Continuing Education Activity

Hypereosinophilic Syndrome (HES) is a rare and complex group of disorders posing diagnostic challenges for clinicians. Characterized by significant increases in eosinophil levels, HES can lead to tissue infiltration and damage. This course is designed to equip clinicians with a comprehensive understanding of the epidemiology, evaluation, and management of HES, offering valuable insights to enhance patient care.

Throughout the course, participants will explore the diagnostic criteria for HES, emphasizing the importance of eosinophil counts, evidence of organ or tissue damage, and the exclusion of alternative causes. Delving into the prevalence rates and demographic patterns, learners will focus on the age group most commonly affected and the prevalence rate ranging from 0.36 to 6.3 per 100,000. Moreover, the course will provide a nuanced classification of HES variants based on the affected organ and initial patient evaluation.

This interprofessional learning experience encourages collaboration among team members, fostering a holistic approach to HES. Participants will gain the expertise required to enhance patient outcomes by exploring the intricacies of epidemiology and diagnosis.

Objectives:

• Interpret diagnostic testing to identify variants of hypereosinophilic syndrome (HES).
• Identify patients who are candidates for medical management and choose the appropriate treatment. 
• Assess the need for emergent treatment in severe HES and evaluate for adverse effects. 
• Collaborate with an interdisciplinary team to manage a complex immunological disorder and improve patient outcomes. 

Introduction

Hypereosinophilic syndrome (HES) encompasses a rare and complex group of heterogeneous disorders characterized by persistent and substantial elevations in eosinophil levels and mediators leading to tissue infiltration and damage.[1] Eosinophilopoiesis plays a vital role in the pro-inflammatory processes of multiple diseases.

The HES criteria are as follows:

• Hypereosinophilia is characterized by >1.5 x 10⁹ eosinophils on CBC on 2 examinations >1 month apart.
• The percentage of eosinophils in the bone marrow (BM) section must exceed 20% of all nucleated cells
• The pathologist's assessment that the tissue infiltration by eosinophils is extensive and/or marked deposition of eosinophil granule proteins is found. 
• Evidence of organ or tissue damage attributable to tissue hypereosinophilia (HE). 
• Exclusion of other disorders or conditions as major reasons for organ damage.

Etiology

Based on the initial patient evaluation, HES can be classified into 5 clinically relevant variants:[2]

Primary/Neoplastic (HESN)

• Myeloid variants (M-HES): Classified into various subtypes, including platelet-derived growth factor receptor alpha FIP1L1-PDGFRA fusion gene (F/P pos variant), which occurs secondary to an interstitial chromosomal deletion on 4q12. Platelet-derived growth factor receptor beta (PDGFRB) such as t(5;12)(q31-35;p13), janus kinase 2 (JAK 2) point mutation and translocation formed by t(8;9)(p22;p24), fibroblast growth factor receptor 1 (FGFR1) rearrangements such as (8p11-12), chronic eosinophilic leukemia (CEL), and HES with myeloid features without known mutation.[1][3][4]
• T-cell lymphocytic variants (L-HES): Caused by aberrant IL-5-producing T-cells, such as CD3-CD4+ T cell-associated disease.

Secondary/Reactive (HESR)

• Specific/defined hypereosinophilic syndromes secondary to an underlying condition such as an infectious or inflammatory process. Examples include: helminth infections, episodic angioedema, and eosinophilic granulomatosis with polyangiitis (EGPA). 

Familial HES (HESFA)

• Namely when there is a family history of documented persistent hypereosinophilia of unknown cause. 

Idiopathic (IHES) 

• Hypereosinophilia with no clear underlying cause associated with end-organ damage. 

Organ-Restricted HES 

• Namely, when tissue hypereosinophilia is present, it causes end-organ damage, but HES blood criteria are unmet. 

