Loeffler's Endocarditis- A cause of endomyocardial fibrosis in a patient of juvenile idiopathic arthritis: A Case Report.

Endomyocardial fibrosis secondary to hyper-eosinophilic syndrome also known as Loeffler's Endocarditis is a rare cause of restrictive cardiomyopathy. If left untreated, it carries a very high morbidity and mortality rate. The case of a 20 years old girl, a known case of polyarticular juvenile idiopathic arthritis since the age of 13 years was reported at Federal Government Polyclinic Hospital, Islamabad on 14th May 2022. She presented with an acute history of shortness of breath and cough for two weeks. Her initial echocardiogram showed suspicion of Loeffler's Endocarditis, which is attributed to be an adverse effect of etanercept- a tumour necrosis factor (TNF) inhibitor, which she had been prescribed for her arthritis. The patient is currently being managed with high doses of steroids, therapeutic anticoagulation with rivaroxaban, carvedilol for tachycardia and mycophenolate mofetil as an immunosuppressant.

Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study.

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

Hypereosinophilic syndrome: a rare cause of ST-elevation myocardial infarction and thrombus formation on the aortic valve.

We present a case of a man in his 30s presenting with ST-segment elevation myocardial infarction and eosinophilia. The patient underwent thrombus aspiration and initially echocardiographic evaluation was normal. The patient was discharged after 2 days, but was hospitalised again after 6 days. Echocardiographic evaluation now revealed a thrombus formation on the aortic valve. Laboratory data revealed increasing eosinophilia, and treatment with high-dosage corticosteroids and hydroxyurea was initiated as eosinophilic disease with organ manifestations could not be precluded. Eosinophils normalised and the patient was discharged again. The combination of hypereosinophilia and absence of infection, rheumatological disorders and malignancy, led to reactive or idiopathic hypereosinophilic syndrome being the most plausible diagnoses. The patient was closely monitored in the cardiology and haematology outpatient clinics. Echocardiographic evaluation, performed 6 weeks after the patient was discharged, showed significant regression in the size of the thrombus mass.

An 85-Year-Old Man with Fever, Dyspnea, and Dry Cough Diagnosed with Idiopathic Hypereosinophilic Syndrome, Successfully Treated with High-Dose Corticosteroids.

BACKGROUND Idiopathic hypereosinophilic syndrome (I-HES) is a rare disease diagnosed as absolute eosinophil count >1500 cells/µl and end-organ involvement attributable to tissue eosinophilia with no secondary cause of underlying eosinophilia. The mean age of presentation for I-HES is 44 years. The skin, lungs, and gastrointestinal (GI) system are most common sites of presenting manifestations, including fatigue, cough, dyspnea, myalgias, angioedema, rash, fever, nausea, and diarrhea. Although cardiac and neurologic symptoms are less common at presentation, they can be life-threatening. CASE REPORT We report the case of an 85-year-old man who presented with fever, malaise, and loss of appetite for 3 weeks, followed by dyspnea and dry cough for 2 weeks. His absolute eosinophil count was 9000 cells/µl, which was not responding to empirical antibiotic therapy, with worsening of symptoms, suggesting a non-infective origin. He was then extensively evaluated to establish underlying an etiology for specific treatment, which was negative for common causes like atypical infections, malignancy, and autoimmune disorders. He was then started on corticosteroid therapy to overcome an exaggerated immune response and reduce inflammation-related injury, to which he responded well. On follow-up, hypereosinophilia was fully cured, with reversal of end-organ involvement including myocarditis and pneumonitis. CONCLUSIONS This report shows that idiopathic HES can present with various clinical features and that accurate diagnosis, excluding known causes of eosinophilia, and early management are essential to prevent long-term organ damage. Our patient responded to prompt treatment with high-dose corticosteroids.

Low-dose anti-IL 5 treatment in idiopathic hypereosinophilic syndrome: towards a precision medicine approach for remission maintenance.

