) and real-world evidence. Original articles, research letters, case-series, case-reports, and reviews were searched on PubMed from 2016 to 2025. The main search terms were “dupilumab”, “asthma”, “eosinophilia”, “hypereosinophilia”, “adverse events”. Authors excluded studies in which the prevalence and clinical manifestations of increased eosinophilia were not described. Additional studies considered pivotal to the completeness of the manuscript were also included.

In addition, relying on the available evidence, some practical insights on baseline assessment and follow-up are provided.

Sizing the Issue

Epidemiological Data in Children

So far, the evidence related to blood eosinophils fluctuation in pediatric patients undergoing dupilumab treatment for severe asthma is small and mostly limited to clinical trials data, whilst no relevant real-world perspectives are available. Generally speaking, according to the published data, peripheral eosinophilia/hypereosinophilia can be considered in that population an expected and generally transient finding.¹²

Across randomized pediatric trials, including children aged 6–11 years, hypereosinophilia was more frequently observed in the dupilumab group (4.1%) compared with patients receiving placebo (0.6%), and these elevations were typically transient and asymptomatic.¹³ Only one case of hypereosinophilia was associated with clinical symptoms that required drug discontinuation and hospitalization in a patient with a prior history of hypereosinophilia.

A small, transient increase in blood eosinophils is reported in a minority of patients during the first 12–24 weeks of treatment.¹⁴

Across the pivotal pediatric RCT VOYAGE and its 52-week open-label extension EXCURSION, dupilumab safety profile was consistent with previous asthma studies without reporting any clinical significant hypereosinophilia.^15,16

In practice, the pediatric safety profile indicates that asymptomatic blood eosinophils fluctuation may occur in a minority of children receiving dupilumab, whereas symptomatic hypereosinophilia occurring under dupilumab therapy appears to be extremely rare.

Epidemiological Data in Adults

In Phase II and III randomized clinical trials including subjects treated with dupilumab for severe asthma, a transient eosinophilia in the treatment arm was consistently reported compared to placebo.^13,17–19 In the phase IIb dose-ranging study, 1 patient out of 611 in the treatment group developed clinically significant hypereosinophilia leading to drug discontinuation and systemic steroid treatment.¹⁸ In the QUEST and VENTURE studies the percentage of patients developing eosinophilia ranged between 4.1% and 14%, but only the 0.2% to 0.9% of them developed clinical manifestations such as hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, asthma exacerbation, neuropathy or other less specific symptoms.^13,18 These patients were treated with systemic steroids (either hydrocortisone, prednisolone or flucortolone) and in selected cases with antibiotics (ie. levofloxacin and piperacillin/tazobactam) or immunosuppressants (ie. rituximab and azathioprine).^13,17,18 In the QUEST study, 3 out 4 subjects developing hypereosinophilia discontinued dupilumab¹³ and in the open-label TRAVERSE study only 2 patients were reported to have biological therapy discontinuation, however this information was not available for the all the reported cases of hypereosinophilia occurrence.¹⁹

Dupilumab is now a well-established and effective therapy for severe T2 asthma, having shown a good safety profile over time. Differently from RCTs studies, real-life experiences usually include smaller populations and/or patients who switched from other biologics and present with more complex clinical scenarios. Indeed, findings from real-life studies reported a tendency toward increased BEC in a slightly higher percentage of cases compared to RCTs, although without raising more safety concerns compared to RCTs.⁹ Specifically, multicentric studies from various countries including Italy (N = 18) and France (N = 64) have shown rates of hypereosinophilia ranging from 16.6 to 25%,^20,21 with severe hypereosinophilia observed in up to 6.3% in the French cohort.²¹ In none of these clinical manifestations were described and dupilumab discontinuation was needed.^20,21 Additionally, an Austrian monocentric study (N = 13) reported no cases of dupilumab-induced hypereosinophilia.²²

Strong A. et al monitored patients at weeks 4 and 16 to screen for new-onset symptoms related to eosinophilia. To note, the authors reported 22% (15/69) of cases of eosinophilia, of which 8.7% were experiencing clinically significant hypereosinophilia. Interestingly, half of them presented with eosinophilia at baseline and 5/6 switched from an anti-eosinophilic strategy. Four out of 6 patients discontinued the treatment with dupilumab.²³