Epidemiology

The true incidence and prevalence of hypereosinophilic syndromes is unknown. A 2010 study utilizing the Surveillance, Epidemiology, and End Results (SEER) database showed an estimated age-adjusted incidence rate between 0.16 and 0.36 per 100,000 and prevalence (calculated as a product of incidence times duration of chronic disease) between 0.36 to 6.3 per 100,000.[5] 

While HES occurs more commonly between the ages of 20 to 50, some pediatric cases are reported.[6][7] Studies suggest that the frequencies of HES variants are similar between children and adults. Children with primary immunodeficiency more commonly present with secondary HES than adults. In addition, children were noted to have higher median peak absolute eosinophil count, more gastrointestinal complaints, and less pulmonary involvement.[8] 

Pathophysiology

As versatile leukocytes, eosinophils exhibit potent pro-inflammatory, prothrombotic, and pro-fibrotic properties. The multifunctional properties can cause organs to become infiltrated, resulting in end-organ dysfunction.[9][10] Tissue infiltration by eosinophils, especially in conditions like eosinophilic pneumonia, is pathological.

Fibroblast activation, proliferation, and secretion of transforming growth factor-beta (TGF-B) and interleukin-1B (IL-1B) play a crucial role. The toxic granule proteins stored within eosinophils, including eosinophil cationic protein (ECP), promote the release of TGF-B, initiating eosinophil-mediated tissue fibrosis. Numerous studies have substantiated the involvement of eosinophil infiltration in inflammatory fibrotic lesions.[11][12][13]

Allergic reactions contribute to the inflammatory process. Th2 cells, fostering an interleukin-5 (IL-5) rich environment, facilitate eosinophil migration, infiltration, and heightened inflammation in the affected organ.[14]

Lastly, eosinophil-mediated disorders are associated with an elevated thrombotic risk, potentially attributed to eosinophil tissue factor (TF) expression. The prothrombotic quality induces a hypercoagulable state influenced by the platelet-activating effects of eosinophilic granules.[15][16]

History and Physical

According to a retrospective analysis of patients between 2001 to 2006, approximately 37% experienced dermatologic signs and symptoms. Around 25% of these were pulmonary, followed by 14% gastrointestinal, 5% cardiac, and 4% neurologic.[17] 

Dermatologic manifestations associated with HES encompass a spectrum of conditions, including eczema, erythroderma, skin lichenification, dermographism, urticaria, and angioedema. Notably, prominent cutaneous symptoms may indicate L-HES, warranting suspicion of potential cutaneous T-cell lymphoma. Initial signs of HES may manifest as skin lesions on the trunk and extremities, presenting as pruritic erythematous macules, papules, plaques, wheals, and nodules.[18] While infrequent, more severe dermatologic manifestations of HES, particularly the FIP1L1-PDGFRA variant, may extend to mucosal ulcerations within the gastrointestinal tract, ranging from the oral mucosa to the rectum. Additionally, signs indicative of lymphomatoid papulosis may be observed in these cases.[19]

Pulmonary manifestations of HES include asthma-like symptoms, including dyspnea, cough, and wheezing. Abnormal findings such as patchy ground-glass infiltrates and consolidation within the pulmonary parenchyma are observed on chest radiography or computed tomography (CT). Although less frequently observed, pulmonary nodules may be present. Other associated features include pleural effusion, intrathoracic lymphadenopathy, and occurrences of pulmonary emboli.[20] Histologic examination by lung biopsy typically reveals eosinophilic infiltrates. 

Gastrointestinal involvement includes colitis or enteritis, eosinophilic gastritis, chronic active hepatitis, focal hepatic lesions, eosinophilic cholangitis, and Budd-Chiari syndrome. These may present as dysphagia, weight loss, abdominal pain, nausea, vomiting, and diarrhea.[21]

Cardiac manifestations exhibit a higher incidence in FIP1L1-PDGFRA-associated HES. This phenomenon arises from the infiltration of eosinophils into the myocardium, leading to myocardial necrosis due to the release of toxic cationic proteins and enhanced leukocyte recruitment or activation.[6] This process can progress to fatal endomyocardial fibrosis.[22] Typically, the clinical presentation includes signs of heart failure, such as dyspnea, chest pain, cough, and palpitations. However, it may also manifest with signs and symptoms of pericarditis, myocardial ischemia, and intracardiac thrombus.[23][24] 

The progression of eosinophil-mediated heart damage comprises 3 main stages, which do not always occur in sequence. The acute necrotic stage, often clinically silent with a normal physical exam, involves myocardial infiltration with eosinophils and lymphocytes, followed by eosinophil degranulation, myocardial necrosis, and the formation of sterile microabscesses. 

