In this article, we have chosen to adopt the classification scheme proposed by Klion et al., on behalf of the Hypereosinophilic Syndromes Working Group that reached a consensus in Bern in 2005 1. Under the umbrella diagnosis of "Hypereosinophilic Syndromes", various disease presentations and pathogenic variants are divided in subgroups (see bullets below). This approach offers the advantage of providing physicians with the full array of differential diagnosis, once underlying diseases (parasitic, allergic, neoplastic etc.) classically known to be associated with hypereosinophilia are excluded by thorough patient evaluation. It provides a basis for developing a diagnostic and therapeutic management algorithm of chronic eosinophil-mediated disease.

The following terms are currently used in medical literature to qualify different patient subsets among those fulfilling the diagnostic criteria of HES:

• FIP1L1-PDGFRA(F/P)-associated HES, or F/P⁺ HES, for patients with clonal hypereosinophilia due to a sporadic hematopoiëtic stem cell chromosomal rearrangement resulting in fusion of two genes (FIP1L1 and PDGFRA) on 4q12; these patients are more appropriately classified as F/P⁺ chronic eosinophilic leukemia.

• Chronic eosinophilic leukemia (CEL), for patients in whom clonality of eosinophils has been demonstrated (including those with the FIP1L1-PDGFRA fusion), or who present increased blasts; occasional reports indicate that some patients with CEL progress towards acute myeloid or eosinophilic leukemia.

• Lymphocytic-HES (L-HES), for patients with chronic reactive (polyclonal) hypereosinophilia secondary to IL-5 over-production by T cells.

• Myeloproliferative-HES (M-HES) may be used for patients with an array of clinical and biological features suggesting the possible existence of an underlying myeloproliferative disorder associated with hypereosinophilia, although underlying molecular defects are not detected (including increased serum vitamin B12, hepato- and/or splenomegaly, anemia and/or thrombocytopenia, circulating myeloid precursors, dysplastic eosinophils, bone marrow hypercellularity with left shift in maturation, myelofibrosis, increased serum tryptase, and response to imatinib); this term is occasionally extended more largely to include patients with known molecular defects (e.g. F/P⁺ CEL or other rare fusions involving the PDGFRA gene) as well.

• Idiopathic hypereosinophilic syndrome, for patients in whom underlying pathogenesis remains unknown.

• Organ-restricted eosinophilic disease, such as eosinophilic esophagitis, eosinophilic gastro-enteritis, eosinophilic dermatitis, eosinophilic pneumonia, Kimura's disease, eosinophilic fasciitis etc., for patients in whom a specific organ or tissue is the exclusive target of eosinophilic infiltration and damage.

Terms such as disseminated eosinophilic collagen disease or Löffler's fibroplastic endocarditis with eosinophilia were used previously to reflect end-organ damage (disseminated or cardiac, respectively) due to direct toxicity of circulating eosinophils in patients with persistent hypereosinophilia, but are currently out-dated.

The clinical manifestations of HES are variable from one patient to another, depending on target-organ infiltration by eosinophils. Organ damage and/or dysfunction develops as a result of eosinophil release of a number of cytotoxic substances, including highly cationic molecules such as eosinophil cationic protein (ECP) and major basic protein (MBP), the ribonuclease eosinophil derived neurotoxin (EDN), oxydating molecules such as eosinophil peroxidase (EPO) and free oxygen radicals, and enzymes such as elastase and collagenase 6. Eosinophils are also able to produce lipid mediators, such as leukotrienes and prostaglandins, which contribute to clinical complications through effects on vascular and bronchial smooth muscle tone. Finally, their ability to secrete cytokines (including pro-inflammatory, Th1 and Th2 cytokines) and chemokines makes them more sophisticated participants in the immune response than was once thought 19. Eosinophilic inflammation is associated with a pro-fibrotic environment, as release of TGF-β by activated eosinophils leads to increased collagen synthesis and extracellular matrix deposition. Other mediators of eosinophil-induced tissue remodeling are the subject of research efforts.

