Hypereosinophilic syndromes (HES) represent a group of rare dis-immune conditions characterized by blood hyper-eosinophilia and eosinophilic related burden. Especially the idiopathic subtype (I-HES) is particularly difficult to diagnose because of its heterogeneous clinical presentation, the lack of specific findings on physical exam, lab tools, and imaging informative enough to unequivocally confirm the diagnosis and the overlap with other entities, including eosinophilic organ-diseases or systemic dis-immune conditions other than I-HES (from atopy to eosinophilic granulomatosis with polyangiitis [EGPA], the last often extremely difficult to distinguish from HES). Taken together, all the features mentioned above account for an extremely difficult early recognition HES and on-time referral to a specialized centre. The referral itself is challenging due to a not univocal specialist identification, because of the variability of physicians managing HES in different settings (including allergist/clinical immunologist, haematologist, internal medicine doctors, pulmonologist, rheumatologist). Furthermore, the approach in terms of personalized treatment identification and follow-up plan (timing, organ assessment), is poorly standardized. Further translational and clinical research is needed to address the mentioned unmet needs, but on practical grounds increasing the overall clinicians\' awareness on HES and implementing healthcare pathways for HES patients represent a roadmap that every clinician might try to realize in his specific setting. The present review aims at providing an overview about the current challenges and unmet needs in the practical approach to HES and rare hypereosinophilic allergo-immunological diseases, including a proposal for an innovative multidisciplinary organizational model.

Loeffler\'s endocarditis (LE) is the cardiac manifestation of hypereosinophilic syndrome. We present a case of LE in a 45-year-old female, resulting in diffuse endothelial fibrosis and severe right-sided heart failure. The patient was admitted with dyspnoea and oedema, with haematology revealing an absolute eosinophil count of 20.9 × 109. Imaging showed near-complete obliteration of the right ventricular apical and formation of thromboses. Endomyocardial biopsy indicated diffuse fibrous hyperplasia of the endocardium with fibrinous thrombi rich in eosinophils. Molecular and cytogenetic analyses of bone marrow cells showed no signs of FIP1L1-PDGFRA fusion, PDGFRB mutation, abnormal myeloid maturation, or a lymphoproliferative disorder. Flow cytometry indicated no clonality, ruling out chronic eosinophilic leukaemia. Gene mutation screening discovered a p.L583_A586delinesS mutation in the JAK2 gene. Following treatment with ruxolitinib, the patient\'s eosinophil levels normalized, but unfortunately, the damage to the heart was irreversible. The patient was hospitalized multiple times due to right heart failure and resistance to diuretics. After thorough discussions with the medical team, it was determined that a heart transplantation would be the most effective treatment. Following the surgery, the patient successfully navigated the postoperative critical period with the support of an intra-aortic balloon pump (IABP), continuous renal replacement therapy (CRRT), and ventilator-assisted ventilation but subsequently developed an acquired Intensive care unit-acquired weakness (ICU-AW) and a depressive state. Fortunately, the patient gradually recovered from these complications.

A 76-year-old woman with persistent diarrhea was referred to our hospital. She had purpura, peripheral eosinophilia (18,177/μL), and an elevated serum IgG4 level (819 mg/dL). Abdominal computed tomography revealed massive ascites and bowel edema. A skin biopsy of the purpura revealed leukocytoclastic vasculitis with prominent eosinophilic infiltration. Biopsies of the gastrointestinal mucosa revealed dense eosinophilic infiltration, indicating eosinophilic gastroenteritis (EG) associated with the hypereosinophilic syndrome. The number of IgG4-positive cells increased in the duodenal mucosa; however, the diagnostic criteria for IgG4-related disease (IgG4-RD) were not met. Whether or not EG with ascites is a manifestation of IgG4-RD warrants further investigation.

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UNASSIGNED: Hypereosinophilic syndrome (HES) is a peripheral eosinophilia characterized by elevated absolute eosinophil cell count ( > 1.500 cells/ μ L) and consequent tissue and end-organ damage. Our aim was to evaluate the mitral annular (MA) and/or tricuspid annular (TA) parameters of patients with HES and to determine whether there are any changes in these parameters compared to healthy individuals.
UNASSIGNED: 17 patients with HES were involved in our study, 2 cases were excluded due to suboptimal image quality (mean age of the evaluated patients: 61.7 ± 11.2 years, 10 males). Their data were compared with those of 24 healthy subjects (mean age: 55.2 ± 7.9 years, 12 males) in the control group. Complete echocardiographic examinations were performed including two-dimensional (2D) Doppler echocardiography and three-dimensional echocardiography (3DE) to assess the MA and the TA.
UNASSIGNED: Comparing the echocardiographic parameters of the HES patients with those of the healthy volunteers, the following changes were seen: the interventricular septum was significantly thickened in HES patients, no other significant changes were detected between the examined patient groups. End-diastolic and end-systolic MA diameters, areas and perimeters were increased and MA fractional area change and MA fractional shortening were decreased in HES patients. From TA morphological parameters, only end-diastolic TA area and end-systolic TA perimeter were significantly increased in HES patients. Functional TA parameters showed no significant alterations in the HES group. In patients with HES, no correlations could be detected between 2D and 3D echocardiographic data with the examined laboratory findings.
UNASSIGNED: The extent of the dilation of the MA is more pronounced than that of the TA in HES. MA functional impairment is present in HES.