In the intermediate phase, thrombus formation occurs due to eosinophil peroxidase generating an acidic compound called hypothiocyanous acid, which diffuses into the endothelial cells, inducing tissue factor expression. Tissue factor promotes thrombogenesis and attaches to the damaged endocardium, leading to serious complications, such as embolic stroke, limb ischemia, and other embolic events.[25][26] Patients should be anticoagulated promptly when the underlying cause is investigated. 

The fibrotic stage, known as eosinophilic myocardial fibrosis (EMF), occurs secondary to myocardial scarring. It may involve ventricles and the subvalvular apparatus or mitral and tricuspid valves. EMF is responsible for restrictive cardiomyopathy of poor prognosis as well as fatal ventricular arrhythmias secondary to alterations of the cardiac conduction system.[27]

Neurologic manifestations of HES may present as central or peripheral symptoms. Central symptoms include encephalopathy and organic psychosyndrome. Peripheral symptoms account for over 50% of neurologic symptoms of HES and present as peripheral neuropathy, mononeuropathy multiplex, autonomic neuropathy, and polymyositis.[28]

Other signs may occur due to thromboembolic disease, such as intracardiac thrombus, encephalopathy likely secondary to microvascular occlusion, peripheral neuropathy, and sinus thrombosis.[28]

Evaluation

Evaluation of patients presenting with eosinophilia should start with a focused history that identifies known and treatable causes. This includes screening for parasitic infections through stool testing for ova and parasites and investigating potential adverse drug reactions, including those associated with natural supplements. Subsequent steps should detect any evidence of end-organ involvement. It is crucial to remember that end-organ damage may manifest insidiously and does not always correlate with the degree of hypereosinophilia.[29]

In patients meeting the diagnostic criteria for HES without an identified underlying cause of eosinophilia, further investigation is warranted to delineate HES variants.[3] Initial laboratory studies should include CBC with differential, comprehensive blood chemistries, liver enzymes, renal function tests, creatine kinase, and troponin levels. Additional diagnostic and imaging studies to initiate include electrocardiogram, echocardiogram, pulmonary function tests, chest radiography, CT of the chest and abdomen, and tissue biopsies if indicated. 

Hematologic evaluation aims at investigating the underlying cause of HES, including:

• Fluorescence in situ hybridization (FISH) to detect CHIC2 deletion or RT-PCR on peripheral blood to test for FIP1L1-PDGFRA mutation.[30]
• Flow-cytometry, staining, and analysis on peripheral blood to detect specific t-lymphocyte phenotypes, such as CD3, CD4, and CD8
• Bone marrow aspiration and biopsy to reveal increased eosinophils and eosinophil precursors. Dysplasia, CD34 expression, fibrosis, mast cells, and karyotyping should be considered.[31]
• Molecular studies to detect the presence of fusion genes such as FGFR1 and PDGFRB, as well as other mutations, including BCR-ABL1, JAK2 V617F, KIT D816V, and clonal T cell receptor arrangements.[32][33]

When suspecting specific variants, certain testing may provide diagnostic benefits.[34]

• M-HES variants are notable for increased serum B12 and FIP1L1-PDGFRA fusion genes. Anemia, thrombocytopenia, elevated serum tryptase, and hepatosplenomegaly have been noted. 
• L-HES presents dermatologic symptoms, although other organs may be involved. Molecular testing could reveal abnormal T cell markers, including CD3-CD4+, CD3+CD4-CD8-, and CD4+CD7-, among others. Further testing includes T cell receptor and cytogenetic studies to determine the presence of T cell clonality and rare karyotypic abnormalities. Presence or exposure to Epstein-Barr virus (EBV) should be defined since chronic infection could drive L-HES.[35]
• Other tests noted in L-HES cases include elevated immunoglobulins such as IgE, elevated serum thymus, activation-regulated chemokine (TARC), and IL-5.

