Eosinophil granule proteins, cytokines, growth factors, and chemokines are synthesized at early stages of eosinophil maturation in the bone marrow and are packaged into various intracellular organelles, including the eosinophil crystalloid granule prior to secretion in response to receptor stimulation [16, 17]. During activation, eosinophils generate an elaborate tubulovesicular network that is composed of small secretory vesicles and elongated tubules, which appear to carry the contents of the crystalloid granule to the cell surface [18, 19]. The crystalloid granule in eosinophils is comprised of two compartments: A core and a surrounding matrix, both of which are enriched with highly cationic proteins, principally MBP [20]. Electron microscopy images of sectioned eosinophils display the strikingly electron-dense crystalline cores in crystalloid granules, visible in eosinophils from many different mammalian species. In the matrix that envelopes the MBP-rich core, EPX, EDN, and ECP are found in high concentrations, along with many other granule proteins, including cytokines. Eosinophils rarely release granule products during transit through the bloodstream, being relatively benign even as they marginate into tissues, predominantly the gut, in healthy individuals [21]. However, in diseases such as allergy and atopic asthma, eosinophils undergo a high degree of proliferation in the bone marrow and are found degranulating in the nasal and airway mucosa [22]. Degranulation is a general term that describes an activated phenotype ranging from piecemeal degranulation to degradation of cells and cytolysis (necrosis). When eosinophils encounter secretagogues, they will release the contents of their crystalloid granules by mobilizing granules and secretory vesicles to the cell surface, inducing granule-membrane fusion in a regulated manner; hence the term, “regulated exocytosis” [23]. In the case of cytolysis, eosinophils release intact membrane-bound crystalloid granules with their lipid bilayer membranes still surrounding their core and matrix components, and whole granules infiltrating tissues may be readily visible upon appropriate staining of tissue sections [24, 25]. Potential mechanisms that control eosinophil cytolysis include adhesion-induced cytolysis of eosinophils that involves the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase-like (MLKL) signalling pathway [26]. Beyond classical degranulation, eosinophils also release extracellular vesicles carrying bioactive molecules such as microRNAs and enzymes, which contribute to intercellular communication and systemic immune modulation [27–29].

Eosinophils respond to activation by a wide range of pro-inflammatory mediators through ligation of their cell numerous surface receptors, facilitating their interaction and response with their environmental milieu. However, in vitro induction of eosinophil degranulation by soluble secretagogues is limited, often requiring potent or multiple stimuli to evoke a significant secretory response. As mentioned, blood eosinophils do not readily degranulate but release their granule contents only after their transmigration into tissues and their activation in the inflammatory foci. In some instances, eosinophils appear to undergo degranulation in response to both soluble and immobilized stimuli that activate multiple receptors. These secretagogue-binding receptors include those to complement factors (C5aR), immunoglobulins (FcRI, FcRII), platelet-activating factor (PAF), and fungal extracts (such as Alternaria acting on protease-activated receptor-2, PAR-2) [18, 19].

Receptors are generally classified by their signalling mechanisms, such as G protein-coupled receptors that activate dissociation of and subunits of heterotrimeric G proteins, and immunoglobulin- or cytokine-binding families that activate a cascade of tyrosine kinase phosphorylation. Eosinophils express many of the signalling components necessary for receptor activation of cellular events [30]. Eosinophils do not undergo degranulation in response to the potent eosinophil differentiation and maturation-inducing cytokines, IL-3, IL-5, or GM-CSF if applied individually, all three must be combined together in a “cytokine cocktail” in order to elicit degranulation in human eosinophils [31]. This is likely associated with the relatively quiescent state of eosinophils during their proliferation and maturation in the bone marrow in response to these cytokines.

Following binding and activation of specific receptors, secretagogues induce the mobilization of granules through the cytoplasm of the eosinophil, which may be associated with the formation of large tubulovesicular structures containing small secretory vesicles and elongated tubules that may extend from crystalloid granules [32, 33]. The tubulovesicular structure appears in the cytoplasm in correlation with piecemeal degranulation, where membrane-bound vesicles bud off from crystalloid granules and selectively shuttle specific granule contents to the plasma membrane for release. The tubulovesicular network is responsible for trafficking cytokines and chemokines such as IL-4 and CCL5/RANTES [34, 35]. The movement of granules and vesicles through the cells is controlled by actin cytoskeleton remodelling, regulated in eosinophils by a family of guanosine triphosphatases (GTPases), particularly Rac2 [36]. When vesicles and granules reach the inner leaflet of the lipid bilayer in the plasma membrane, they bind to specific intracellular receptors known as soluble N-ethylmaleimide-sensitive attachment protein receptors (SNAREs), which facilitate their docking and fusion with the cell membrane. This is followed by membrane fusion, in which the internal surface of the granule membrane becomes exposed to the outside of the cell membrane [37–39]. Concurrently, vesicle fusion is mediated by another membrane-bound GTPase, Rab27a, which conveys the secretagogue signal through to SNARE binding and ensures that granule membranes come into close proximity with cell membrane lipid bilayer with granule polarization focused on their leading edges during shape change and degranulation [40], suggesting that they may have the ability to focus their granule contents onto target surfaces, as previously observed in vitro using opsonized helminthic parasites [41]. There is a substantial body of clinical evidence that suggests that eosinophils degranulate upon recruitment and activation at inflammatory foci; these observations largely are the result of the examination of tissue biopsies from different organs and in association with diseases including allergies and asthma [39, 41, 42]. Eosinophil degranulation is thought to be an essential component of the late-phase mucosal tissue response to allergen challenge. There is significant evidence for eosinophil degranulation in tissues in association with AR, cutaneous allergic reactions, and atopic asthma; this observation often correlates with a deteriorating clinical outcome [42]. Furthermore, eosinophils and their major granule proteins have been detected at high levels in tissues and body fluids in response to fungal, parasitic, and viral infections [42–45] and likewise participate in the formation of eosinophil traps that are critical for host defence against bacterial sepsis [46].

In healthy individuals, eosinophils are present in the circulation in low numbers and are rarely found in the lungs, being mostly confined to the tissues surrounding the gut. Eosinophil accumulation during inflammatory events is complex, involving their maturation in and release from the bone marrow, adhesion to and transmigration through the post-capillary endothelium, followed by their chemotaxis to and activation/degranulation at inflammatory foci [47, 48]. The processes controlling eosinophil accumulation are of obvious importance and represent potential therapeutic targets for the antagonism of their accumulation in allergic-based disease. Asthma pathology is characterized by excessive leukocyte infiltration that leads to tissue injury. Cell adhesion molecules, i.e., selectins, integrins, and members of the immunoglobulin superfamily control leukocyte extravasation, migration within the interstitium, cellular activation, and tissue retention. Numerous animal studies have demonstrated essential roles for these cell adhesion molecules in lung inflammation, including L-selectin, P-selectin, and E-selectin, ICAM-1, VCAM-1, together with many of the β1 and β2 integrins. These families of adhesion molecules have therefore been under intense investigation to inform the development of novel therapeutics [49]. In addition, eosinophil accumulation is orchestrated by chemokines such as the eotaxins CCL11, CCL24, CCL26, and their receptor CCR3, as well as local stromal interactions and extracellular matrix (ECM) remodelling, which together determine both physiological tissue surveillance and pathological infiltration in diseases such as asthma and EoE [14, 50–52].