Mepolizumab at the dose of 300 mg/4 weeks has been recently approved as an add-on therapy for patients with uncontrolled hypereosinophilic syndrome (HES) without any identifiable non-hematologic secondary cause. According to the available real-life evidence mepolizumab 300 mg and 100 mg, licensed for severe eosinophilic asthma, are comparable in terms of drug efficacy. However, the clinical rationale for selecting one dose or the other has not been explored. We investigated the efficacy and safety of mepolizumab 100 mg in idiopathic HES (I-HES) patients as a steroid sparing strategy for disease remission maintenance by assessing clinical conditions, blood eosinophil count (BEC) and adverse events at baseline and at 3-6-12 months follow-up. Overall, 11 patients were enrolled (females 4-36%) with a median age of 62 years (IQR 55.0-72.0). At 3-month visit both prednisone daily dose and BEC significantly decreased from baseline, whilst a substantial improvement of Brief fatigue inventory score (BFI) was not recorded before the 6 months assessment. More than 70% of patients completely stopped prednisone at 12-months follow-up, without any flare in terms of BEC and BFI. No adverse event was registered. Although larger studies are needed, our report firstly describes that in a well-defined population, diagnosed with I-HES and in disease remission, low dose mepolizumab is a safe and effective steroid-sparing option for remission maintenance. It suggests that a personalized treatment dose might be explored according to the disease classification and activity at the time of biologic treatment start.

Idiopathic hypereosinophilic syndrome presenting as capsular warning syndrome: A case report and literature review.

RATIONALE: Few reports of idiopathic hypereosinophilic syndrome exist presenting as ischemic cerebrovascular disease, and the majority are watershed infarction. We report the first case of idiopathic hypereosinophilic syndrome that has clinical features of capsular warning syndrome lasting 6 weeks. PATIENT CONCERNS: A 26-year-old man complained of recurrent right limb weakness, accompanying slurred speech, and right facial paresthesia. DIAGNOSES: The patient was diagnosed with idiopathic hypereosinophilic syndrome (IHES). INTERVENTIONS: Adequate glucocorticoid and anticoagulant treatments were given. OUTCOMES: The patient's motor ability improved, and he was discharged 2 weeks later. Muscle strength in the right-side extremities had fully recovered at a 3-month follow-up after discharge. LESSONS: This case suggests that idiopathic hypereosinophilic syndrome should be considered as a cause of capsular warning syndrome, and the dose of glucocorticoid and the efficacy evaluation index needs to be reevaluated for the treatment of ischemic cerebrovascular disease associated with idiopathic hypereosinophilic syndrome.

Biologics and Hypereosinophilic Syndromes: Knowledge Gaps and Controversies.

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders defined by blood and/or tissue hypereosinophilia and clinical manifestations attributable to the eosinophilia. Although various clinical subtypes of HES have been described, the general approach to therapy in all subtypes has focused on the reduction of blood and tissue eosinophilia to improve symptoms and halt disease progression. Until recently, this typically involved the use of corticosteroids and/or other immunosuppressive or cytotoxic drugs with significant toxicity. Whereas imatinib, the first targeted therapy approved for treatment of HES, has dramatically changed the prognosis of patients with primary (myeloid) forms of HES, it is ineffective in patients with other HES subtypes. For these nonmyeloid patients with HES, the development of eosinophil-targeting biologics (most notably, mepolizumab, the first biologic approved for the treatment of HES) has been transformative. Nevertheless, important issues remain with respect to the efficacy and safety of these biologics in the treatment of the varied subtypes of HES. Moreover, with the increasing number of commercially available biologics with direct or indirect effects on eosinophils, questions related to the choice of initial biologic, potential reasons for biologic failure, and treatment options in the setting of incomplete response are becoming increasingly common.

The portrait of a stranger: the hypereosinophilic syndrome with cardiac involvement.