Treatment / Management

Whether a patient needs treatment for HES depends on the underlying cause and disease severity. Individuals with undetermined causes of HES should undergo a comprehensive evaluation to identify treatable factors, such as drug hypersensitivity and helminth infection, and assess for M-HES associated with the FIP1L1-PDGFRA transcription gene. Therapeutic objectives include reducing the eosinophil count, improving disease symptoms, and preventing disease progression.[36] The timing of therapy is contingent upon disease severity, including the degree of hypereosinophilia and the impact of symptoms on the patient’s well-being. For pauci-symptomatic patients, regular follow-up every 3 months to evaluate for end-organ involvement is sufficient. 

Severe HES is defined by an absolute eosinophil count of 100 x 10⁹/L (>100,000 cells/µL) and signs of hyperleukocytosis involving the nervous and pulmonary systems. In cases of severe HES, treatment involves high-dose intravenous prednisone 1 mg/kg/ day or 1 g/day of methylprednisolone. Patients should be tested for Strongyloides serology before initiating treatment if uncertainty exists regarding prior exposure. Prophylaxis with ivermectin at 200 mcg/kg/daily for 2 days in patients with potential Strongyloides exposure is recommended.[37] A responsive patient should experience a 50% reduction within the first 24 hours, whereas an unresponsive patient will exhibit no change in eosinophil count. It is crucial to remain vigilant of potential intracranial hemorrhage, which may persist up to a week after treating hyperleukocytosis. This risk is attributed to reperfusion injury after restoring blood flow.

In cases of clinically stable HES, when the decision to proceed with treatment is established, the initial approach should be guided by the variant of HES.[38] Systemic glucocorticoids serve as the primary line of therapy for most HES variants. According to a multicenter retrospective analysis of 188 HES patients, 85% achieved partial or complete symptom remission within 1 month, and maintenance therapy was sustained for a minimum of 2 months to a maximum of 20 years. The median maintenance dose of prednisone for remission maintenance was 10 mg daily, with a median maximal dose of 40 mg.[17] Patients displaying resistance to steroids should be re-evaluated and initiated on imatinib. In instances of secondary HES, treatment should be directed at addressing the underlying cause. 

Tyrosine kinase inhibitors, such as imatinib mesylate (IM), have demonstrated notable efficacy in treating F/P pos HES at the recommended daily dosage of 400 mg. The mechanism of action involves the inactivation of downstream phosphorylation by occupying the kinase pocket, which functions as the ATP-binding site in the inactive conformation of genes abl, c-kit, PDGFRA, and PDGFRB.[39] Patients with F/P pos status typically experience a rapid response within a few days, whereas those with F/P neg status observe a response over several weeks. 

Hydroxyurea serves as a viable second-line treatment for individuals who are unresponsive to glucocorticoid monotherapy. Its mechanism of action centrally targets eosinophil development, making it less suitable when an acute decrease in eosinophil count is needed. Hydroxyurea can be prescribed as monotherapy or combination therapy with prednisone. The recommended dose is 0.5 to 2 g daily, contingent on patient tolerance. Studies have shown that a combination therapy approach (2 g hydroxyurea with 1 mg/kg of prednisone daily) results in complete remission for 60% of patients, surpassing the 33% remission rate observed with hydroxyurea monotherapy alone.[40]             

Interferon-α (IFN-α) is a pleiotropic cytokine that can target eosinophils, inhibit the proliferation of CD4 T cells, and inhibit IL-5 production by CD3-CD4+ T cells in vitro. Prior studies have demonstrated its viability as a treatment option for F/P neg HES, particularly when used with glucocorticoids. However, its extensive side effect profile, encompassing flu-like symptoms, myelosuppression, transaminitis, fatigue, myalgias, depression, and suicidal ideation, has posed a challenge and led to treatment interruptions in multiple cases.[41][17][42] IFN-α treatment has been well-received by patients with the L-HES variant. At the same time, individuals with other causes may benefit from a hydroxyurea or IFN-α trial.[43][17] The optimal dosage schedule for IFN-α remains undefined. However, a suggested starting dose is 1 million units per injection daily, with incremental increases of 0.5 to 1 million units per injection every 2 weeks until the desired effect is reached. Dosages can range from 1 to 4 million units per dose up to 7 times weekly. Pegylated IFN-2α, exhibiting efficacy and side effect profiles similar to IFN-α, requires weekly treatment, rendering it a more tolerable option. 