Eosinophil fate is also important; apoptosis and the disposal of apoptotic cells by phagocytic removal (efferocytosis) are vital aspects of inflammation resolution in all multi-cellular organisms. Eosinophils have a limited lifespan in the circulation of 8–18 hours and 3–4 days in the tissues, and up to two weeks in tissue culture conditions that favour their survival. As with neutrophils, they are terminally differentiated cells programmed to undergo apoptosis in the absence of viability-enhancing stimuli [53]. Eosinophil persistence in the tissues is enhanced by the presence of several asthma-relevant cytokines that prolong eosinophil survival by inhibition of apoptosis; these include IL-3, IL-5, IL-9, IL-13, IL-15, and GM-CSF [54]. Furthermore, thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 represent a triad of cytokines released by airway epithelial cells in response to various environmental stimuli or by cellular damage. They act in concert to drive Th2 polarization through overlapping mechanisms, causing remodelling and pathological changes in the airway walls, suggesting pivotal roles in the pathophysiology of asthma. All three have been shown to have multiple effects on eosinophil function, including enhancement of their receptor expression, adhesion, and viability through inhibition of apoptosis [55–57]. Eosinophil interactions with the proteins of the ECM also contribute to their persistence within the tissues. For example, integrin-mediated eosinophil adhesion to fibronectin results in the autocrine production of viability-enhancing cytokines GM-CSF, IL-3, and IL-5 [58]. These interactions between multiple cytokines and ECM components antagonize eosinophil programmed cell death, thereby prolonging their longevity for weeks. Thus, a balance in the tissue microenvironment between pro- and anti-apoptotic signals is likely to greatly influence the load of eosinophils in the tissues [59].

Allergic asthma is a chronic disease characterized by airway inflammation, reversible airway obstruction, and airway hyperresponsiveness. Its pathogenesis is complex and involves interactions among multiple immune cells and inflammatory mediators [60]. Among these, eosinophils play a critical role in the pathological process of allergic asthma. Eosinophils are classic effector cells of the type 2 (T2) immune response, and their activation and infiltration are considered one of the hallmarks of allergic asthma [61]. In patients with allergic asthma, eosinophils directly contribute to the initiation and maintenance of airway inflammation by releasing inflammatory factors [62, 63]. These factors not only induce airway epithelial damage but also further exacerbate the inflammatory response by activating immune cells [64].

Eosinophils in allergic asthma are not only involved in the regulation of inflammation but also participate in the complex modulation of the immune system [65]. Research has elucidated that eosinophils modulate the polarization of Th2 immune responses through interactions with immune cells such as T cells and dendritic cells, thereby influencing disease progression [66–68]. In the early stages of allergic asthma, eosinophilic infiltration is one of its characteristic pathological manifestations [69]. Eosinophils promote airway hyperresponsiveness and mucus hypersecretion by releasing Th2-type cytokines such as IL-5 and IL-13 [70, 71]. As a critical factor for eosinophil survival and activation, IL-5 levels in both blood and tissues are significantly correlated with asthma severity [72]. Furthermore, eosinophils exacerbate the inflammatory response by releasing chemokines such as CCL11 and CCL24, which recruit additional eosinophils and other inflammatory cells to the airways [73, 74]. In the chronic phase of allergic asthma, the role of eosinophils extends beyond simple inflammation. Studies suggest that eosinophils may also influence the establishment of immune tolerance by modulating the function of regulatory T cells [75]. For instance, by modulating T cell secretion of cytokines such as transforming growth factor-β (TGF-β) and IL-10, eosinophils may suppress the overactivation of Th2 immune responses, thereby mitigating disease progression to some extent [76]. However, this regulatory function is often impaired in asthma patients, contributing to the persistence and exacerbation of the inflammatory response.

The involvement of eosinophils in the pathogenesis of allergic asthma also encompasses complex biophysical mechanisms. Eosinophils directly alter the structure and function of airway epithelial cells by releasing EPX and MBP [65]. These proteins disrupt tight junctions between epithelial cells, increase airway permeability, and thereby promote the infiltration of both inflammatory cells and mediators [77]. Furthermore, eosinophils exacerbate tissue damage and inflammation by releasing ROS and the lipid mediator leukotriene C4 (LTC4), which induce bronchoconstriction and increase mucus secretion [78, 79], further exacerbating airway inflammation and remodelling. These biophysical alterations not only lead to airway wall thickening and fibrosis but also heighten airway sensitivity to stimuli, thereby exacerbating asthma symptoms.

As discussed above, the interaction between eosinophils and the ECM plays a pivotal role in their activation and tissue retention. In the airways of asthma patients, provisional ECM components, such as tenascin-C, periostin, and thrombospondin, are enriched and are associated with the tissue activation of eosinophils [80, 81]. ECM proteins not only provide structural support but also act as signalling platforms that modulate eosinophil behaviour, including adhesion and migration [82]. Research indicates that β1-integrin serves as a key receptor for eosinophil interaction with the ECM. Its binding to collagen IV (COL IV) promotes eosinophil adhesion and signal transduction. Activation of β1-integrin not only enhances eosinophil adhesive capacity but also regulates their functions—including cell survival, differentiation, and release of inflammatory mediators—through the downstream FAK/Bag3 phosphorylation signalling pathway [83]. Additionally, eosinophil-derived molecules such as EPO directly modify the ECM, contributing to tissue remodelling and the inflammatory response [80].

The mechanical properties of the tissue microenvironment, including stiffness and physical forces, also modulate eosinophil function. ECM stiffness is transduced intracellularly via integrin-mediated mechanosensing pathways, driving FAK phosphorylation and activation of the RhoA/ROCK signalling axis. This cascade regulates actin cytoskeleton reorganization [84], ultimately impacting eosinophil morphological plasticity and chemotactic migration capacity. Within the stiffened ECM of asthmatic airway remodelling zones, eosinophils exhibit enhanced morphological polarization, accelerated migration velocity, and augmented adhesion strength to the matrix, collectively promoting their recruitment to inflammatory foci [85]. Concurrently, fluid shear stress within blood vessels and tissue tension generated by contractile forces activate mechanosensitive ion channels such as Piezo1, triggering intracellular Ca²⁺ influx that modulates eosinophil activation states [86].

