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

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.

Eosinophilia in children: characteristics, etiology and diagnostic algorithm.

Eosinophilia is common in children and may be caused by various disorders. Large-cohort studies, including mild cases, are limited in children. This study aimed to reveal underlying etiologies of childhood eosinophilia and to create a diagnostic algorithm. Children (< 18 years) with absolute eosinophil counts (AECs) ≥ 0.5 × 109/L were reviewed from medical files. Clinical characteristics and laboratory values were recorded. Patients were grouped based on the severity of eosinophilia as mild (0.5-1.5 × 109/L), moderate (≥ 1.5 × 109/L) and severe (≥ 5.0 × 109/L). An algorithm was formed to evaluate these patients. We included 1178 children with mild (80.8%), moderate (17.8%) and severe eosinophilia (1.4%). The most common reasons of eosinophilia were allergic diseases (80%), primary immunodeficiency (PID) (8.5%), infectious diseases (5.8%), malignancies (0.8%) and rheumatic diseases (0.7%). Only 0.3% of children presented with idiopatic hypereosinophilic syndrome. Allergic diseases and PIDs were the most common etiologies in mild/moderate and severe groups, respectively. The median duration of eosinophilia was 7.0 (3.0-17.0) months in the study population and was the shortest in severe cases (2.0 (2.0-5.0) months). Multiple logistic regression analysis demonstrated food allergy [OR:1.866, 95%CI:1.225-2.842, p = 0.004] and PIDs [OR:2.200, 95%CI:1.213-3.992, p = 0.009] as independent factors for childhood eosinophilia. A diagnostic algorithm including mild form was presented for childhood eosinophilia.    Conclusion: Eosinophilia was frequently determined due to secondary causes; allergic diseases in mild/moderate eosinophilia, PIDs in severe group. Etiology of eosinophilia was diverse, and an algorithm concerning the severity of eosinophilia would be practical and rational. What is Known: • In children, eosinophilia is common, and mild eosinophilia occurs frequently. • Malignancies presents frequently with severe eosinophilia. What is New: • Primary immunodeficiencies were not a rare cause of eosinophilia, especially in countries such as the Middle East and eastern Mediterranean countries, where the countries consanguineous marriages are common, and should be investigated in children with eosinophilia who do not have allergic or infectious diseases. • In literature, there are many algorithms about childhood hypereosinophilia. However, mild eosinophilia is extremely important in children. Because all patients with malignancy and most of the patients with rheumatic diseases presented with mild eosinophilia. Therefore, we proposed an algorithm for childhood eosinophilia that includes mild eosinophilia besides moderate and severe cases.

B-acute Lymphoblastic Leukemia With Hypereosinophilia Associated With Severe Cardiac Complications: A Clinical Case.

Hypereosinophilia (HE) is rare but often secondary to a nonhematologic disease such as allergic disorders and parasitic infections. HE can also be associated with hematologic malignancies and be the result of a clonal proliferation or reactive to another hematologic condition. Association of HE with acute lymphoblastic leukemia (ALL) is rare in children. We reported a case of a teenager presented with HE secondary to B-ALL who experienced severe cardiac complications with severe absolute eosinophil count. We compared his clinical evolution with other published cases and we reported 2 mutations linked to B-ALL never described before in this context.

Causes of hypereosinophilia in 100 consecutive patients.

BACKGROUND: Hypereosinophilia (HE, persistent peripheral blood eosinophilia > 1.5 × 109 /L) and hypereosinophilic syndrome (HES, HE with end-organ damage) are classified as primary (due to a myeloid clone), secondary (due to a wide variety of reactive causes), or idiopathic. Diagnostic evaluation of eosinophilia is challenging, in part because secondary causes of HE/HES such as lymphocyte-variant HES (L-HES) and vasculitis are difficult to diagnose, and emerging causes such as immunoglobulin G4-related disease (IgG4-RD) have rarely been examined. OBJECTIVE AND METHODS: We reviewed 100 consecutive patients with HE/HES who underwent extensive evaluation for primary and secondary eosinophilia at a single tertiary care center to determine causes of HE/HES in a modern context. RESULTS: Six patients had primary HE/HES, 80 had a discrete secondary cause identified, and 14 had idiopathic HE/HES. The most common causes of secondary eosinophilia were L-HES/HES of unknown significance (L-HESus) (20), IgG4-RD (9), and eosinophilic granulomatosis with polyangiitis (EGPA) (8). CONCLUSIONS: In contrast to other large published series of HE/HES, most patients in this study were found to have a discrete secondary cause of eosinophilia and only 14 were deemed idiopathic. These findings highlight the importance of extensive evaluation for secondary causes of eosinophilia such as L-HES, IgG4-RD, and EGPA.