Although virtually any tissue or organ can be affected in HES, clinical complications arise most frequently (in more than 50% of patients) in the skin, heart, lungs, and nervous system 5:

• Cutaneous manifestations are common and non-specific, and generally consist either in angioedematous and urticarial lesions, or erythematous, pruritic papules and nodules resembling eczema. In patients with L-HES, such lesions are often the predominant clinical complication of hypereosinophilia 1620. Typical features that compose Gleich's syndrome, or episodic angioedema with eosinophilia, have been reported in some patients with L-HES 202122. Mucosal ulcerations are possible, especially in patients with F/P-associated HES 13.

• Cardiac involvement generally evolves in three stages. The early necrotic stage which involves the endo-myocardium is often asymptomatic, but may present as acute heart failure in rare instances. This stage is followed by a thrombotic stage in which thrombi develop along the damaged endocardium in the cardiac chambers and may detach, causing peripheral emboli. In the final fibrotic stage, endomyocardial fibrosis results in irreversible restrictive cardiomyopathy, and damage to atrioventricular valves may lead to more acute presentations with congestive heart failure 23. Endomyocardial fibrosis is the most pre-occupying non-malignant complication of F/P-associated disease, as it is generally irreversible 24. Chest discomfort, cough, dyspnea or orthopnea, edema of the lower extremities are typical symptoms reflecting cardiac involvement, and patients may develop arrhythmias.

• Neurological manifestations may involve both central (diffuse encephalopathy) and peripheral (polyneuropathy) nervous systems. Diffuse encephalopathy presents as altered behavior and cognitive function, confusion, and memory loss. Peripheral neuropathies present as symmetric or asymmetric sensory changes, pure motor deficits, or mixed sensory and motor complaints. Stroke or transient ischemic episodes may occur following peripheral embolism of intracardiac thrombi. Thrombosis of intracranial veins (longitudinal and/or lateral sinus) is a possible complication of the pro-coagulant state associated with persistent hypereosinophilia in some patients. To date, no patients with L-HES have been reported to present neurological complications, in contrast to F/P⁺ and idiopathic patients.

• Lung involvement can range from chronic dry cough and/or bronchial hyperreactivity in absence of radiological abnormalities, to restrictive disease with pulmonary infiltrates. The latter may occur more frequently in patients with F/P-associated disease 13. In rare instances, development of acute respiratory distress syndrome has been reported. Pulmonary fibrosis may develop after prolonged disease.

• Hematological manifestations include anemia, thrombocytopenia, hepatomegaly and splenomegaly, all of which are more typically encountered in association with the F/P fusion 1325. Mild lymphadenopathy is occasionally observed in patients with L-HES; and appearance or modification in size of lymph nodes should arouse suspicion of T cell lymphoma.

• Coagulation disorders may be observed in HES, and it is believed that chronic hypereosinophilia may cause damage to the endovascular surface, accounting for peripheral vasculopathy, and may also activate coagulation directly. Special attention should be paid to the presence of nail-fold splint hemorrhages, as peripheral thromboembolic phenomena may result in occlusion of terminal vessels in some patients 26 (e.g. digital necrosis).

• Gastrointestinal symptoms may include abdominal pain, diarrhea, nausea and vomiting. Eosinophilic gastritis, enterocolitis, or colitis may be present, and the latter may be associated with ascitis if eosinophilic infiltrates involve deeper layers of the intestinal wall. Such digestive complications are observed in all forms of HES, including those with unknown pathogenesis.

• Constitutional symptoms include weakness, fatigue, anorexia, fever, night sweats, weight loss, arthralgia and myalgia.