Eosinophils exhibit significant functional plasticity, enabling dynamic adaptation of their phenotype and functions in response to local signals. In allergic asthma, tissue-resident eosinophils acquire a distinct activation state characterized by upregulated expression of integrins CD11c and CD11b, alongside adhesion molecules, which facilitates their interactions with the ECM and other immune cells [87]. This tissue-activated phenotype mirrors eosinophils engaged in pulmonary morphogenesis, suggesting that evolutionarily conserved morphogenetic programs may drive eosinophil functionality across both physiological and pathological contexts. Furthermore, eosinophils interface with group 2 innate lymphoid cells (ILC2s) and CD4⁺ Th2 cells to establish a self-perpetuating inflammatory circuit that amplifies T2 immunity through cytokine-mediated feed-forward loops [88]. Eosinophil-derived IL-13 potently recruits and activates ILC2s. In turn, ILC2s amplify T2 inflammation by producing IL-5 and IL-13, which enhance eosinophil survival and activation through autocrine-paracrine signalling loops.

The pathogenic role of eosinophils extends beyond allergic asthma to encompass multiple T2 inflammatory disorders, including EoE, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and atopic dermatitis—all characterized by tissue-specific eosinophil infiltration driving core pathological manifestations. In EoE, eosinophil infiltration into the oesophageal mucosa drives tissue remodelling and fibrosis through the release of pro-fibrotic mediators such as TGF-β, which directly activate subepithelial fibroblasts and stimulate collagen deposition [89]. In CRSwNP, eosinophils serve as pivotal orchestrators of T2 inflammation [90]. Through the release of cytotoxic granule proteins (e.g., MBP and EPO) and pro-inflammatory cytokines (e.g., IL-5, IL-13), they drive polyp formation and sustain chronic inflammation by disrupting epithelial integrity and amplifying immune cell recruitment. Atopic dermatitis is also characteristically defined by eosinophil infiltration into the dermal compartment [91]. These cells potentiate pruritus and inflammation through the release of histamine, proteases (e.g., EDN), and pruritogenic cytokines, directly activating cutaneous sensory neurons and amplifying T2 immune responses.

Therapeutic strategies targeting eosinophils have shown promise in the management of allergic asthma and other eosinophil-associated disorders. The biologics mepolizumab and reslizumab are humanized anti-IL-5 mAb [92, 93], while benralizumab is a monoclonal antibody specific for the a-chain of the human IL-5 receptor [94–96]. These biologics have been demonstrated to be effective in reducing blood and tissue eosinophil counts, glucocorticoid usage, disease exacerbations, together with improved lung function in patients with severe refractory asthma. Additionally, interactions between eosinophils and other immune cells provide novel therapeutic angles for asthma. The crosstalk between eosinophils and ILC2s plays a significant role in allergic asthma pathogenesis. ILC2s promote eosinophil activation and recruitment through IL-5 and IL-13 release, while eosinophils reciprocally activate ILC2s via cytokine and chemokine secretion, establishing a pathogenic positive feedback loop [97]. However, the efficacy of these therapies varies across distinct asthma phenotypes, underscoring the necessity of developing personalized treatment approaches based on the underlying eosinophil biology and disease mechanisms.

While eosinophils clearly respond to signals from other leukocytes, most notably cytokines from Th2 cells such as IL-5, it has become clear that these cells in turn release cytokines and granule proteins that provide signals that promote local immune regulation and have an impact on the function of other leukocyte lineages [98]. Eosinophils have also been implicated in directing the functions of both B and T lymphocytes, including expression of MHC class II, the co-stimulatory molecules CD80 and CD86, together with the observation that eosinophils can process antigen and direct antigen-specific T cell proliferation and cytokine release [99, 100]. Eosinophils can also promote humoral immune responses by promoting the production of antigen-specific IgM [101] and supporting plasma cell growth and development in the bone marrow [102]. Eosinophils also interact directly with innate immune cells and have a role in supporting the viability of alternatively activated macrophages in adipose tissue [103], promote the migration and activation of myeloid dendritic cells [104], participate in extensive bidirectional signalling with tissue resident mast cells [105] and elicit production and release of pro-inflammatory mediators from isolated peripheral blood neutrophils [106].

As discussed above, eosinophils are recruited to the airways and are a prominent feature of the asthmatic inflammatory response, where they are broadly perceived as promoting pathophysiology. Respiratory virus infections can exacerbate this response. Among the recent concepts under exploration is the role of eosinophils in promoting antiviral host defence in this and other settings [107, 108], including the observation that eosinophils can respond to lipopolysaccharide from gram-negative bacteria by releasing mitochondrial DNA complexed with cationic proteins to form distinctive extracellular traps [109, 110]. There is also evidence for a role of eosinophils to provide host defence against bacteria in general and/or bacterial pathogens [111]. This hypothesis is particularly attractive, given the predominance of resident eosinophils in the intestines and the possibility of a more complex role involving eosinophils with commensal bacteria in the gut [112, 113].

Traditionally, eosinophils have been considered destructive agents in allergic responses, primarily due to their characteristic release of cytotoxic granules [114, 115]. However, emerging evidence demonstrates that eosinophils also play essential roles as regulators of homeostasis [116, 117], contributing to the defence against bacterial and viral infections [118], and even facilitating tissue repair [119, 120]. This evolving perspective has shifted the conceptualisation of eosinophils from being viewed solely as cytotoxic effector cells responsible for pathology to being recognized as multifunctional immunomodulators with regulatory capabilities. The ongoing debate focuses on the context-dependent function of eosinophils. Distinct subsets—regulatory and inflammatory—have been identified, and studies in conditions such as cancer [121] or inflammatory bowel disease (IBD) [122, 123] have reported conflicting results regarding their protective versus harmful effects. This challenges the simplistic view of eosinophils as either “friend” or “foe”.

It is now understood that not all eosinophils are identical. There are two main subsets: regulatory eosinophils (rEos) and inflammatory eosinophils (iEos), each distinguished by unique gene expression profiles and anatomical locations [124], challenging the idea of a single eosinophil function. The ongoing debate centres on whether eosinophil function is determined by pre-programmed subsets or by environmental plasticity [125, 126]. Advocates for the “subset” theory argue that eosinophils exist as developmentally distinct lineages, each characterized by specific surface markers and functional identities. For instance, iEos display signs of activation, such as increased granule density or cytoplasmic vacuolation [127]. These cells are typically marked by high expression of Siglec-F and CD101^hi, low expression of CD62L, and are highly dependent on IL-5 for survival [128, 129]. In contrast, rEos are typically found in healthy lung parenchyma, express CD62L and low levels of CD101, possess a ring-shaped nucleus, are largely IL-5 independent, and have the capacity to inhibit Th2 responses [130, 131].

Opponents of the fixed subset theory argue that eosinophils are highly sensitive to their microenvironment and “reprogram” their function upon entering a different tissue [132]. In fact, local signals (like IL-33 or TSLP) can induce eosinophils to express markers like CD80 or PD-L1, effectively shifting them from a “basal” state to an “activated” or “regulatory” state in response to local stress [133].