Workup for eosinophilia.

With automated differentials being a common part of routine blood counts, the finding of eosinophilia is a relatively frequent occurrence. The first step in elucidating the cause is to determine the absolute eosinophil count (AEC), which is calculated from multiplying the percentage of eosinophils by the total white blood cell count. Eosinophilia is defined as an AEC of >500 eosinophils/µL, whereas hypereosinophilia is defined as an AEC of ≥1500 eosinophils/µL, a separation that is useful as an initial approach to the evaluation of such patients. Peripheral blood eosinophilia is most commonly secondary to allergies but can also be caused by certain infections, medication reactions, autoimmune diseases, or other conditions. However, hypereosinophilia is rarely, if ever, explained by allergy alone and should always prompt a further workup. A meticulous approach to exploring key aspects of the medical history is recommended for assessing increased AECs because it helps to narrow the list of possible etiologies, and treatment varies, depending on the underlying diagnosis. Special attention should be paid to the onset of eosinophilia and any coincident events, such as travel or the start of new medications. Another critical part of the history is a thorough attempt to identify any possible eosinophil-associated end-organ damage, although a biopsy of suspected involved areas is often necessary for confirmation. Because the causes of an elevated AEC are broad, determining the trigger or underlying disorder becomes an important intellectual riddle that can usually be solved with careful attention to history, physical examination, and appropriate laboratory work.

A multimodality work-up of patients with Hypereosinophilia.

The work-up of patients with hypereosinophilia (HE) is complex. Following the recently revised World Health Organization criteria, we retrospectively reviewed 125 patients who were referred to us to exclude a neoplastic cause of HE (2003-2016). The clinical laboratory work-up confirmed secondary HE in 25 (20%) patients; myeloid/lymphoid neoplasms with rearrangements of PDGFRA (n = 9) or PDGFRB (n = 2) (9%); HE associated with a well-defined myeloid neoplasm in 8 (6%); and abnormal bone marrow and/or molecular genetic abnormalities consistent with chronic eosinophilic leukemia (CEL), not otherwise specified (NOS) in 21 (17%) patients. For the remaining 60 (48%) patients, a specific diagnosis was not identified, and 56 patients had HE related findings consistent with idiopathic hypereosinophilic syndrome (HES), while 4 patients who were asymptomatic. With a median follow up of 35.3 months (range, <1-104), patients with CEL, not otherwise specified (NOS) had a median OS of 26.1 months, significantly inferior to patients with idiopathic HES (not reached, P < .01). Thus, our experience in a single tertiary cancer center shows that the work-up of HE following WHO recommendations requires a multimodality-based approach; and a correct diagnosis determines risk stratification and proper patient management. However, the causes of HE remain unknown in approximately half of referred patients, indicating the need for further studies.

Hypereosinophilia: A rare presentation of acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) presenting as peripheral blood hypereosinophilia is very rare and the incidence is <1%. The characteristic feature of patients with ALL and hypereosinophilia is the absence of blasts in peripheral blood, and this might lead to misdiagnosis of ALL. It is important for clinicians and pathologists to be aware of this uncommon initial presentation of ALL to avoid delay in diagnosis. We report a 37-year-old man who presented with fever and respiratory symptoms and was found to have hypereosinophilia in peripheral blood. His bone marrow and lymph node biopsies were diagnostic of ALL.

Multiparametric cardiac magnetic resonance imaging (CMR) for the diagnosis of Loeffler's endocarditis: a case report.

BACKGROUND: Endocarditis parietalis fibroplastica Löfflein (EPF) is a rare form of primary restrictive cardiomyopathy with poor prognosis. It is generally caused by hypereosinophilic syndrome with eosinophilic penetration of the heart. This leads to congestive heart failure in three different stages. As a frequent manifestation of neoplastic diseases, cardiac involvement means poor prognosis. CASE PRESENTATION: The present report deals with a case of EPF caused by non-specified T-cell lymphoma (T-NOS). Besides an elevated Troponin-T enzyme, the electrocardiogram and the transthoracic echocardiography did not show any characteristic results. Due to risk/benefit assessment and low thrombocyte amounts, endomyocardial biopsy and catheterization were discarded. Using cardiovascular magnetic resonance (CMR) with steady-state free precession sequences, T2-mappping, strain analysis and late gadolinium enhancement, we were able to clearly highlight cardiac involvement at different stages. These findings characterized T-NOS as a palliative situation. CONCLUSION: Multiparametric CMR can not only identify EPF but also characterize the patchy disease state. This provides an individual prognosis assessment. Aside from prognosis estimation, it can also be used for therapy monitoring.