Fisch et al reported symptomatic eosinophilia in 6 out of 100 asthmatic patients established on dupilumab. Interestingly, the latest adverse event developed after 17 months after the beginning of the biological trial. All patients were switched to one of the available anti-eosinophilic strategies, while in 2 a combination therapy with two biologics was undergone.²⁴

More recently, Caminati et al showed that, in a cohort of 195 patients, around one out of two patients treated with dupilumab for asthma and/or sinonasal disease experienced eosinophil increased but less then 20% developed hypereosinophilia. Of these, only 22 patients reported symptoms, most commonly an asthma exacerbation or myalgia. Only one third of them required dupilumab discontinuation. Of note, hypereosinophilia was detected only in a half of patients experiencing adverse reactions during the treatment course; however, an increased baseline BEC showed a 3.3 times higher risk of developing symptoms.²⁵ Similarly, Li SH et al reported an overall hypereosinophilia rate of 11.3% (16/142) with only 4 patients developing related clinical manifestations; of them more than 80% remained on dupilumab treatment.²⁶ Case series reporting clinically significant manifestations associated with hypereosinophilia showed higher rates of dupilumab discontinuation but also, in some cases, the association with a second biological therapy such as anti-IL-5 agents.^27–34

Overall, common clinical manifestations included asthma exacerbations, EGPA, pulmonary infiltrates, and fever; less frequently, neurological or cardiovascular disorders, HES, and eosinophilic gastritis.²⁸

Differently from RCTs, evidence from Real-World studies is affected by important limitations, including small sample sizes, retrospective observational designs, and selection and reporting bias. In particular, case series and case reports should be intended as guidance for managing complex patient, emphasizing the need for a precise and accurate phenotyping before initiating any biological initiation. To summarize, the findings from RCTs and real-life experiences highlight that most BEC increases during dupilumab therapy are transient, benign and asymptomatic. However, in a smaller subset of cases, persistent moderate-to-severe hypereosinophilia may occur, and be associated with significant clinical manifestations. Even tough, according to the nature of the events, dupilumab discontinuation is not always required.

From Detection to Management

Red-Flags at Baseline and Follow-Up in Children

In children with severe asthma, before starting dupilumab, it is essential to exclude alternative or coexisting conditions that may mimic or complicate asthma management. The baseline work-up should serve to characterize the underlying inflammatory phenotype and identify potential contraindications to treatment. Upper and lower airway conditions such as chronic rhinosinusitis, bronchiectasis, primary ciliary dyskinesia, and cystic fibrosis should be considered in the appropriate clinical context. Chest imaging is reserved for “red flags” such as focal findings, recurrent lobar collapse, hemoptysis, or growth failure.

The characterization of the phenotype of children with severe asthma typically includes peripheral blood eosinophil count, total IgE, and fractional exhaled nitric oxide (FeNO), evaluation of allergen sensitization, and other atopic conditions such as allergic rhinitis, atopic dermatitis, food allergy, and obesity.¹⁴ Identifying underlying systemic or primary eosinophilic disorders is particularly important.³⁵ Persistent eosinophilia over 1500/mm³ warrants further investigation to exclude EGPA, HES, or parasitic infections by assessing laboratory tests and organ involvement including chest imaging, cardiac or neurologic evaluation, depending on clinical presentation.³⁶

Active helminth infections (guided by exposure and travel history, stool ova/parasites and/or serology as indicated) represent a relative contraindication to dupilumab, as IL-4/IL-13 blockade may impair parasite clearance; treatment should consequently be postponed until the infection is resolved.³⁷

This systematic baseline assessment not only ensures appropriate patient selection for dupilumab but also consents to early detection of atypical eosinophilic or systemic reactions during follow-up, thereby improving both the safety and effectiveness of therapy.³⁸

After Dupilumab initiation, careful follow-up is necessary to ensure safety, evaluate treatment response, and detect early signs of eosinophilic or systemic complications during dupilumab treatment in children with severe asthma. The recommended approach combines clinical visits, lung-function assessment, and targeted laboratory assessments including BEC evaluation, adjusted according to disease severity and comorbidities.^38,39

Initial follow-up should occur 4–8 weeks after treatment initiation to evaluate tolerability, injection-site reactions, and early symptom response. Subsequent assessments are typically scheduled every 3–6 months, in line with most pediatric severe-asthma protocols and biologic therapy guidelines.^38–40