INTRODUCTION: Hypereosinophilic syndrome is a rare clinical condition, and cardiac involvement confers a poor prognosis. Hypereosinophilic myocarditis is a medical emergency and targeted treatment should be started promptly even before a definitive diagnosis could be made. CASE PRESENTATION: A 27-year-old female patient is hospitalized for exertional dyspnea, chest pain, and fatigue for the past 2 weeks. She also describes left leg paresthesias. Clinical examination was in normal limits. ECG showed sinus tachycardia, QS pattern in V1-V4, and diffuse flattened T waves. Laboratory tests revealed increased inflammatory markers, hypereosinophilia, elevated cardiac enzymes, high NT-proBNP. Echocardiography revealed LV dysfunction (EF 31%), while cardiac MRI showed diffuse delayed enhancement with predominant subendocardial disposition. The electromyogram was suggestive of left tibial nerve neuropathy. We interpreted the case as eosinophilic myocarditis with an urgent requirement of therapy and initiated high-dose glucocorticoid therapy and the GDMT 4-pillar heart failure treatment. We excluded common infectious, myeloproliferative syndromes, and frequent associated autoimmune diseases. With prednisone, the eosinophil count rapidly normalized and we gradually tapered the dose by 5 mg per week, however continuing with heart failure therapy. At monthly follow-up visits, there was a significant clinical improvement, with normalization of the eosinophilic count, and a near-normalization of myocardial function. The only symptom that persisted was paresthesias linked to left tibial neuropathy. CONCLUSION: The surprisingly rapid and favorable course of the disease offers a high index of suspicion for a toxic or a reactive transitory etiology, however still unidentified. In our case, the cause of eosinophilia remained unknown, although we managed to narrow down the possible etiologies. A surprisingly good clinical response was obtained with non-specific treatment targeting mainly hyperosinophilic myocarditis.

Pediatric hypereosinophilic syndrome associated with liver damage, portal vein, splenic vein and superior mesenteric vein thromboses: a case report.

BACKGROUND: The hypereosinophilic syndrome (HES) is a group of rare blood disorders characterized by persistent eosinophilia and damage to multiple organs. HES can be either primary, secondary or idiopathic. Secondary HES are commonly caused by parasitic infections, allergic reactions or cancer. We described a pediatric case of HES associated with liver damage and multiple thrombi. A 12-year-old boy with eosinophilia was complicated with severe thrombocytopenia, liver damage, portal vein, splenic vein, and superior mesenteric vein thromboses. The thrombi recanalized after treatment with methylprednisolone succinate and low molecular weight heparin. No side effects appeared after 1-month. CONCLUSIONS: Corticosteroids should be used at an early stage of HES to prevent further damage to vital organs. Anticoagulants should be recommended only in cases with thrombosis which should be actively screened as a part of evaluation of end organ damage.

Lymphomatoid papulosis associated with myeloid neoplasm with eosinophilia and FIP1L1::PDGFRA rearrangement: Successful imatinib treatment in two cases.

Lymphomatoid papulosis (LyP) is a benign condition, listed among primary cutaneous CD30+ lymphoproliferative disorders. Its typical picture consists of relapsing-remitting papular lesions and it can be encountered in the course of a hematologic disease, at times representing its first manifestation. Hypereosinophilic syndromes are a heterogeneous group of disorders characterized by persistent peripheral blood hypereosinophilia that may lead to life-threatening organ damage. Among eosinophilic disorders, the subtype identified as myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions has aroused particular interest due to its excellent response to tyrosine kinase inhibitors, including imatinib. Here, we described the case of two 33-year-old men presenting with LyP and myeloid neoplasm with eosinophilia and FIP1L1::PDGFRA rearrangement who achieved complete clinical and molecular remission of both conditions a few months after starting imatinib.

Hypereosinophilic syndrome with cutaneous manifestations successfully treated with Dupilumab as a sole agent: A case report.

Hypereosinophilic syndrome describes a process in which eosinophils in the peripheral blood are persistently increased, with variable clinical manifestations. Finding efficacious treatments for this disease can be challenging. This case describes a 72-year-old man with idiopathic hypereosinophilic syndrome with cutaneous manifestations who was successfully treated with dupilumab as a single agent therapy. There was complete clinical and biochemical resolution of disease (eosinophils levels decreased from 4.13 to 0.92) without complications.