HES patients are also heterogeneous with regard to associated biological features. Total leukocyte counts can be normal or increased, and absolute eosinophil numbers are often well over the defined 1.5 × 10⁹/L. A number of hematological abnormalities may be observed in peripheral blood, especially in F/P⁺ disease, including presence of myelocytes, thrombocytopenia or thrombocytosis, and anemia. Marked increases in serum vitamin B12 levels are observed in patients with F/P⁺ disease, and are considered as indicative of M-HES (i.e. probable myeloproliferative disorder due to yet unidentified molecular defects), together with the above-mentioned hematological abnormalities and organomegaly 1325. High serum immunoglobulin E (IgE) levels and polyclonal hypergammaglobulinemia are more typical of, but not restricted to, L-HES 20.

Chusid's initial paper and the following published series clearly illustrated the great clinical heterogeneity and highly variable prognosis of HES, ranging from paucisymptomatic disease requiring no treatment and associated with prolonged survival, to rapidly fatal disease course due to the sudden development of congestive heart failure or acute leukemia. With the recent distinction of myelo- versus lympho-proliferative variants, subgroups of patients with more homogenous clinical profiles can be defined. Thus, patients with F/P-associated disease often present heart involvement and mucosal ulcers, and are overall more likely to develop disease-related morbidity and mortality 13, whereas patients with L-HES often present predominant cutaneous manifestations, while their cardiovascular system is often spared 20. As for long-term hematological outcome, patients with F/P-associated disease are at risk for developing acute leukemia (eosinophilic or myeloid) 25, at times shortly after diagnosis of HES, while patients with L-HES are at risk of developing T cell lymphoma, generally after many years of indolent pre-malignant disease 16202728.

Although prognosis of HES was very poor when the syndrome was first described (88% mortality at 3 years, see 3), it has steadily and significantly improved over time for a number of reasons including earlier detection of complications, better surgical management of cardiac and valvular disease, and use of a wider spectrum of therapeutic molecules for controlling hypereosinophilia. Currently, prognosis depends on two major aspects of disease: heart involvement and the increased likelihood of developing hematological malignancies. It is likely that current and future therapeutic strategies taking pathogenic disease variants into account will further improve outlooks for patients with HES in the near future.

As mentioned in the paragraph on diagnosis of disease variants, optimal patient management relies on early testing for the F/P fusion gene. There is general consensus among experts in the field that patients in whom this chromosomal rearrangement is detected should be treated with the tyrosine kinase inhibitor imatinib (Gleevec^®) as first line therapy 1. A number of clinical studies showing the striking rapidity and potency of its effects in this selected patient population have been published, and to date, no case of primary resistance to the molecule has been reported 10112432. Response to therapy in terms of eosinophil levels occurs within days in most cases, and many clinical manifestations can be reversed (including dermatitis, mucosal ulcers, restrictive lung disease, gastrointestinal involvement, central nervous system manifestations, certain cardiac manifestations, anemia, thrombocytopenia, and splenomegaly). The dose required to induce and maintain remission is generally lower (100 mg/day) than for patients with CML (≥ 400 mg). Influence of imatinib on clinical manifestations related to HES heart involvement are variable, and some authors have reported that endomyocardial fibrosis and related loss of function are not reversible 2425. Reversal of bone marrow pathology and molecular remission, a major endpoint when dealing with disease mediated by constitutively activated tyrosine kinases, can be achieved in most patients with the F/P fusion gene 2433. Overall, imatinib used at doses effective for HES is well tolerated, as most side effects including edema, muscle pain and fatigue, are dose-dependent. However, there is some concern regarding adverse effects of imatinib on heart function. Firstly, a few F/P⁺ HES patients have developed severe congestive heart failure within days after initiation of therapy, and this was felt to be due to massive liberation of toxic eosinophil contents following imatinib-induced eosinophil death 3435. Rapid administration of corticosteroids has proven effective in handling this preoccupying complication 34. Authors have suggested that heart function be monitored closely prior to and at the beginning of treatment, and serial measurements of cardiac troponin T be performed to predict this potentially fatal adverse event. Patients with increased levels prior to therapy should be treated preventively with corticosteroids a few days before initiating imatinib. Secondly, a recent study investigating cardiomyocytes from CML patients treated with imatinib (generally used at higher doses than for HES patients) and subsequently developing left ventricular dysfunction (after a mean of 7.2 months of treatment), has shown presence of membrane whorls and pleomorphic mitochondria with effaced cristae 36. The mechanisms underlying imatinib-induced myocyte toxicity were investigated in mice, in which mitochondria were also identified as the chief target of this compound. Energy rundown due to mitochondrial dysfunction was shown to be responsible for cardiotoxicity.

