Proposed refined diagnostic criteria and classification of eosinophil disorders and related syndromes

Abstract

Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE-induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be "non-clonal" cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials.

Keywords: classification; diagnostic criteria; eosinophilic leukemia; hypereosinophilic syndrome; personalized medicine.

FIGURE 1

Diagnostic algorithm for patients with documented hypereosinophilia (HE). Patients with documented HE are examined for the presence of an underlying disease (etiology) and for the presence of eosinophil‐induced organ damage by applying basic diagnostics and specific staging investigations as well as specific molecular, laboratory, immunologic, hematologic, morphologic, and histopathologic investigations. The initial basic investigation includes a family history which may reveal familial HE (HE_FA). In a next step, clinical and laboratory features of a reactive process are documented or excluded. In the case of a secondary reactive HE (HE_R), the underlying disease process (inflammation, infection, tumor, others) needs to be defined. When no underlying reactive condition, no sign of clonality (neoplastic condition), and no signs of overt organ damage are found the provisional diagnosis is HE of unknown significance (HE_US). These patients must be carefully monitored over time. When neoplastic HE (HE_N) is detected, the final diagnosis of an underlying hematologic neoplasm must be determined by using WHO criteria and criteria provided by the ICOG‐EO group. When HE is accompanied by specific (HE‐induced) (multi)organ damage, the diagnosis of HES can be established. HES can occur in any type of HE and can present as secondary/reactive HES (HES_R), primary/neoplastic HES (HES_N), or idiopathic HES (HES_I).

FIGURE 2

Diagnostic algorithm for patients suffering from hematologic diseases accompanied by clonal/neoplastic hypereosinophilia (HE_N). In a first step, the presence of HE must be confirmed by measuring blood counts and the percentage of eosinophils by microscopy. In a next step, leukocytes are examined by PCR and next‐generation sequencing for the expression of certain gene variants known to be present in myeloid and stem cell neoplasms associated with HE. In addition, leukocytes from the bone marrow or blood are examined for specific abnormalities by conventional karyotyping and fluorescence in situ hybridization (FISH). At the same time, the underlying stem cell or myeloid neoplasm is defined by detailed studies of bone marrow and blood cells, including histomorphological, immunohistochemical, immunological, and biochemical analyses. When the patient is suffering from a lymphoid neoplasm (NHL), HE is considered to be non‐clonal and the diagnosis usually changes to HE_R. In a final step, the patient is examined for the presence of signs and symptoms of specific organ involvement that could qualify as HE syndrome (HES). Here, it is of utmost importance to explore the case history and to ask the patient about previous potential HES‐related events, such as a thromboembolic complication. Abbreviations: +HES, with concomitant hypereosinophilic syndrome; AML, acute myeloid leukemia; CEL, chronic eosinophilic leukemia; CMML, chronic myelomonocytic leukemia; FISH, fluorescence in situ hybridization; HE, hypereosinophilia; −HES, without HES; NHL, Non Hodgkin lymphoma; PDGFR, platelet‐derived growth factor receptor; SM, systemic mastocytosis

FIGURE 3

Organs potentially involved in patients with HE and HE‐related organ damage (HES). Compilation of disorders that are accompanied by eosinophilia and affect distinct organ systems. Organ involvement depends on the underlying etiology (disease), the exogenous (infectious), molecular and immunological triggers, and the number and degree of activation of infiltrating eosinophils. In patients with HES, multiple organs may be involved, and the same holds true for patients with defined syndromes, such as Gleich's syndrome or patients with eGPA. However, there are also patients with HES or other conditions accompanied by HE where only a single organ system is involved. Examples are eosinophilic colitis, eosinophilic gastritis, or eosinophilic pneumonia. In cases with primary (neoplastic) HES, the cardiovascular system is often affected, but cardiovascular complications may develop in any form of HES. Abbreviations: eGPA, eosinophilic granulomatosis with polyangiitis.