The concept of “hypereosinophilic syndromes” (HES) was introduced by Hardy and Anderson in 1968 (1), and Chusid et al. later suggested in 1975 diagnostic criteria for HES (2). These readable and easy-to-use criteria comprised chronic (i.e., longer than 6 months) hypereosinophilia (HE) (i.e., above 1.5 × 10⁹/L) with no identifiable cause, associated with clinical manifestations. Nowadays, given the various identified molecular mechanisms underpinning HE (e.g., T-cell-dependent IL-5 production, clonal abnormalities of the myeloid lineage) and the subsequent heterogeneity of diseases encompassed in the spectrum of HES, this first set of diagnostic criteria has become outdated. Hereafter, we will review the main classifications in HES, and discuss their strengths and potential pitfalls.

Initially, the concept of HES was commonly applied to patients with multi-organ damage (often involving the heart) and unexplained chronic HE above 1.5 × 10⁹/L. Yet, different clinico-biological phenotypes were already observed in the first published series of patients with HES, suggesting that various underlying pathophysiological processes could be involved (2, 3). Hence, a subgroup of patients presented with features suggestive of myeloproliferative neoplasm (i.e., anemia, splenomegaly, myelofibrosis, etc.), which led to the concept of myeloproliferative (“leukemic” for Chusid) HES. Decades later, clonal abnormalities involving fusion transcripts (among which PDGFRA and PDGFRB genes) were identified in the same subgroup of patients, thereby validating ex post the initial hypothesis (4). Next, the lymphoid variant of HES was defined in another subgroup of patients with dermatologic manifestations that responded to corticosteroids and were originally classified as hypersensitivity (or non-malignant or allergic) HES but in which abnormal clonal T-cells (e.g., CD3⁻CD4⁺ T-cells) that produced eosinophilopoietins were later identified (5).

In the early 2000s, numerous expert classifications embedded the above-defined concepts of molecularly defined myeloproliferative-HES, lymphoid HES, and idiopathic HES (when no molecular or immunological abnormality can be found) (6, 7). Yet, less than two decades later, these classifications already seem outdated due to recent major breakthroughs in molecular biology. Currently, the two main—and partially redundant—classifications are the one proposed by the WHO (which covers only primary/neoplastic HES) (8) and the one proposed by the International Cooperative Working Group on Eosinophil Disorders (ICOG-EO) in 2011 (9). The ICOG-EO (an international and multidisciplinary panel of experts) agreed on unifying terminologies and criteria, and suggested a classification that delineates various forms of HE and HES (including primary and secondary variants) based on specific hematologic and immunologic conditions.

In the 2005 and 2010 classifications of HE/HES, experts brought to the forefront “good old fashioned” features suggestive of a myeloid neoplasm (i.e., hepatosplenomegaly, increased serum vitamin B12 or tryptase, anemia, thrombocytopenia, myelofibrosis) as criteria for “myeloproliferative-HES,” even in the absence of a molecularly proven HES_N (6, 7). With the exception of the blast cell count, the ICOG-EO and WHO classifications have nearly completely excluded these patients—which are now classified as HES_I—from the field of HES_N. This distinction of patients with presumed myeloid neoplasm is clinically relevant as response to different treatment options differs (less response to steroids, more likely to respond to imatinib). Hitherto, such patients carry a guarded prognosis [the latter being closer to HES_N than that of other HES_I patients (13, 14)] and, as patients with HES_N, may require treatment with tyrosine kinase (TK) inhibitors, cytotoxic drugs, or even bone marrow transplantation. Hence, the current distinction between patients with molecularly defined HES_N from those with similar clinical features but without any identifiable mutation is questionable, and it seems desirable that further updates of HE/HES classifications should individualize these myeloproliferative-HES patients as a specific subgroup even in the absence of an identified mutation.

Next, due to the development of new sequencing methods and tools in malignant hematology [especially the next-generation sequencing (NGS)], the field of neoplastic HES has considerably evolved. Since the FIP1L1–PDGFRA fusion transcript gene was discovered in 2003, the list of genetically defined HE has regularly been implemented over the years and now comprises 72 distinct entities consisting mostly of TK fusion genes (10).

The identification of numerous mutations in myeloproliferative disorders and myelodysplastic syndrome raise the question whether these new mutations should be included in further classifications of HES. Two recent studies report NGS results in two cohorts of 98 and 51 patients with HE_US and/or HES (15, 16). Interestingly, such mutations (including ASXL1, TET2, SETBP1, CSFR3, and SF3B1) were identified in 11 and 28% of patients, respectively, suggesting that a significant proportion of patients otherwise classified as HE_US and/or HES_US might rather belong to the HE_N and HES_N subgroups. Yet, none of these studies provided convincing elements demonstrating the transforming capacity of these mutations, suggesting that they may not be the true driving mutation for HES/HE_US. In addition, the impact of NGS-identified mutations on survival remains an open question, a poorer prognosis in patients with NGS-mutations being suggested in a single study (16). Hence, NGS seems to be a highly powerful tool to identify molecular defects in HE/HES. Yet, large prospective registries are needed in order to evaluate its potential usefulness in daily practice regarding patients’ treatment and prognosis, before this tool be included as a new criterion for HE_N or HES_N.