Relapse of hypereosinophilia during treatment with imatinib has been reported in two F/P⁺ patients, and was associated with appearance of a T674I point mutation in the ATP-binding site of the PDGFRA moiety, similar to the T315I mutation observed in patients with CML that become refractory to treatment 1037. It has been recommended that the dose of imatinib used for patients with F/P⁺ HES should be adjusted to ensure molecular remission, in order to decrease the risk of acquired resistance to treatment 1. Several alternative tyrosine kinase inhibitors have been tested in vitro and in vivo (murine model of F/P-associated disease) for effects on F/P activity. One molecule, nilotinib (AMN107), is able to inhibit kinase activity of wild-type F/P 38. Two other compounds, PKC412 which is structurally unrelated to imatinib 39, and sorafenib 40, are able to inhibit kinase activity of both wild-type F/P and its imatinib -resistant T674I mutant form.

Although imatinib has clearly become first-line therapy for patients with F/P-associated disease, overall follow-up of treated patients is short, and a number of questions remain unanswered. Namely, it is currently unclear whether imatinib can be curative for HES, through permanent eradication of the leukemic F/P⁺ clone. Several reports have shown that interruption of imatinib in F/P⁺ patients in molecular remission, is followed by recurrence of the molecular defect within months 3341.

To date, no general consensus has been reached on the ideal treatment algorithm for HES patients without the F/P fusion. In general, corticosteroids are administered as first line therapy, starting with a dose of 1 mg/kg/d or 60 mg prednisone. If a response is observed, prednisone is carefully tapered to the lowest possible dose that maintains eosinophil counts and/or clinical manifestations under control, defining the level of corticosteroid-dependency. Depending on the dose of corticosteroids required and on patient tolerance, physicians frequently attempt to further reduce the dose by introducing a corticosteroid-sparing agent. If no response to corticosteroids is observed (i.e. corticosteroid-resistance), second-line therapy is warranted.

Compounds that are used for corticosteroid-sparing and for second-line purposes include hydroxycarbamide, IFN-α and imatinib. Recent studies indicate that monoclonal anti-IL-5 antibodies may represent an interesting therapeutic alternative. Other compounds such as ciclosporin, vincristine, and anti-CD52 antibodies (alemtuzumab) have proven useful in some patients. Available data on administration of cytotoxic molecules such as cyclophosphamide, methotrexate, busulfan, and chlorambucil, are not that encouraging and there are currently no recommendations in favor of their use in HES. Choice of which agent to use in a given patient is up to the clinician, and the following paragraphs review briefly the characteristics of available alternatives.

Hydroxycarbamide has been used extensively for treating HES, generally at doses between 1 and 2 g/d 15. The effect of hydroxycarbamide on eosinophilia is central, meaning that reduction of eosinophil levels is not to be expected before two weeks after initiation of therapy. Adverse events are frequently observed, including hematological toxicity and gastrointestinal intolerance. Published reports on successful treatment of HES with hydroxycarbamide lack detailed clinical and diagnostic information that would allow speculations on which disease variants could benefit from therapy. Theoretically, this compound would appear more useful for treating patients with myeloproliferative features; however, it effectively lowered eosinophil levels in one patient with a CD3^-CD4⁺ clone. Some investigators have combined hydroxycarbamide and IFN-α in order to lower individual doses of each compound, thereby increasing overall tolerance 42.

