Interleukin-5 (IL-5) is central to eosinophil differentiation, survival, and activation. Subsequent studies confirmed IL-5 receptor expression and mapped downstream signaling, showing that IL-5 promotes not only survival but also trafficking and effector functions, including adhesion, degranulation, reactive oxygen species generation, mediator release (cytokines and cysteinyl leukotrienes), and extracellular trap formation. However, the roles of eosinophils vary across diseases and tissue compartments. Multi-omics analyses of blood and tissue eosinophils across transcriptomic, proteomic, and lipid-metabolic layers reveal disease- and site-specific molecular states. These data support two opposing classes of modulators that shape IL-5-driven programs: pro-inflammatory signals (IL-4/IL-13, IL-33, NOD2-mediated innate signaling, and IFN-γ) that drive inflammatory eosinophil changes and can cooperate in some settings, and counter-regulatory signals (IFN-α and all-trans retinoic acid [ATRA]) that restrain these changes. Such modulation may influence tissue retention, effector functions, and broader eosinophil activities, including antiviral and homeostatic roles. Clinical studies of anti-IL-5 and/or anti-IL-5Rα biologics in severe eosinophilic asthma, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndromes, and other eosinophilic diseases have improved outcomes, underscoring that disease activity often depends on IL-5-driven eosinophil activation despite disease-specific IL-5-independent signals. In this review, we summarize IL-5 biology from mechanisms to therapy and discuss how integrated multi-omics signatures and clinical biomarkers may guide patient stratification, therapy selection, and treatment sequencing toward precision medicine for eosinophilic respiratory and systemic diseases. .

Löffler's syndrome is classically described as a transient pulmonary disorder associated with eosinophilic infiltration of the lungs, most commonly triggered by helminthic larval migration. While eosinophilia is considered a defining feature, rare cases lacking peripheral or pulmonary eosinophilia have been reported, complicating recognition and diagnosis. Disseminated helminthic infection with multiorgan involvement is an additional uncommon manifestation that may further obscure clinical identification. We describe a case of a 40-year-old woman with extensive environmental and animal exposure who developed pulmonary, neurologic, gastrointestinal, and cutaneous symptoms following suspected household zoonotic helminthic transmission. Despite elevated immunoglobulin E (IgE) levels and characteristic clinical features suggestive of larval migration, peripheral eosinophilia was absent. Multiple household members developed similar symptoms, supporting a shared exposure. The patient improved following empiric antihelminthic therapy and coordinated treatment of household contacts and domestic animals. This case highlights a rare non-eosinophilic variant of a Löffler-like pulmonary syndrome associated with disseminated helminthic infection and underscores the importance of considering parasitic disease in patients with multisystem symptoms and environmental exposure, even in the absence of eosinophilia.

Current oral food challenge (OFC) protocols for FPIES exhibit significant variability, creating potential for inconsistent diagnostic outcomes and severe reactions. Based on the published evidence and our clinical experience, we propose a practical, standardized OFC dosing protocol that emphasizes patient safety, goals based on age-appropriate servings, and clinical monitoring. A recent systematic review reported that most patients with persistent FPIES who underwent OFCs reacted to just 25% of an age-appropriate serving (AAS), with low rates of severe reactions. Thus, we recommend that most patients undergoing a medically-supervised FPIES OFC receive a cumulative dose of 25% AAS, followed by observation for a minimum of 4 hours. Supervised challenges should be followed by gradual up-titration to an AAS at home. A lower dose may be considered for patients with a history of severe FPIES symptoms to trace amounts of food. For patients with atypical FPIES, we recommend a slightly modified protocol, using graded dosing per IgE-mediated food allergy protocols, followed by extended FPIES OFC monitoring. Anticipated outcomes from implementation of this standardized OFC protocol include improved diagnostic accuracy, enhanced patient safety, and a structured approach to food reintroduction. Standardizing practices for FPIES OFCs will also permit harmonization of data to advance research.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare pediatric vasculitis that can be difficult to diagnose, especially when antineutrophil cytoplasmic antibody (ANCA) is negative. We describe the case of a 10-year-old girl with severe asthma, recurrent leukocytoclastic vasculitis, peripheral eosinophilia, and pulmonary nodules. Infectious and immunologic workup was unremarkable, and skin biopsy confirmed eosinophilic vasculitis. She was diagnosed with ANCA-negative EGPA based on the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria and started on high-dose corticosteroids with plans for mepolizumab maintenance. This case highlights the diagnostic challenges in pediatric EGPA, the masking effects of biologic therapy, and the importance of multidisciplinary evaluation for early recognition and optimal management.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV)-granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA)-as well as anti-glomerular basement membrane disease (anti-GBM disease) are systemic small-vessel vasculitides with high mortality. Diagnosis relies on serology/laboratory testing, organ screening, and exclusion of differential diagnoses. Biopsy must not delay therapy initiation in fulminant cases. In GPA and MPA, loss of T‑ and B‑cell tolerance and ANCA-mediated activation of neutrophils are pivotal. Diagnostic hallmarks include myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA. Kidney biopsy reveals pauci-immune necrotizing and extracapillary proliferative glomerulonephritis. Remission induction consists of glucocorticoids (GC) combined with rituximab (RTX) or cyclophosphamide (CYC). Maintenance therapy is preferably performed with RTX. EGPA is defined by eosinophilic tissue infiltration, often accompanied by asthma and nasal polyposis; ANCAs are present in 30-40%. Diagnostic evaluation includes blood count, inflammatory markers, immunoglobuline E (IgE), ANCA, and ENT, pulmonary, and cardiac evaluation. Nonorgan-threatening disease is treated with GC, whereas relapsing disease is managed with interleukin (IL)-5 pathway inhibitors. Organ- or life-threatening manifestations require GC plus CYC or RTX, followed by IL‑5 pathway inhibitors for maintenance therapy. Anti-GBM is driven by autoantibodies against type IV collagen and presents with a nephritic syndrome and/or alveolar hemorrhage. Within 24 h, diagnostic evaluation should include testing for anti-GBM antibodies and ANCA, thoracic imaging, exclusion of infection, and a kidney biopsy demonstrating linear IgG deposits. Treatment consists of plasmapheresis combined with GC and CYC, with RTX as an alternative. Maintenance therapy is not required unless concomitant ANCA positivity is present.