Routine laboratory monitoring is not generally required, as dupilumab does not induce systemic immunosuppression.¹⁴ However, a complete blood count with differential should be obtained at baseline and repeated after 3–6 months, particularly in patients with elevated baseline eosinophils, to detect potential transient eosinophilia. Persistent eosinophilia >1500/mm³ or the emergence of new systemic symptoms should prompt evaluation for eosinophilic disorders.^36,37

The clinical red flags during dupilumab treatment include new or worsening respiratory symptoms despite adherence, systemic symptoms (fever, arthralgia), unexplained fatigue or cardiac involvement, neurological deficits or neuropathic pain, vasculitic or purpuric rash, and recurrent or refractory parasitic infection.^36,37 The appearance of these findings should prompt a reevaluation of treatment safety and consideration of referral to a pediatric pulmonologist or immunologist.

When stable disease control is achieved, follow-up intervals can be extended to every 6–12 months, continuing annual spirometry and seasonal review of adherence, comorbid allergic disease (rhinitis, dermatitis, sinusitis). The need for OCS should be reviewed at each visit to minimize systemic steroid adverse events.

Red-Flags at Baseline and Follow-Up in Adults

Taking a broader perspective and considering all approved indications for dupilumab, including asthma, CRSwNP, atopic dermatitis or eosinophilic esophagitis, findings from the literature and EudraVigilance database have been recently summarized in a systematic review focusing on eosinophilic complications during dupilumab therapy.⁴¹ Their occurrence was found to be extremely rare, however mostly related to respiratory indications, which sustains the need for exploring the issue and providing a focused approach when considering that patients’ category. According to the mentioned systematic review, factors predicting eosinophils-related events within specific patient characteristics at baseline could not be highlighted.⁴¹ Retrospective data from US patients treated with dupilumab for atopic dermatitis and/or respiratory indications sustains that baseline BEC alone should not be considered as a predictor of treatment-related clinical manifestations.⁴² Analogously, hypereosinophilia showed to occur 4.34 times higher in patients with concomitant asthma and CRSwNP, regardless of the level of eosinophil peak reached during the treatment, suggesting that comorbidities more than blood eosinophils might sustain the occurrence of complications during dupilumab treatment.²⁵ This observation aligns with post-marketing data showing that eosinophilic adverse events primarily occurred in patients with coexisting asthma and CRSwNP.⁴³

A previous treatment with anti-IL-5 agents also seems to contribute to symptomatic eosinophils fluctuation. Indeed, in real-life experiences, up to 50% of the patients developing clinical manifestations concomitant with hypereosinophilia had switched from an anti-eosinophilic biological strategy.^23,24,28 This finding could not be extrapolated from RCTs, due to stricter eligibility criteria commonly excluding patients coming from a previous biologic treatment. This, again, could explain the different incidence of eosinophilia in the two different settings. Similarly, the well-known steroid-sparing effect of dupilumab may be linked to the same mechanism. Indeed, a BEC fluctuation, whether symptomatic or not, cannot be excluded after discontinuation of systemic steroids. Based on this, steroid withdrawal concomitant with dupilumab initiation may “unmask” a previous eosinophilia or a natural evolution from asthma to other systemic eosinophilic conditions such as EGPA, especially in patients with concomitant upper and lower airways impairment, or HES.²⁵ Additional mechanisms may be related to the increase in peripheral blood eosinophils observed with dupilumab in patients switching from an anti-eosinophilic strategy. For example, a post-hoc analysis of the GALATHEA study involving COPD patients treated with the anti-IL-5 receptor mAb benralizumab reported a sustained increase in IL-5 and eotaxin-1 levels. A positive feedback mechanism in patients with a complete depletion of eosinophils might persist after anti-eosinophilic biologics discontinuation and drive the BEC increase at dupilumab initiation.⁴⁴

Generally speaking, it should not be neglected that severe asthma in patients eligible to anti T2 monoclonal antibody, including dupilumab, might represent a prodromic stage of the so called “eosinophilic march” potentially although rarely evolving to more systemic conditions such as EGPA or hypereosinophilic syndrome. BEC increase, whether related to dupilumab or not, especially when approaching or overcoming hypereosinophilia threshold and when associating with clinical manifestations, including asthma worsening, should be considered a potential hallmark of that evolution and an extensive differential diagnosis work up should be performed even in the case it was negative before biologic treatment initiation.