Hypereosinophilic syndrome presenting with gastrointestinal manifestations.

Hypereosinophilic syndrome (HES) is a spectrum of diseases characterised by an elevated eosinophilic count causing end-organ damage. Differential diagnoses of hypereosinophilia are vast and include drug hypersensitivities, allergies, infections, cancers, autoimmune disorders and rare eosinophilic syndromes. Herein, we describe a case of a patient presenting with gastrointestinal (GI) symptoms including progressive dysphagia, abdominal distension, vomiting, diarrhoea and abdominal pain with significant peripheral eosinophilia who was found to have an overlap HES involving the GI tract. This patient's eosinophilia was rapidly corrected with intravenous methylprednisolone, and the patient experienced gradual resolution of clinical symptoms with maintenance oral prednisone. Due to the rarity and diverse presentation of HES, there are few large, longitudinal studies that describe disease progression and inform treatment guidelines. This case demonstrates the difficulty in designing a treatment regimen for these patients and emphasises the clinical need for improved understanding of HES.

French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.

Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients' association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

JAK inhibition for CD3- CD4+ lymphocytic-variant hypereosinophilic syndrome.

Alternatives are urgently needed in patients with CD3- CD4+ lymphocytic-variant hypereosinophilic syndrome (L-HES) requiring high-level steroids or who are unresponsive and/or intolerant to conventional alternative therapies. We report five L-HES patients (44-66 years) with cutaneous involvement (n = 5) and persistent eosinophilia (n = 3) despite conventional therapies, who successfully received JAK inhibitors (tofacitinib n = 1, ruxolitinib n = 4). JAKi led to complete clinical remission in the first 3 months in all (with prednisone withdrawal in four). Absolute eosinophil counts normalized in cases receiving ruxolitinib, while reduction was partial under tofacitinib. After switch from tofacitinib to ruxolitinib, complete clinical response persisted despite prednisone withdrawal. The clone size remained stable in all patients. After 3-13 months of follow-up, no adverse event was reported. Prospective clinical trials are warranted to examine the use of JAKi in L-HES.

Hypereosinophilic syndrome in Europe: Retrospective study of treatment patterns, clinical manifestations, and healthcare resource utilization.

BACKGROUND: The burden of hypereosinophilic syndrome (HES) in Europe is not well characterized. OBJECTIVE: To evaluate real-world patient characteristics, treatment patterns, clinical manifestations, and healthcare resource utilization for patients with HES from France, Germany, Italy, Spain, and the United Kingdom. METHODS: In this retrospective, noninterventional study, data for patients with a physician-confirmed diagnosis of HES were abstracted from medical chart reviews. Patients were aged 6 years or older at the time of HES diagnosis and had 1 or more years of follow-up from the index date (first clinic visit between January 2015 and December 2019). Data on treatment patterns, comorbidities, clinical manifestations, clinical outcomes, and healthcare resource utilization were collected from diagnosis or index date to end of follow-up. RESULTS: Data for 280 patients were abstracted from medical charts by 121 physicians treating HES, with multiple specialties. Most patients (55%) had idiopathic HES, and 24% had myeloid HES; the median number (interquartile range [IQR]) of diagnostic tests per patient was 10 (6-12). The most common comorbidities were asthma (45%) and anxiety or depression (36%). Most patients (89%) used oral corticosteroids; 64% used immunosuppressants or cytotoxic agents, and 44% used biologics. Patients had a median (IQR) of 3 clinical manifestations (1-5), most commonly constitutional (63%), lung (49%), and skin (48%). Twenty-three percent of patients experienced a flare, and 40% had a complete treatment response. Some patients (30%) were hospitalized with a median (IQR) stay of 9 days (5-15) for HES-related issues. CONCLUSION: Patients with HES across 5 European countries had a substantial disease burden despite extensive oral corticosteroids treatment, highlighting the need for additional targeted therapies.