Hypereosinophilic syndrome (HES) encompasses a heterogeneous and complex group of different subtypes within the wider group of hypereosinophilic disorders. Despite increasing research interest, several unmet needs in terms of disease identification, pathobiology, phenotyping, and personalized treatment remain to be addressed. Also, the prospective burden of non-malignant HES and, more in general, HE disorders is currently unknown. On a practical note, shortening the diagnostic delay and the time to an appropriate treatment approach probably represents the most urgent issue, even in light of the great impact of HES on the quality of life of affected patients. The present document represents the first action that the Italian Society of Allergy, Asthma, and Clinical Immunology (SIAAIC) has finalized within a wider project aiming to establish a collaborative national network on HES (InHES-Italian Network on HES) for patients and physicians. The first step of the project could not but focus on defining a common language as well as sharing with all of the medical community an update on the most recent advances in the field. In fact, the existing literature has been carefully reviewed in order to critically integrate the different views on the topic and derive practical recommendations on disease identification and treatment approaches.

UNASSIGNED: Löffler\'s endocarditis (LE) is a frequently encountered condition in hypereosinophilic syndrome and is associated with a significant morbidity and mortality rate.
UNASSIGNED: A 22-year-old man presented with acute dyspnoea, recurring wheezing, and cough, leading to his hospital admission. Multimodal diagnostic imaging revealed a manifestation of eosinophil-mediated cardiac injury in the thrombus formation stage. Moreover, a mural thrombus and thickened endocardium had caused severe obstruction of the right ventricular outflow tract (RVOT) and complete obliteration of the right ventricular apex, resulting in a significant reduction in right ventricular cardiac output. The patient received a diagnosis of LE and was treated with high-dose corticosteroids and anticoagulants. To alleviate the RVOT obstruction, an emergency surgical intervention was conducted through median sternotomy to the removal of the mural thrombus and resection of the thickened endocardium. Subsequently, eosinophil counts normalized within 1 month. Follow-up imaging examination demonstrated the existence of a residual section of thickened endocardium within the right ventricular free wall. Importantly, no mural thrombus was detected with complete relief of the RVOT obstruction. Notably, a transthoracic echocardiography examination at the 3-month postoperative unveiled a significant regression in right ventricular endomyocardial fibrosis. The patient\'s condition exhibited tangible improvement, with no adverse events observed.
UNASSIGNED: Multimodal imaging is essential for the early diagnosis and accurate staging of LE. Timely surgical intervention, combined with corticosteroid therapy, is an effective therapeutic approach in selected patients with LE. This approach is crucial to achieve remission of acute phase symptoms and improve prognosis.

Here, we reviewed clinical-morphological data and investigated mutational profiles by NGS in a single-center series of 28 consecutive patients admitted to our hospital between September 2011 and November 2021 for idiopathic hypereosinophilia (HE).Bone marrow (BM) morphology was evaluated in 22 patients: while in six subjects BM was unremarkable, in the remaining cases an increase in BM eosinophils was observed, together with a slight increase in BM fibrosis (MF-1) in 5/22 patients.A total of 4/28 patients had at least one genetic lesion by targeted NGS. In particular, the genes involved were: two each of TET2 and DNMT3A; and one each of JAK2V617F, ASXL1, PPM1D, and ZBTB33. Notably, JAK2V617F and TET2 mutations co-occurred, with the JAK2V617F-mutated sample also carrying TET2 lesions. Median VAF was 21%, with the exception of the oncodriver JAK2V617F, which showed a VAF > 50% in the reported case. Of note, of the four cases bearing lesions, 2/4 had multiple hits in different genes.While in recent years mutational analysis using NGS has proven to be able to differentiate clonal hematopoietic neoplasms from reactive processes in diagnostically difficult cases, we found somatic mutations in only 14.3% of patients who acceded to our hospital for idiopathic HE. More importantly, excluding the JAK2V617F-mutated case with an underlying MPN-Eo diagnosis, NGS was able to identify somatic mutations in only three cases, all older than 70 years. Consequently, the detection of these mutations in idiopathic HE patients should be interpreted with caution and only in the context of other supportive clinical-pathological findings.

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Mepolizumab, an anti-interleukin-5 antibody, has been proven a safe and effective glucocorticoid-sparing drug for many patients with non-clonal hypereosinophilic syndrome (HES) and is now approved in many countries. It remains unclear however which patients are most likely to benefit from therapy and whether the currently approved dosing regimen is appropriate for all. This observational retrospective study included all HES patients who were enrolled in the MHE104317 compassionate use program (CUP) in our center. Patient and disease characteristics, mepolizumab dosing, and both clinical and hematological responses to treatment were collected from medical files. Treatment responses and mepolizumab dosing requirements were analyzed according to disease characteristics. Eighteen HES patients were enrolled in the CUP, of which 9 are still on treatment. The median duration of exposure to mepolizumab was 45 months (maximum 18 years). A lower number of affected organs, requirement for glucocorticoid dosing ≤10 mg prednisone-equivalent, and single-organ HES were associated with a higher likelihood of complete response. Lymphocytic variant (L-) HES was less treatment-responsive, leading to withdrawal and/or requiring higher mepolizumab dosing to achieve some degree of disease control. In contrast, all patients with single-organ disease had a complete response that could often be maintained despite increasing between-dose intervals. Few potentially treatment-related adverse events were observed despite prolonged exposure. This study confirms the efficacy and safety of mepolizumab in HES, although patients with L-HES rarely experience a complete response. In contrast, patients with single-organ disease affecting the lungs are often super-responders, and decreasing mepolizumab dosing may be attempted.