The lack of standardized diagnostic criteria and evidence-based management protocols complicates the clinical decision-making when hypereosinophilia occurs. This currently represents a crucial matter of discussion among authors.

A number of authors proposed strategies to manage blood hyper-eosinophilia, as well as to avoid unnecessary drug discontinuation.¹¹ Several points of convergence emerge across the available algorithms: routine BEC monitoring is recommended during the early phases of dupilumab therapy (from 1 to up to 6 months), particularly in patients with elevated baseline eosinophil counts or a recent switch from other biologics, in particular, anti-IL-5 agents. When hypereosinophilia is not accompanied by clinical manifestations, treatment discontinuation is not warranted by definition, and systemic evaluation is advised only in cases of persistent BEC elevation or associated symptoms. Multidisciplinary assessment is essential for the management of atypical or complex hypereosinophilia occurring during dupilumab treatment, providing complementary perspectives from haematology, rheumatology and immunology. However, significant unmet needs remain, as none of the available protocols have achieved universal consensus. Furthermore, none of the proposed strategies have addressed the possibility of dupilumab rechallenge following hypereosinophilia-related discontinuation, the management of recurrent or persistent eosinophilia, or the development of standardized criteria for defining clinically significant hypereosinophilia co-occurring with dupilumab therapy.

Practical Guide for Dupilumab Initiation for Adults and Children

Combining the currently published literature and the authors’ opinion, Figure 1 provides some practical suggestions related to “red-flags” to be identified and evaluated at baseline and follow-up and timing of assessment following the treatment start in asthma adults and children undergoing dupilumab treatment. Generally speaking, the indicated cut-off values repropose what the World Health Organization has defined in terms of eosinophils thresholds and eosinophilic disorders.⁶ More in detail, patient’s features which might associate with the occurrence of eosinophils fluctuation, whether symptomatic or not, are highlighted in the baseline evaluation boxes as “red-flags” suggesting an extensive differential diagnosis work-up before the biologic treatment initiation and a careful monitoring of those patients during the follow-up. In particular, in adults dupilumab should be avoided when BEC values are ≥5000/mm³, even without the evidence of an underlying condition accounting for that value. If BEC ranges between 1500/mm³ and 5000/mm³, and/or if any clinical red flags are present, an extensive workup and/or a multidisciplinary discussion should be undertaken. If the diagnosis and treatment indication are confirmed, a strict monitoring should follow the treatment initiation.

Figure 1 Red-flags based flow chart for the management of eosinophils increase during dupilumab treatment in asthma adults and children. Abbreviations: MDA, multi-disciplinary assessment; BEC, blood eosinophil count; CRSwNP, Chronic Rhinosinusitis with Nasal Polyps; EGPA, Eosinophilic Granulomatosis with Polyangiitis; HES, Hypereosinophilic Syndrome; mOCS, maintenance Oral Corticosteroid.

In children, precise baseline cut-offs are less well-defined; however, the threshold for withholding treatment should reasonably correspond to that established for adults. In addition, different follow-up protocols in terms of timing according to different clinical and BEC related scenarios are proposed alongside some management tips.

Thus, regular BEC monitoring, following different schedules according to different situations summarized in Figure 1, is part of good clinical practice regardless the specific ongoing biologic therapy.

Conclusions

The mechanisms underlying the onset of eosinophilia/hypereosinophilia over dupilumab treatment course and the reasons why its occurrence mostly associates with respiratory indications and develops in some patients only still remain controversial. Although characterized by limited populations, heterogeneous study designs and contexts, the literature related to both children and adults prescribed with dupilumab for severe asthma supports the poor clinical relevance of that phenomenon.

However, an extensive baseline diagnostic work-up, which should actually be performed in every asthma patient regardless the specific biologic agent he is a candidate for, and a proper follow-up evaluation can contribute to an optimal approach to dupilumab treated patients. In fact, early detection of adverse events, whether related to eosinophils fluctuation or not, is certainly part of good clinical practice, as well as on the other side avoiding unnecessary dupilumab exclusion if eligibility is fully satisfied, or discontinuation if the treatment response is optimal.

Further real-world evidence is needed, especially in the pediatric field, to clarify the mechanisms underlying the occurrence of eosinophilia/hypereosinophilia and the determinants associated with its potential clinical relevance.