Interferon-α has also been used successfully for management of HES 31. Although highly variable dosing regimens have been used, it appears that doses of 1–2 million units/d are often sufficient to control eosinophil levels. It may take weeks before a response is observed, meaning that it may take months before a stable effective dose is reached. Common side effects include flu-like symptoms that tend to improve over time, depression, fatigue, and increased liver transaminases. Many IFN-α responders reported in the literature present a number of features suggestive of myeloproliferative disease, but these reports pre-date description of F/P-associated disease and L-HES. A corticosteroid-sparing effect of IFN-α has been observed in two of our patients with CD3^-CD4⁺ clones, which could be related to inhibition of IL-5 production 43 and anti-proliferative effects. However, these encouraging results are challenged by the observation that IFN-α prolongs survival of clonal CD3^-CD4⁺ cells in vitro by inhibiting spontaneous apoptosis, and may therefore provide these cells with a selective advantage 44. Given the malignant potential of aberrant T cells associated with L-HES, we would recommend avoidance of IFN-α as monotherapy in this setting, and prefer combining with corticosteroids.

In F/P-negative HES patients, the place of imatinib among therapeutic options has not yet been defined. Several investigators have reported responses to imatinib in a variable proportion of such patients, suggesting that an unidentified cytogenetic rearrangement leads to acquisition of imatinib-sensitive autonomous tyrosine kinase activity. To date, there is no data available on potential biomarkers that would help identify F/P-negative patients with imatinib-sensitive disease. A short course of imatinib 400 mg daily could be proposed to patients with clinical and biological findings typically encountered in myeloproliferative disease (see those listed above for "M-HES") and those resistant to therapy with corticosteroids; rapid evidence of a hematological response would be encouraging for treatment prolongation. In a recent review of 94 published cases of HES treated with imatinib, it was suggested that presence of splenomegaly or lung disease could be associated with a higher probability (89% and 96% respectively) of complete hematological response to imatinib 45. In contrast to patients with F/P-associated disease, response of F/P-negative patients to imatinib is variable, and may only be transient in some cases, or may require higher doses.

The recent development of humanized anti-IL-5 mAbs, designed to target eosinophils in allergic disorders by interfering with ligation of IL-5 to the α -chain of the IL-5R on their surface, has raised considerable interest among investigators dealing with HES 46. There is strong scientific rationale for treatment of HES patients with anti-IL-5 mAb, given the specificity of this cytokine for the eosinophil lineage, and the assumption that tissue damage in HES is directly related to presence of activated eosinophils. Initially, two molecules were developed for intravenous use (mepolizumab by GlaxoSmithKline and formerly SCH55700 by Schering Plough) and tested in HES patients, some of whom were corticosteroid non-responders, in the setting of compassionate use programs. Encouraging results were reported, with a rapid decline of blood eosinophil counts shortly after administration in most patients 474849. This was associated with decreased eosinophil degranulation, reflected by reduced serum eosinophil cationic protein (ECP) levels 47. In most cases, successful eosinophil depletion in blood was associated with improvement of a wide spectrum of clinical manifestations (including rash, angioedema, mucosal ulcers, myalgia, arthralgia, dysphagia, vomiting, nasal congestion and polyposis), correlating with significant reductions of eosinophil numbers in the skin and esophagus of patients with eosinophilic dermatitis 47 and severe eosinophilic esophagitis 48, respectively. Among patients under corticosteroids before treatment initiation, several could be tapered down or off after mepolizumab infusions, supporting its use as a corticosteroid-sparing agent in HES. Eosinophil depletion and clinical remission following administration of 750 mg mepolizumab appears to last weeks or even months in some cases, and two patients with eosinophilic dermatitis have experienced persistent remission (with follow-up of 17 months in one case) following treatment discontinuation 47. These individual compassionate case studies have suggested that HES patients with various profiles could benefit from treatment with anti-IL-5, including corticosteroid-responders and non-responders, and patients with both myeloproliferative (including one patient in whom the F/P fusion gene was later demonstrated 49) and possible T cell mediated disease 47.