Studies confirm that eosinophils are highly adaptable cells, changing their function (phenotype) and abundance (frequency) to suit the requirements of different tissues like the gut or lungs [134]. In these contexts, they become crucial for tissue maintenance, repair, and immune regulation, influenced by local signals like the aryl hydrocarbon receptor in the gut [135].

Recent 2026 data suggest a residency-time model that bridges both views: Eosinophils continue to mature after entering tissues [136, 137]. In tissues like the small intestine, where they are long-lived (> 15 days), they undergo deep transcriptional reprogramming and diversify into multiple distinct, stable subsets with unique gene and protein signatures that support metabolic regulation and barrier integrity. In contrast, in tissues where they are short-lived, such as the lung (< 5 days), they remain more uniform as there is insufficient time for them to fully specialise. Consequently, in these tissues, they appear more homogeneous and “plastic”, responding quickly to acute inflammatory signals but forming stable, resident subtypes. In this view, this model suggests that eosinophil “plasticity and subsets” are two stages of the same biological process. Upon entering a tissue, all eosinophils initially exhibit plasticity, responding to local environmental cues (like IL-33 or TSLP). If the cell remains in a specific niche long enough, continuous exposure to these cues “locks” the cell into a fixed subset identity [137] (Table 1).

Our understanding of the immunological role of the eosinophil is continually evolving, from earlier dogma that emphasised a role in combating helminthic parasitic infections and as a key effector cell in allergic inflammation to more recent discoveries suggesting important roles in immunomodulation. Other emerging roles include functions against numerous pathogens such as respiratory viruses [98, 99], a role in gastrointestinal disease [138], and in interactions with nerves that impact the pathology of many diseases [139]. In summary, eosinophils play multifaceted roles in the pathogenesis of allergic asthma and other allergic diseases, encompassing complex interactions with the immune system, tissue microenvironment, and biophysical processes. Their functional plasticity and adaptability to local signals position them as central players in T2 inflammation and tissue remodelling. Understanding the biophysical aspects of eosinophil function, particularly interactions with the ECM and mechanical forces, may yield novel insights into disease mechanisms and therapeutic strategies. Future research should elucidate the molecular and biophysical determinants of eosinophil function across disease contexts, paving the way for innovative and targeted therapeutic approaches.

Eosinophils are central effector cells in both the physiology and pathology of the upper airways [140]. Normally, they participate in tissue maintenance and repair. Still, in response to inflammatory triggers, such as allergens, pathogens, and environmental irritants, their recruitment and activation initiate a cascade of events that underpin local tissue inflammation, resulting in epithelial injury, remodelling, and sustained immune cell infiltration [141, 142].

Eosinophilic infiltration of the sinonasal mucosa is a pathobiological hallmark across a wide spectrum of upper airway diseases associated with T2 inflammation. This inflammatory milieu is shaped by cytokines such as IL-4, IL-5, and IL-13, as well as epithelial alarmins including TSLP and IL-33, which further support the survival, activation, and migration of eosinophils, mast cells, and ILC2s [143–146].

Disorders such as AR and CRSwNP are among the most common diseases with an eosinophilic component. According to recent European data, CRSwNP affects nearly 11% [143] of the population, with marked geographic variations, while AR impacts approximately 10–23% of individuals in Western countries, ranking among the most prevalent chronic conditions globally [143]. The burden of these diseases is amplified by their frequent coexistence with other eosinophilic disorders, most notably asthma and non-steroidal anti-inflammatory drugs (NSAIDs)–exacerbated respiratory disease (N-ERD). For example, the prevalence of asthma in patients with CRSwNP reaches up to 50%, especially in severe and late-onset eosinophilic phenotypes, while in allergic fungal rhinosinusitis (AFRS), asthma coexistence has been reported in as many as 73% of cases [143]. N-ERD, which encompasses the triad of asthma, CRSwNP, and hypersensitivity to NSAIDs, is a classic example of the clinical and immunological continuum that links the upper and lower airways.

These strong associations have led to the unified airways disease concept, which views the respiratory tract as a single functional and immunological unit [143, 145, 146]. The clinical relevance of this model is underscored by evidence that treating upper airway inflammation can improve asthma outcomes, and, conversely, effective management of asthma may ameliorate sinonasal disease [147].

The degree of eosinophilic infiltration and activation has important clinical implications: It correlates with disease severity, the risk of recurrence after surgical intervention, and an increased likelihood of resistance to corticosteroid therapy. As such, eosinophils occupy a central role at the crossroads of innate and adaptive immunity and are now recognized as crucial therapeutic targets in upper airway diseases driven by T2 inflammation.

While traditionally associated with asthma, eosinophilic inflammation has also been recognized in other chronic airway conditions, including COPD and eosinophilic bronchitis (Table 3).

Eosinophilic COPD refers to a phenotype of COPD characterized by increased eosinophilic inflammation in the airways and/or peripheral blood [233, 234, 266, 267]. This phenotype is typically identified by elevated BECs, often using thresholds such as ≥ 2% of total leukocytes or ≥ 150–300 cells/μL, though there is no universally agreed-upon cutoff. The prevalence of eosinophilic COPD varies based on the diagnostic thresholds used: A BEC of ≥ 3% cells/µL identifies approximately 20% of COPD patients [268], while using a sputum eosinophil threshold of ≥ 3% increases the prevalence to 36% [269]. Some patients may only exhibit this eosinophilic phenotype during disease exacerbations (about 28% of COPD exacerbations) [268]. GOLD notes that BECs are a practical surrogate for airway eosinophilia, but they can fluctuate over time, are influenced by infections, comorbidities, and corticosteroid therapy [270]. Repeated measurements are often necessary to confirm persistent eosinophilic status, as single measurements may not reliably reflect the underlying inflammatory phenotype.

Notably, eosinophilic COPD occurs both in patients with and without a history of asthma [269], suggesting a distinct endotype rather than an overlap syndrome in many cases; therefore, its identification should not be limited to those with asthma-COPD overlap (ACO) [271]. It is present in approximately 20–40% of patients with COPD, independent of a history of asthma, and is associated with a T2 inflammatory profile, including increased IL-5, IL-4, and IL-13 activity, even in the absence of asthma [266, 270]. Molecular studies have shown similar T2 marker expression in eosinophilic COPD and eosinophilic asthma, but the T2 signature is generally more restricted and less robust than in asthma, and the correlation between eosinophilia and T2 markers is weaker in COPD than in severe asthma [272]. The eosinophilic subtype of COPD most commonly affects men, ex-smokers, individuals with higher body mass index (BMI), and those with a history of ischemic heart disease [273].

Why only some patients develop eosinophilic airway inflammation remains unknown. The mechanisms driving this phenotype are multifactorial and incompletely defined. Genetic predisposition, environmental exposures, and local immune microenvironments, such as spatially confined aggregates of T2 cells and eotaxin-producing cells, may contribute to the development of eosinophilic inflammation in only some individuals [270, 274].