Hypereosinophilic syndrome.

BACKGROUND: Hypereosinophilic syndrome (HES) is a myeloproliferative disorder characterized by persistent eosinophilia associated with multiple organ damage. OBJECTIVE: To increase awareness of the rare but potentially life-threatening disease and to provide a brief overview of the clinical presentation, diagnosis, and management of HES. METHODS: Pertinent data from the patient's clinical course was incorporated with salient articles on the topic. RESULTS: A case of HES is presented, followed by discussion of the clinical characteristics, diagnosis, and management. Clinical pearls and pitfalls are emphasized for the practicing allergist, clinical immunologist, and fellow-in-training. CONCLUSION: A diagnosis of HES should be considered in patients with an absolute eosinophil count of >1500 cells/µL documented on two occasions at least 1 month apart, and/or in those with pathologic confirmation of tissue hypereosinophilia. The decision to treat HES should be guided by both the clinical presentation and results of laboratory and mutational analysis.

Cutaneous B-lymphoblastic lymphoma with IL3/IgH translocation presenting with hypereosinophilia and acute endocarditis.

Hypereosinophilia is a rare phenomenon associated with childhood malignancy, predominantly acute lymphoblastic leukaemia. Causation is unclear and likely to have multiple mechanisms. We report a six year old boy presenting with hypereosinophilia and associated Loeffler endocarditis. Three months following his initial hypereosinophilia he developed cutaneous B-lymphoblastic lymphoma. Re-analysis of apparently uninvolved bone marrow, taken at initial presentation, revealed a single, previously unidentified, t(5;14)(q31;q32) positive cell. Using fluorescent in situ hybridisation, we demonstrate IL3/IgH@ fusion in cutaneous lymphoma cells. Our case confirms the association of hypereosinophilia and B-lymphoblastic lymphoma and strengthens the association between IL3 hypersecretion and hypereosinophilia.

[The Hypereosinophilic Syndromes in Childhood]. / Die Hypereosinophilie-Syndrome (HES) im Kindesalter.

The hypereosinophilic syndromes are rare disorders in childhood and require extensive differential diagnostic considerations. In the last years the earlier "idiopathic HES" called syndromes could be differentiated into molecular biologically, immunophenotypically and clinically more characterized heterogeneous diseases with high therapeutic and prognostic relevance. Nowadays the term HES summarizes diseases, which go hand in hand with a local or systemic hypereosinophilia (HE) connected with an organ damage. Depending on the cause of the HE one differentiates primary/neoplastic HES (HESN) from secondary/reactive HES (HESR). The latter develops reactively in connection with allergies, parasitosis, medications, neoplasia or a clonal increase of T-lymphocytes among others. With HESN the HE results from a clonal increase of eosinophilic granulocytes. While for some subgroups of the HESN (among others FIP1L1-PDGFRA fusion gene) the administration of a tyrosine kinase inhibitor is a new and effective therapy option, glucocorticoids still represent the medication of first choice for many not PDGFRA associated variants. Different immunomodulatory drugs or cytostatic agents are necessary to allow dose reduction of glucocorticoids. The promising therapy with anti-IL-5 antibodies is still not approved in infancy, could however become a treatment option in the future. Due to the present lack of knowledge about the HES in infancy the establishment of a register should be aimed for the treatment of HES in infancy.

World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS), lymphocyte-variant HE, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3)) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second-line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited number of patients. Although clinical trials have been performed with anti-IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

Chronic eosinophilic leukemia: a rare cause of hypereosinophilic syndrome.

Hypereosinophilic syndromes are a wide group of entities. We present a 24-year-old-male with left lower quadrant abdominal pain, elevated eosinophil counts and splenomegaly. Molecular analysis was positive for FIP1LI -PDGFRA gene compatible with chronic eosinophilic leukemia. He was managed with Imatinib producing resolution of the disease.