Many pathologic conditions can induce reactive blood and/or tissue eosinophilia (HE_R), due to the overproduction of eosinophilopoietic cytokines, mostly IL-5. Yet, in many of these situations, skin and organ damage seem to be due to an autoimmune process (e.g., bullous pemphigoid), a malignant disease (e.g., cutaneous lymphoma, histiocytosis, mastocytosis) or to the massive tissue infiltration by IgG4⁺ plasma cells (e.g., IgG4-related disorders) rather than to eosinophilic tissue infiltration. From a pathological viewpoint, substantial effort (including assessment of extracellular deposition of eosinophil granule proteins by immunohistostaining) has been made by the ICOG-EO classification to define eosinophilic tissue infiltration. Yet, these laboratory techniques are often neither standardized nor performed routinely, and not used as a diagnostic tool in daily practice.

On the other side, in some patients with solid cancer, lymphoma or helminthiasis, a pronounced blood and tissue eosinophilia may occur in organs other than those affected by the underlying disease. In such situations, a true eosinophilic endomyocardial fibrosis due to eosinophil toxicity—as well as many other organ involvements—have been reported. Hence, physicians must be aware that the same disease may induce a bystander blood and/or tissue HE without meaningful consequences related to eosinophils, or a true reactive HES_R.

According to the clinical context, the initial workup of an unexplained HE/HES must include broad investigations in order to rule out with certainty an underlying disease likely to favor HE_R/HES_R. The choice of keeping HES_R as part of the ICOG-EO’s nosology has clinical implications: (1) HES_I is an exclusion diagnosis which supposes that all etiologies of HES_R must be excluded and (2) the treatment of the underlying cause may reverse HE_R, but in case of organ damage and/or dysfunction attributable to tissue HE (i.e., HES_R), corticosteroids may be considered from the outset in addition to the treatment of the underlying disease.

HES_L, a subtype of HES_R, is a chronic clonal indolent T-cell lymphoproliferative disorder in which mature peripheral T-cells secrete high amounts of IL-5, leading to the polyclonal expansion of eosinophils. Hence, to some extent, HES_L can be considered as the archetype of Th-2 driven eosinophilic disorders (17). Patients can be aymptomatic or poorly symptomatic for years, with HE being the sole manifestation of the indolent T-cell proliferative disorder (18). Diagnosing HES_L is important for three reasons: (1) its treatment can differ from that of HES_I, notably because of frequent corticosteroid dependency requiring additional corticosteroid-sparing-treatments, (2) clonal T-cells that are found in blood and tissues of HES_L patients can be mistaken for aggressive T-cell lymphoma, and patients wrongly treated as such with chemotherapy, and (3) authentic T-cell lymphomas (e.g., angioimmunoblastic T-cell lymphomas) may occur during disease course of these patients, who should be closely monitored (18–20).

Diagnosing HES_L usually requires the detection of an abnormal T-cell subset in the peripheral blood. Experts agree that three main subsets of HES_L must be systematically searched by flow cytometry: CD3⁻CD4⁺TCRab⁻, CD3⁺CD4⁺CD7⁻, and CD3⁺CD4⁻CD8⁻TCRab⁺ (21). Although lacking specificity, further confirmation of HES_L is supported by a clonal TCR rearrangement.

Yet, a clear definition of what should (or should not) be diagnosed as HES_L is lacking in all current classifications. Pertinently, should a cutoff of absolute or relative counts of such abnormal T-cells be defined? Is the demonstration of their ability to produce high levels of IL-5 necessary? Is a clonal TCR rearrangement necessary or sufficient to define HES_L? Could other abnormal subsets of blood cells (e.g., type 2 innate lymphoid cells) define HES_L? Last, several biological biomarkers such as IL-5, CCL-17/TARC, IgE, which demonstrated in many studies potential utility in their ability to distinguish between various subtypes of HES (18, 22) could also be added as additional diagnostic criteria in future classifications.

The concept of HES has evolved considerably since the first classification by Chusid in 1975, and the recent ICOG-EO classification has successfully embedded most of the field’s recent breakthroughs. These include, albeit not exclusively, the identification of numerous TK fusion genes, the concept of HES_R (among which HES_L), and the need for a clear histopathological definition of eosinophilic tissue infiltration. Moreover, this classification puts an end to many longstanding issues in the HE/HES domain and is a useful tool for the physician in daily care, allowing for better classification of patients between single-organ disease, HES_N, HES_R, HES_I, and HE_US (a condition that does not require therapy). Nevertheless, due to the lack of large prospective cohorts of HE/HES patients, one major limitation of the ICOG-EO classification is that it is mainly expert based and, thus, remains low-evidenced. Pertinently, many points (e.g., the need for a clear definition of HES_L; how to treat patients with a myeloproliferative phenotype but for whom a clonal mutation is not (yet) evidenced; improving the diagnostic workup of patients suspected of ANCA-negative EGPA versus HES_I) are open for improvement and should be the starting point of future HE/HES-targeted research. Hence, the implementation of international multicentric registries is awaited in order to improve current classifications of HE/HE and subsequently patient care.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest. The handling editor declared a past supervisory role with one of the authors GL.