Benralizumab, an eosinophil-depleting anti-IL-5 receptor α antibody, has demonstrated efficacy in severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis and shown promising results in hypereosinophilic syndrome (HES). NATRON was a randomized, double-blind placebo-controlled phase 3 study evaluating the efficacy and safety of benralizumab in FIP1L1::PDGFRA-negative HES. The primary endpoint was time to first HES flare. In total, 133 patients (median (range) age 51 (14-87) years, 62% female) were randomized (1:1) to receive benralizumab 30 mg every 4 weeks or placebo for 24 weeks, in addition to background therapy. Benralizumab significantly reduced the risk of first flare versus placebo (hazard ratio 0.35, 95% CI 0.18 to 0.69, P = 0.0024). Adverse events occurred in 64.2% and 66.7% of benralizumab- and placebo-treated patients, respectively. Benralizumab's safety was consistent with its known profile. These results demonstrate the efficacy and safety of add-on benralizumab in the treatment of HES. ClinicalTrials.gov identifier: NCT04191304 .

Depemokimab (depemokimab-ulaa; EXDENSUR) is an anti-IL-5 antibody being developed by GSK for the treatment of asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Add-on treatment with depemokimab reduced asthma-related exacerbations in patients with severe asthma with an eosinophilic phenotype, in addition to reducing the severity of nasal polyps and nasal obstruction in patients with CRSwNP. This article summarizes the milestones in the development of depemokimab leading to this first approval in the UK as an add-on maintenance treatment of asthma in adult and adolescent patients aged ≥ 12 years with type 2 inflammation characterised by an eosinophilic phenotype who are inadequately controlled on maximum moderate-dose or high-dose inhaled corticosteroids plus another asthma controller; and as add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate control.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are usually classified as distinct entities, such as granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA). In everyday practice, however, some patients display overlapping features of both conditions, making classification and treatment decisions more challenging. We report a case of a 51-year-old man with late-onset asthma who presented with constitutional symptoms, purulent rhinosinusitis, hemoptysis, and arthralgia. Imaging demonstrated cavitary pulmonary nodules and nasal polyposis. Laboratory testing showed marked eosinophilia and positivity for proteinase 3 (PR3) c-ANCA. Nasal biopsy revealed necrotizing granulomatous inflammation rich in eosinophils. The patient received induction therapy with high-dose glucocorticoids and cyclophosphamide, followed by rituximab for maintenance, with clinical improvement and sustained remission. This case highlights the limitations of current classification frameworks and is compatible with a GPA-EGPA overlap phenotype (or spectrum). It underscores the value of an individualized approach guided by the predominant organ-threatening manifestations and the associated biological profile.

Significant advances in the management of diseases driven by eosinophilic inflammation in the age of biologics provide us with an untapped opportunity to extend these highly effective treatments to other lung diseases that have eosinophils as a central effector cell. Currently, rare diseases such as chronic eosinophilic pneumonia and allergic bronchopulmonary aspergillosis (ABPA) are treated with oral corticosteroids (OCS) and often require long courses of exposure to high doses of OCS. In this era of increased awareness of OCS toxicity and a heightened interest in OCS stewardship, we are obligated to leverage our understanding of the pathophysiology of these diseases to implement strategies that include the use of biologics as therapeutic options. This review focuses on available literature on employing biologics to treat acute and chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, and hypereosinophilic syndrome.

Eosinophilic lung diseases encompass a heterogeneous spectrum of disorders characterized by the accumulation of eosinophils within the lung parenchyma. Etiologies range from primary eosinophilic syndromes to secondary causes such as parasitic and fungal infections, hematologic malignancies, allergic conditions, and systemic autoimmune diseases. Given their overlapping clinical and radiologic presentations, accurate and timely diagnosis is critical for guiding appropriate management and avoiding both overtreatment and delays in therapy. This review synthesizes current evidence and expert perspectives on the differential diagnosis of eosinophilic lung diseases, drawing on clinical, laboratory, radiologic, and histopathologic approaches. Key emphasis is placed on distinguishing primary eosinophilic syndromes from secondary causes, the role of molecular and immunologic testing, and the integration of multidisciplinary expertise. A comprehensive diagnostic algorithm is presented to assist clinicians in routine practice, with particular emphasis on addressing unmet needs such as biomarker development and the establishment of standardized definitions for disease activity. By elucidating diagnostic processes and minimizing common errors, this article seeks to enhance the precision of differential diagnosis and improve clinical outcomes for patients with eosinophilic lung involvement.