Biologic therapies for hypereosinophilic disorders: From tyrosine kinase inhibitors to monoclonal antibodies. Towards an increasingly customized management?

Hypereosinophilic syndromes (HES) encompass a wide range of disorders characterized by persistent peripheral blood hypereosinophilia (HE) (i.e., an eosinophil count ≥1.5 × 109/L and ≥ 10% eosinophils preferably with a minimal duration of 6 months if documentation is available) associated with organ damage and/or dysfunction attributable to tissue eosinophilic infiltrate and release of granule contents. In most cases, HE is associated with atopic conditions/allergies, parasitic infections, medications, autoimmune disorders and/or solid tumors in most cases. More rarely, it can be one of the dominant manifestations of an underlying myeloid/lymphoid neoplasm. With regard to hematological forms, in recent decades the advances in understanding the pathogenic aspects of HES have led to a growing interest in these diseases, and in the 2016 WHO classification multiple subgroups were defined according to the molecular profile with the aim of better characterizing these syndromes and establishing which patients will benefit from specific pharmacological targeted therapies. This review article will provide a comprehensive overview of possible therapeutic approaches for HES in the light of each specific molecular alteration, considering both tyrosine kinase inhibitors and monoclonal antibodies, either implemented in clinical practice or currently still under development.

Systemic thrombo-embolic events in a middle-aged male with Loeffler endocarditis without peripheral eosinophilia-a case report.

BACKGROUND: Loeffler-endocarditis (LE) is considered a chronic restrictive cardiomyopathy and manifestation of eosinophilic myocarditis characterized by eosinophilic infiltration. LE is a rare underdiagnosed disease and associated with high morbidity and mortality. CASE PRESENTATION: We report a case of a 46-year-old man suffering from LE associated with thromboembolic events without peripheral eosinophilia. The patient presented with typical clinical signs of acute onset of limb ischaemia, predominantly on the right limb, indicating immediate iliacal thrombectomy and due to a severe compartment syndrome additional fasciotomy. Total occlusion also of left popliteal artery suggesting an impaired chronic and aggravated impaired perfusion indicated also urgent left sided revascularization. Subsequent echocardiography revealed severe left ventricular dysfunction with a striking amount of spontaneous echo-contrast, noticeable in the left ventricular cavity. Furthermore the initial CT scan demonstrated asymptomatic left kidney- and brain infarctions. Diagnostic workup including endomyocardial biopsy (EMB) of the left ventricle, uncovered an underlying LE without peripheral eosinophilia. CONCLUSIONS: This case demonstrates and highlights the findings, treatment and outcome of a patient with LE and associated thrombo-embolic events without peripheral eosinophilia and emphazises the importance of awareness for LE in patients presenting with an acute cardiac decompensation and thrombo-embolic events. EMB should be performed early in unstable patients unsuitable for cardiovascular magnetic resonance imaging.

Approach to the patient with suspected hypereosinophilic syndrome.

Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders with clinical manifestations ranging from fatigue to life-threatening endomyocardial fibrosis and thromboembolic events. Given the broad differential diagnosis of HES, a comprehensive approach is needed to identify potential secondary (treatable) causes and define end-organ manifestations. Classification by clinical HES subtype is also useful in terms of assessing prognosis and guiding therapy. Corticosteroids remain the mainstay of initial therapy in the setting of acute, life-threatening PDGFR mutation-negative HES. Whereas the recent availability of eosinophil-targeted therapies with extraordinary efficacy and little apparent toxicity is changing the treatment paradigm, especially for idiopathic HES and overlap syndromes, questions remain unanswered regarding the choice of agent, impact of combination therapies, and long-term effects of eosinophil depletion. This review provides a case-based discussion of the differential diagnosis of HES, including the classification by clinical HES subtype. Treatment options are reviewed, including novel eosinophil-targeted agents recently approved for the treatment of HES and/or other eosinophil-associated disorders. Primary (myeloid) disorders associated with hypereosinophilia are not be addressed in depth in this review.