The key pathophysiological mechanisms underlying eosinophilic inflammation in COPD involve both ILC2s and Th2 lymphocytes, which drive the production of IL-5 and other T2 cytokines [270, 274]. In eosinophilic COPD, ILC2s and Th2 cells are present in the airway mucosa and contribute to the local T2 immune microenvironment, as evidenced by spatial association with GATA3+ cells and patchy eosinophil-rich foci in lung tissue. IL-5 is central to eosinophilopoiesis, promoting eosinophil maturation, survival, and recruitment to the airways. Overexpression of IL-5, along with chemotactic signalling by eotaxin-1 (CCL11) and CCL24, facilitates eosinophil trafficking into the lung parenchyma. The patchy and focal nature of eosinophil-rich microenvironments in the lung further underscores this heterogeneity [274].

The GOLD Science Committee also noted that the airway microbiome may play a role, as eosinophilic inflammation is associated with distinct, non-Haemophilus-dominant microbiome patterns, in contrast to neutrophilic COPD [270]. It has been suggested that TSLP is upregulated in the airways of some patients with COPD and may contribute to eosinophilic airway inflammation by promoting T2 immune responses [275, 276]. However, the association between TSLP and eosinophilic inflammation in COPD is less robust than in asthma. While TSLP and its receptor are present and upregulated in COPD airways, the correlation between TSLP levels and BECs is not as strong as in atopic asthma, and some studies suggest that TSLP may be more closely linked to airway remodelling and non-eosinophilic inflammation in COPD [277].

The typical symptoms of eosinophilic COPD are chronic cough, exertional dyspnoea, and sputum production, often with persistent and progressive airflow limitation [267, 270]. A highly positive bronchodilator response (increase in FEV₁ > 15% and > 400 mL) in a patient with eosinophilic COPD is clinically significant because it suggests a phenotype with overlapping features of asthma and COPD, but not necessarily true ACO [278]. This degree of reversibility is uncommon in typical COPD and is more characteristic of asthma or ACO [271]; however, in eosinophilic COPD, it identifies a subgroup with heightened T2 inflammation and corticosteroid responsiveness [270]. Indeed, such patients are more likely to experience better responses to ICS therapy [279] with greater improvements in lung function and symptom control, and a marked reduction in exacerbation risk when ICS is continued. Conversely, withdrawal of ICS in these patients is associated with an increased risk of exacerbations, particularly in those with a history of frequent exacerbations and elevated BECs [270, 280].

Patients may also experience wheezing and are at increased risk for episodes of worsening dyspnoea, cough, and sputum, sometimes with increased sputum purulence. These symptoms are similar to those of non-eosinophilic COPD, but the eosinophilic phenotype is distinguished by a higher frequency of exacerbations, particularly those not associated with bacterial infection [268, 270, 281]. This is supported by evidence that higher BECs are associated with increased exacerbation risk, especially in those with a history of frequent exacerbations, and that these exacerbations are less likely to be driven by bacterial pathogens.

In contrast, eosinophilic bronchitis is a distinct cause of chronic cough characterized by sputum eosinophilia (> 3%) in the absence of variable airflow obstruction, airway hyperresponsiveness, or abnormal spirometry, features that differentiate it from asthma. According to the GOLD Science Committee, eosinophilic COPD represents a T2-high, corticosteroid-responsive phenotype with airflow limitation, whereas eosinophilic bronchitis is defined by isolated cough and sputum eosinophilia in the absence of physiological compromise [270]. Patients typically present with a chronic, non-productive cough, normal lung function, and no evidence of airway hyperreactivity on methacholine challenge testing [282, 283]. There is no dyspnea, wheezing, or airflow limitation, and patients do not experience the acute exacerbations characteristic of COPD [284]. While both eosinophilic bronchitis and eosinophilic COPD involve elevated eosinophilic inflammation, they differ significantly in pathophysiology. In eosinophilic bronchitis, the eosinophilic infiltration is limited to the bronchial mucosa, without the structural or functional changes seen in asthma or COPD [285].

The treatment approach for eosinophilic COPD differs from that for eosinophilic bronchitis in several key ways (Table 2). For eosinophilic COPD, GOLD recommends ICSs in combination with long-acting bronchodilators (LABA and/or LAMA) for patients with frequent exacerbations and elevated BECs, as these patients are more likely to benefit from ICS-containing regimens [237]. In select cases with persistent exacerbations despite optimal inhaled therapy and elevated eosinophils, biologic agents targeting T2 inflammation (such as anti-IL-5, such as mepolizumab and reslizumab, or anti-IL-5R therapies, such as benralizumab) may be considered, though their benefit is limited and not universal [270]. Indeed, these therapies do not significantly improve lung function or quality of life beyond what is achieved with standard inhaled therapy, and their use should be restricted to highly selected patients with persistent exacerbations and evidence of eosinophilic inflammation [286–288]. Dupilumab inhibits IL-4 and IL-13 signalling, which is central to T2 inflammation that is not fully addressed by anti-IL-5 therapies [286]. It has demonstrated a clinically meaningful role as an add-on therapy for patients with COPD who have evidence of T2 inflammation, specifically those with elevated BECs (≥ 300 cells/μL) and a high risk of exacerbations despite receiving maximum inhaled triple therapy [289, 290]. The effect is most pronounced in patients with higher eosinophil counts and/or elevated FeNO. The GOLD Science Committee specifically supports a phenotype-driven approach to ICS and biologic use in COPD [270]. However, mepolizumab is not approved for eosinophilic COPD by either the United States FDA or EMA, while dupilumab is approved for this indication by the FDA but not by the EMA (Table 4).

In contrast, the mainstay of treatment of eosinophilic bronchitis is ICSs alone, which are highly effective in reducing cough and airway eosinophilia, but the optimal dose and duration are not clearly defined in the literature [282, 283, 291]. Long-acting bronchodilators are not indicated because this condition is defined by the absence of variable airflow obstruction and airway hyperresponsiveness and does not feature the bronchoconstriction or exacerbation risk that these therapies are designed to address [291]. Systemic corticosteroids may be considered in exceptional cases where symptoms are severe and refractory to high-dose ICSs, but this is uncommon [291, 292]. Long-term systemic corticosteroid use is avoided due to well-established risks [293]. Biologic therapies should not be considered part of routine management for eosinophilic bronchitis, and their use should be limited to select, refractory cases after careful consideration of risks, benefits, and costs [294, 295].

Leukotriene receptor antagonists (e.g., montelukast) may be considered in select cases, but their efficacy in eosinophilic bronchitis is less well established, and they are not first-line [296]. Patients with eosinophilic bronchitis who are most likely to benefit from leukotriene receptor antagonists, such as montelukast, as alternative or adjunct therapy are those with coexisting atopic features (e.g., AR), aspirin-exacerbated respiratory disease, or exercise-induced symptoms, and those who are unable to tolerate or are poorly adherent to ICSs [296]. However, in patients with severe, corticosteroid-dependent disease and persistent airway eosinophilia, the addition of montelukast has not demonstrated significant further reduction in eosinophilic inflammation [297].