Immunomodulatory agents, such as mepolizumab and benralizumab, a humanized monoclonal antibody against IL-5, have also proven effective in F/P neg HES cases.[44][45] In a significant randomized control trial assessing its efficacy in patients with F/P neg HES on prednisone monotherapy, results indicated that 84% of patients managed to reduce their prednisone dosage without a subsequent increase in the clinical activity of HES. This underscores mepolizumab as a favorable steroid-sparing option.[46][47] The indicated dosage entails 3 subcutaneous injections of 100 mg, totaling 300 mg, administered once every 4 weeks.

Differential Diagnosis

The differential diagnosis of HES varies depending on the extent of eosinophilia.[48] 

In mild to moderate eosinophilia cases, consideration is given to reactive eosinophilia attributed to infectious and parasitic diseases. This possibility requires a meticulous evaluation, a detailed history and examination, and testing for ova, parasites, and helminth infections. It is important to rule out drugs or natural supplements as primary etiologies.

In cases of more moderate to severe manifestations of HES, hematologic and other neoplastic diseases should be considered. Acute eosinophilic leukemia presents an increased number of immature eosinophils in the peripheral blood, bone marrow, or tissues, accompanied by more than 10% blasts in the marrow, distinguishing it from HES. Chronic myeloid leukemia is another diagnosis that may be differentiated from HES as it typically does not cause clinical complications of eosinophilia and can be identified by the detection of BCR:ABL fusion mRNA. 

Systemic mastocytosis with eosinophilia is a relevant differential diagnosis characterized by its association with D816V mutations in the KIT gene. Notably, systemic mastocytosis with eosinophilia has an equal sex distribution compared to HES, which is more predominant in men. Moreover, the ratio of absolute eosinophil count (AEC) to serum total tryptase (AEC/tryptase) is <100 in systemic mastocytosis with eosinophilia vs >100 in HES.[49][50]

Another crucial differential in the diagnostic workup of HES is eosinophilic granulomatosis with polyangiitis (EGPA). The key distinguishing factor between HES and EGPA is the presence of vasculitis in the latter.[51]

Prognosis

While specific prognostic markers for patients with HES are not well-established, the prognosis varies widely. It spans from mildly symptomatic cases, manageable through observation and follow-up, to severe disease resulting in the development of fatal, end-organ damage such as leukemia or irreversible heart failure. 

In recent years, the prognosis of HES has improved, secondary to advancements in the earlier detection of complications, enhanced surgical management of cardiac involvement, and a broader array of therapeutic modalities targeting the underlying cause of HES. 

Further studies regarding the pathophysiology of different disease variants hold promise for refining therapeutic strategies and enhancing a favorable prognosis.[4]

Complications

Complications of HES are attributed to the type and degree of end-organ involvement. The most fatal complications are leukemias, irreversible heart failure, endocarditis, and severe restrictive cardiomyopathy, causing ventricular arrhythmia due to alterations in the cardiac conducting system.

Deterrence and Patient Education

Patients should seek medical attention if they have multiple unexplained symptoms such as dyspnea, chest pain, cough, fevers, chills, palpitations, gastritis, or other dermatologic symptoms such as eczema or dermatitis. Patients should provide physicians with detailed history, including past medical history, travel and social history, medications, and over-the-counter supplements.

Enhancing Healthcare Team Outcomes

HES is a multisystemic condition that necessitates a comprehensive, interprofessional approach. Consultation with sub-specialists should be pursued as necessary, contingent upon end-organ involvement. Active communication among specialists from diverse fields could lead to early detection of HES, identifying the most suitable treatment strategy, and enhancing quality of life.

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Disclosure: Elizabeth Mikhail declares no relevant financial relationships with ineligible companies.

Disclosure: Abhijeet Ghatol declares no relevant financial relationships with ineligible companies.