Although SCH55700 is no longer available, mepolizumab has recently been administered to a large number of F/P-negative corticosteroid-responsive HES patients in the setting of an international multicentric, randomized, double-blind, placebo-controlled clinical trial (750 mg administered intravenously every 4 weeks) 50. This study has shown that mepolizumab allows effective corticosteroid-sparing compared to placebo, while maintaining disease control, and is well tolerated. An open-label extension study is currently on-going, addressing the optimal dosing interval between mepolizumab infusions, as well as long-term side effects associated with treatment itself and prolonged eosinopenia. Hopefully, additional analysis will identify biomarkers predictive of response to therapy with anti-IL-5.

Although anti-IL-5 mAbs display an excellent safety profile with minimal if any reported side effects, some concern regarding rebound hypereosinophilia between infusions or after cessation of therapy has been raised. One study using SCH55700 at low doses (1 mg/kg) has shown that serum IL-5 levels actually increased during treatment, and this appeared not to be related to increased IL-5 production by peripheral blood leukocytes 49; mechanisms underlying IL-5 over-production or decreased IL-5 clearance during therapy remain to be clarified. Whether a similar phenomenon occurs with mepolizumab, remains unknown, and will be evaluated in the setting of the above-mentioned clinical trials.

An interesting therapeutic target in patients with L-HES is the CD52 antigen, which is expressed both on T cells and eosinophils. In a recent report, alemtuzumab, a monoclonal anti-CD52 antibody, was shown to be effective treatment for a patient with a CD3^-CD4⁺ T cell subset, inducing rapid normalization of eosinophil levels and clinical remission 51.

Ciclosporin interferes with calcium-mediated intracellular signaling pathways and inhibits nuclear translocation of the transcription factor NF-AT, which is essential for a number of T cell functions including cytokine synthesis. Ciclosporin is classically used for treating auto-immune disorders, by targeting T cells. A few authors have reported successful use of ciclosporin as a corticosteroid-sparing agent in a limited number of HES patients 52. Given the pathogenic role of T cells in L-HES, and dependence of CD3^-CD4⁺ T cells on IL-2 for proliferation and cytokine production 53, ciclosporin or other agents interfering with IL-2/IL-2R interactions, may theoretically be useful for this HES variant. This remains entirely to be assessed.

Vincristine is a cytotoxic agent that is rarely used for management of HES. It may prove useful for rapidly lowering eosinophilia in patients with extremely high eosinophil counts (> 100 × 10⁹/L), and has been proposed in some pediatric cases that are refractory to classical therapeutic regimens 1. The recommended dose for adults is 1–2 mg intravenously.

Finally, HES patients that are refractory to classical therapy and who present progressive life-threatening end-organ damage may be candidates for allogeneic stem cell transplantation (SCT), whether they test positive for the F/P fusion or not. Obviously, this strategy requires careful thought given the inherent morbidity and mortality related to the procedure. Potential indications for SCT may include patients with F/P-associated disease who are intolerant to or no longer respond to imatinib 1, and patients initially presenting L-HES who develop peripheral T cell lymphoma, as eradication of malignant T cells is not easily achieved using classical chemotherapeutic regimens.

Overall, management of patients with HES has improved significantly, especially since the rapid initiation of imatinib in patients with F/P⁺ disease. As for L-HES, there is now increased awareness that despite the clinically "benign" presentation with relative sparing of end-organs, patients should be closely monitored for development of T cell malignancy. However, the molecular picture of L-HES remains uncomplete and specific molecular targets for therapy have not been identified, meaning that in the meantime therapy relies largely on corticosteroids, with eventual addition of corticosteroid-sparing agents such as IFN-α. Interesting options for future investigation may include alemtuzumab, extracorporeal photopheresis, and efalizumab (J. Huss-Marp, personal observation).