EGPA and allergic bronchopulmonary aspergillosis (ABPA) are considered clinical and pathological entities within the spectrum of eosinophilic-driven diseases. From a historical perspective, the description of these diseases has followed very different trajectories according to their natural history and the systems of classification.

Eosinophilic lung diseases include: 1) acute and chronic eosinophilic pneumonias (CEP) characterized by increased eosinophils in peripheral blood and bronchoalveolar lavage (BAL) fluid and/or by eosinophilic infiltration of lung parenchyma; 2) other lung diseases characterized by eosinophilic infiltration, like Lӧffler syndrome, ABPA, drug-induced EP, and EGPA—Churg-Strauss syndrome [314].

Eosinophilic lung disease may be acute or chronic, idiopathic or due to known causes, and is usually severe and does not resolve without treatment. High-resolution computed tomography (HRCT) is the gold standard imaging procedure for eosinophilic lung diseases diagnosis. Lung biopsy may be useful to characterize the histopathology of pulmonary eosinophilic infiltrates and define the diagnosis.

HESs are defined as a wide spectrum of diseases characterised by blood and/or tissue eosinophilia. These syndromes can present with a variety of clinical manifestations and cause hypereosinophilia (HE)-associated organ damage. Over the last few decades, the most difficult aspect of HES classification has been distinguishing between known causes of HE, such as parasitic, allergic, drug-induced, or malignant forms, and idiopathic forms. The latter are characterised by confirmed blood eosinophil levels of > 1,500/mm³ that have been sustained or persistent for a period of 2–4 weeks and are accompanied by eosinophil-mediated organ damage or dysfunction. However, the discovery of haematological variants of HESs characterised by identifiable molecular clonal mechanisms, as well as the description of organ-specific eosinophilic disorders such as CEP and eosinophilic gastrointestinal disorders, which are not necessarily accompanied by high BEC levels, has prompted a change in the practical approach to patients with hypereosinophilia [254].

Eosinophilic myocarditis (EM) is an inflammatory heart disease whose clinical presentation can be variable and complex, with a significant mortality rate [345]. Eosinophilic inflammatory infiltration is the characteristic histological feature and the target of treatment. Inflammatory myocardial cell damage is secondary to eosinophilic infiltration, often image of peripheral eosinophilia. Intramyocardial eosinophilic infiltration can range from mild to severe. Notably, the most common causes of EM are allergic reactions/hypersensitivity (34% of patients), EGPA (about 13%), early giant cell myocarditis, idiopathic HES (about 8%). It should also be emphasized that EM can also manifest itself during myeloproliferative disorders, infections also including parasitosis and malignancy [346, 347]. Moreover, it should be remembered that chemotherapy is not free from organ complications. Indeed, chemotherapy of acute myeloid leukaemia (AML) can also induce the onset of severe eosinophilia and consequently of EM among the possible cardiac complications [346]. Lipof et al. [348] described a case of AML with a pathogenic mutation involving plant homeodomain finger 6 (PHF6) and eosinophilia who developed EM. Furthermore, EM may be part of the visceral manifestations of chronic immune-mediated inflammatory diseases, including systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis (SSc), sarcoidosis, dermatopolymyositis (DPM), chronic IBD, EGPA, and other vasculitis [349]. It should be noted that giant cell myocarditis and necrotizing EM represent an autoimmune process. On the other hand, the borderline between EM and autoimmune myocarditis is extremely thin since it should never be forgotten that in addition to the intramyocardial eosinophilic infiltrate, it is now established that many heterogeneous factors play a role in the onset and maintenance of the inflammatory process. Among these, viral infections, HLA, gender, exposure to cryptic antigens, mimicry, and a deficit in thymic training/induction of Treg cells can certainly play a triggering role. Once the inflammatory process has been triggered, various elements of the immune response maintain the intramyocardial inflammation with specific immunopathogenic characteristics. Th17 cells favour the chronicization of the inflammatory process, as in any chronic immune-mediated inflammatory diseases [318, 350] that can clinically evolve into dilated cardiomyopathy. Chronicity is supported by fibroblasts, which in turn maintain inflammation through specific cytokines and consequently intramyocardial fibrosis [351–353]. Furthermore, eosinophils also support microvascular damage, resulting in activation of the coagulation process, and promote and maintain autoimmune activation [354, 355]. Notably, Barin et al. [356] demonstrated the important role of IFN-γ and IL-17A in the inflammation of EM, so much so that IFNγ^−/−IL17A^−/− mouse models developed rapidly fatal EM. There seems to be a genetic predisposition in some forms of EM. In particular, the HLA-DRB1*07 and HLA-DRB4 gene alleles have been shown to represent genetic risk factors for EGPA [357, 358]. In support of this, Wojnicz et al. [359] demonstrated a strong diffuse expression of HLA-A, -B, -C antigens localized exclusively on microvascular endothelium, other interstitial cells, and induced HLA-A, -B, -C antigens on cardiac myocytes in proximity to areas of inflammatory infiltration. Increased expression of HLA class II antigens found on endothelial cells and other interstitial cells. However, making a more realistic estimate of the incidence of EM does not appear simple, even if it would seem to be approximately 20% in hearts removed for transplantation and in 0.5% of unselected autopsies [360, 361]. However, the clinical and technical limitations of endomyocardial biopsy (EMB) and the fact that peripheral eosinophilia is not present in approximately 25% of patients still make EM difficult and underestimated. In confirmation of this, myocarditis still represents 6% of the causes of sudden cardiac death as reported in a Danish study [362]. There are no significant differences in the onset of EM between males and females, with an age at diagnosis of around 41 years if accompanied by histological examination and 46 years if only clinical and without histological examination [347].

However, EM, like any form of myocarditis, can manifest itself clinically in a paucisymptomatic form, or with severe manifestations including potentially lethal arrhythmias, cardiogenic shock, and even sudden death [363, 364]. It should be emphasized that approximately 40% of cases of acute myocarditis have a favourable evolution with spontaneous remission [365], while in the remaining patients, there is a chronicity supported by the anomalous immune response, with development of dilated cardiomyopathy and clinical progression towards heart failure [366, 367]. Patients usually complain of acute chest pain or tightness and dyspnoea, sometimes asthenia, nausea, and myalgia that can confuse the clinical picture. Laboratory tests show elevated levels of creatine kinase MB and troponin. In patients with EM during EGPA, in addition to bronchial asthma attacks, chronic rhinosinusitis, and nasal polyposis, the patient may develop myocarditis, pericarditis, coronary vasculitis, heart failure, and often peripheral neuropathy [368]. The prognosis is clear and will depend on the multiorgan involvement and the consequent damage. In suspected EGPA, ANCA should be tested, although these are generally present in ANCA-related nephritis, but often absent in cardiac involvement [369, 370]. In cases where there is an absolute eosinophil count greater than 1.5 × 10⁹/L for more than six months, the possibility of being faced with an HES must be taken into consideration. Therefore, it will be necessary to investigate the involvement of other viscera such as the bone marrow and the nervous system in addition to the heart. It should be remembered that HES can be idiopathic, i.e., without a well-defined cause, or secondary in most cases associated with myelo- or lymphoproliferative haematological diseases [354]. In patients with HES, in many cases, EM is paucisymptomatic/asymptomatic, while in the forms of chronic myocarditis, it evolves towards cardiac failure with dyspnoea and oedema of the legs. It is hoped that in the face of severe peripheral hypereosinophilia, the presence of skin lesions/rash and itching is sought and leads to the suspicion of HES [371, 372]. It should be noted that patients who develop EM do not always have peripheral eosinophilia and that it may appear later than the onset of EM [353]. There are no elements suggestive of myocarditis in the standard 12-lead electrocardiogram (ECG), while echocardiography can help exclude other possible causes of acute heart failure, including cardiomyopathies, genetic heart disease, and valvular heart disease, and the presence of associated pericardial effusion [373]. Cardiovascular magnetic resonance imaging (CMR) represents the gold standard diagnostic imaging for the confirmation of myocarditis. The Lake criteria, defined in 2009, allow to confirm the diagnosis of myocarditis with CMR. In particular, hyperemia, intracellular and interstitial oedema, necrosis, and fibrosis are considered specific markers, and are identified with T1 and T2 images, and with early and late acquisitions after infusion of gadolinium [374]. Notably, the acute phase is characterized by oedema that is hyperintense on T2 sequences. The chronic phase evolves into fibrosis or necrosis, with a patchy subendocardial distribution, highlighted on sequences with late gadolinium enhancement [375]. This allows us to differentiate chronic myocarditis fibrosis from post-ischemic fibrosis, which, on the contrary, has a transmural distribution along the territory of one or more coronary arteries [375]. In patients with EGPA-associated myocarditis, CMR, in addition to the typical features of acute/chronic inflammation, allows to confirm abnormalities of the coronary macro- and microcirculation and/or small vessel vasculitis, which occur during systemic vasculitis and also in subclinical cases [376]. Cardiac involvement in EGPA is extremely variable, so much so that three variants are recognized on the basis of cardiac enzymes, CMR, and EMB, namely EGPA-EM, chronic inflammatory myocarditis/cardiomyopathy, and EGPA-control [377]. However, EMB is the invasive diagnostic gold standard that allows confirmation of the presence of myocardial inflammatory infiltrates, non-ischemic degeneration/necrosis, and thus, the confirmation of myocarditis. The Dallas criteria include the histological elements [378]. It should be noted and underlined that the absolute contraindications for performing EMB are represented by acute myocardial infarction, left ventricular thrombosis, and ventricular aneurysm. Furthermore, the importance of EBM is also evident from the fact that it allows to define myocytolysis, which is characterized by severe interstitial and perivascular eosinophilia. The severity of myocytolysis depends on the degranulation of eosinophils and the action of the specific enzymes released, up to the most serious picture of necrotizing EM [379]. EM therapy involves both a pharmacological and a non-pharmacological approach. Physical activity should be limited in acute EM and for 6 months thereafter. The pharmacological approach primarily involves the administration of drugs that reduce myocardial remodelling such as low-dose beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and aldosterone receptor antagonists. The treatment of haemorrhagic EM is based on the administration of immunosuppressive agents, including high-dose corticosteroids, in order to limit the progression of cardiac damage, towards thrombotic necrosis and fibrosis. Corticosteroids have a potent anti-inflammatory action. The use of corticosteroids is the first-line therapy in EM associated with EGPA, HES, and EM hypersensitivity [353, 375]. There are still no definitive indications on the initial dosage of corticosteroids. However, good clinical practice suggests adjusting the initial dosage and duration of treatment to the severity of EM, and, therefore, to the presence and severity of left ventricular dysfunction, to troponin I levels, to whether EM was associated with EGPA, HES and, finally, to the evolution of inflammation, given their ability to induce rapid improvement also in cardiac kinetics. Useful in this regard during the follow-up, the outcome of any control biopsy and/or CMR [380]. The use of DMARDs, in particular cyclophosphamide, methotrexate (especially EM associated with EGPA), azathioprine, hydroxyurea, or interferon-α (especially in cases of steroid-refractory HES), in association with corticosteroids, represents the most indicated therapeutic armamentarium in the advanced stages of EM [381]. Among biological drugs, mepolizumab, a monoclonal antibody that acts by blocking IL-5, is gaining increasing consensus and represents an effective choice in EM associated with EGPA and HES, even initially in association with corticosteroid therapy, with the aim of reducing corticosteroid doses and preventing side effects [375]. Benralizumab, a humanized antibody against the IL-5 receptor, is proving effective in reducing eosinophilia in peripheral blood and tissues [381]. The administration of anticoagulant drugs should also be considered as prophylaxis in the acute phase of EM to prevent the formation of mural and intravascular thrombi, in subjects with persistent eosinophils that favor thrombotic and fibrotic evolution, determining the evolution in Loeffler’s endomyocarditis [382]. Finally, albendazole is indicated in the therapy of EM associated with helminthic infections [383].

The main mechanisms of pathogenesis and myocardial damage in EM are reported in Figure 2.

Eosinophilic gastrointestinal diseases (EGIDs) comprise a spectrum of chronic, immune-mediated disorders of the gastrointestinal tract that are defined by dense tissue eosinophilia in the absence of secondary causes. The spectrum includes EoE and the less common non-esophageal forms such as eosinophilic gastritis (EoG), enteritis, and colitis. While these conditions share key pathogenic mechanisms such as Th2-driven inflammation and epithelial barrier disruption, they differ in their anatomical location, clinical manifestations, histologic thresholds, and treatment strategies. In addition, eosinophilia is a hallmark of many parasitic infections, particularly those involving tissue-invasive helminths, where it may reflect both protective immunity and tissue-damaging inflammation. This chapter reviews the current understanding of EoE, non-esophageal EGIDs, and eosinophil-associated parasitic diseases, with emphasis on epidemiology, pathogenesis, diagnosis, and treatment, and highlights both shared mechanisms and distinct features across these conditions.

Anaphylaxis and drug reaction with eosinophilia and systemic symptoms (DRESS) are both severe hypersensitivity reactions, but they differ in onset and immune mechanisms. Anaphylaxis is a life-threatening, systemic hypersensitivity reaction characterised by its rapid onset and potential for fatal outcomes. It is mostly triggered by food, drugs, or insect stings. While the activation of mast cells and basophils via IgE-mediated pathways is widely regarded as the central mechanism driving anaphylaxis, increasing evidence indicates that other immune pathways, effector cells, and mediators may also contribute significantly to its pathophysiology [517, 518]. Among these, eosinophils play a secondary but potentially significant role in anaphylaxis by amplifying inflammation [518]. In contrast, DRESS is a delayed T-cell-mediated multisystem life-threatening drug hypersensitivity reaction mostly associated with anticonvulsants, antibiotics, and allopurinol, characterised by marked eosinophilia [519]. In DRESS, eosinophils are central to disease pathology, promoting tissue damage and systemic symptoms through the release of cytotoxic granules and proinflammatory mediators [519].

Eosinophils express receptors for IgE (FcεRI), IL-5, eotaxins, and other chemokines on their surface; their engagement induces their recruitment and activation and the release of a broad range of mediators including cationic proteins (EPX, MBP, ECP, EDN), lipid mediators (LTC4, PAF), and a variety of cytokines (IL-1, IL-3, IL-4, IL-5, IL-13, GM-CSF, TGF-a/b, TNF-a), chemokines (CCL3, CCL5, CCL11), and neuromodulators (SP, vasoactive intestinal peptide) [518]—which could sustain or augment the immune response.

Changes in eosinophils and eosinophil-derived proteins have been observed in both blood and tissues during or following anaphylactic reactions. Increased expression of eosinophil-related genes has been reported in patients presenting to emergency departments with severe anaphylaxis, as well as in murine models of anaphylaxis [520]. Additional evidence shows that eosinophil counts tend to decline during anaphylactic episodes, suggesting active migration from the bloodstream to target tissues [521]. This migration is associated with PAF, which not only recruits eosinophils but is also secreted by them—establishing a feedback loop that may intensify tissue inflammation and allergic symptoms [521]. Postmortem studies of fatal anaphylaxis cases reveal eosinophilic infiltration in bronchial smooth muscle [522] and elevated serum levels of ECP [523]. Similarly, patients with food-dependent exercise-induced anaphylaxis exhibit elevated serum levels of ECP and EDN, indicating eosinophil activation during anaphylactic episodes [524]. Recent findings suggest that while eosinophils are not essential for the acute phase of oral food allergen-induced anaphylaxis, they play a key role in early life by regulating mast cell proliferation and production of allergen-sIgE during sensitisation [525].

Eosinophilia associated with the use of drugs is not uncommon. In a Spanish study, using a Pharmacovigilance Program for Laboratory Signals based on abnormal laboratory values, 274 cases of drug-induced eosinophilia were identified among 164,379 admissions (incidence of 16.67 per 10,000 admissions). Of the 274 cases, 154 (56.2%) were asymptomatic hypereosinophilia, but there were 64 cases of potential DRESS, which is the main drug reaction associated with eosinophilic inflammation [519]. The diagnosis of DRESS is based on characteristic clinical features, laboratory findings, and the use of several scoring systems: the Bocquet criteria, the RegiSCAR criteria (the most frequently used in Europe), and the Japanese J-SCAR criteria; all of them refer to eosinophilia (> 1.5 × 10⁹/L) as a diagnostic feature [526]. While eosinophilia is present in over 90% of reported cases, DRESS can occasionally occur with normal eosinophil levels [527]. Hematological abnormalities, including atypical lymphocytes and elevated eosinophil counts, are defining features of DRESS.

The pathophysiology of DRESS is multifactorial and associated with aberrant drug metabolism, specific human leukocyte antigens, and viral reactivation of latent infectious, especially of the Herpesviridae family. Viral reactivation seems to play an important role in promoting and sustaining abnormal T-cell and eosinophil responses to drugs and other offenders, leading to organ damage. The main proposed mechanisms of drug-induced T cell activation in DRESS are the hapten/prohapten, the pharmacological interaction (p-i concept), and the altered self-peptide model [528]. Drug-specific T-cells infiltrate the dermis and visceral organs, releasing cytotoxic proteins like granulysin, granzymes, and perforin. The expansion of regulatory T cells (T-regs) and T helper cells (Th1 and Th2) occurs especially in a later stage of DRESS [529]. Eosinophils may be stimulated by IL5 from innate-like lymphoid cells after alarmin release from infected and damaged cells, promoting a shift of CD4+ T cells to a Th2 profile with an increase of IL4, IL5, and IL13. Besides primary eosinophil activation following cell damage, systemic eosinophilic responses may be sustained by T-cell activation. IL-5 in synergy with other Th2-associated chemokines (TARC and macrophage-derived chemokine) promotes further eosinophil attraction, activation, proliferation, and infiltration in tissues, leading to eosinophilic inflammation and tissue damage due to the release of its toxic mediators from granules (MBP, EPO, EDN), enzymes, and an extensive panel of cytokines.

The most common histopathological findings in DRESS are dyskeratosis, spongiotic changes, vacuolisation, perivascular lymphocytic infiltration, and eosinophilic infiltration. More severe DRESS is associated with increased keratinocyte necrosis [530]. CD4+ and CD8+ T lymphocytes are identified in biopsies of the skin and of the internal organs. IL-5 produced by the Th2 cells and innate lymphoid cells induces differentiation, activation, and migration of eosinophils to the peripheral blood and to tissues, which explains the eosinophilia.

Persistently elevated eosinophil counts are thought to correlate with the organ damage and eosinophil infiltration of tissues such as the skin, the liver, the heart, and the nervous system. Although tissue damage is often driven by drug-specific T lymphocytes, eosinophils may directly contribute to complications such as EM. In fact, the myocardium is a preferential site for eosinophilic infiltration, and myocarditis is one of the main prognostic factors in DRESS patients.

A recent retrospective study showed a correlation between cardiac involvement and the degree of eosinophilia. Patients exhibited high eosinophil counts and elevated levels of ECP, which correlated with higher RegiSCAR scores, supporting the role of eosinophils in DRESS pathogenesis. The study proposed including ECP measurements in routine evaluations for DRESS [531].

Another indirect evidence of the implication of IL5 and eosinophils in the pathophysiology of DRESS is the rising data pointing to the potential benefits of the use of biological agents targeting the IL-5 axis (IL-5 antagonist mepolizumab and reslizumab or the IL-5 receptor blocker benralizumab) in the treatment of complicated or steroid-resistant DRESS, drugs that are already FDA and EMA approved for other eosinophilic disorders [532].

In summary, eosinophils play a multifaceted role in the pathophysiology of anaphylaxis and DRESS, though their involvement differs in extent and mechanism. While they are less central than mast cells in the immediate allergic response in anaphylaxis, their ability to modulate immune activity and promote prolonged inflammation positions them as potential therapeutic targets. Despite these findings, eosinophils appear to play a less dominant role in anaphylaxis compared to asthma. Further research is needed to fully elucidate their mechanisms and to explore new treatment strategies. In contrast, eosinophilic inflammation is a hallmark of DRESS, where eosinophils are key effectors contributing directly to tissue damage and organ dysfunction. Persistent eosinophilia, elevated eosinophil-derived proteins, and eosinophilic infiltration correlate with disease severity. Given their pathogenic role, particularly in DRESS, targeting the IL-5/eosinophil axis offers a promising therapeutic approach for severe or steroid-refractory cases in both conditions.