Approach to Hypereosinophilic Syndrome (PDF)

Approach to the Patient with Suspected Hypereosinophilic syndrome Presented by: Amani Taher Supervised by: Dr. Ala’a Al-Khazzar Hypereosinophilic syndromes ❖ Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders with clinical manifestations ra...

Approach to the Patient with Suspected Hypereosinophilic syndrome Presented by: Amani Taher Supervised by: Dr. Ala’a Al-Khazzar Hypereosinophilic syndromes ❖ Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders with clinical manifestations ranging from fatigue to life_threatening endomyocardial fibrosis and thromboembolic events. ❖ Eosinophilia, defined as an ❖ Hypereosinophilia (HE; AEC ≥ absolute eosinophil count (AEC) 1.5. 10 9 / L) is extremely rare, > 0.45. 10 9 / L, is quite common, with an estimated incidence of occurring in 1 % to 2 % of the 0.315 to 6.3 per 100 000 in the general population. United States Disorders associated with marked eosinophilia: Category Examples Comments Atopic disorders Asthma; atopic dermatitis; chronic Typically cause mild to moderate rhinosinusitis eosinophilia Drug hypersensitivity Varied; drug rash, eosinophilia, and systemic Can occur with any drug or symptoms; eosinophilia-myalgia syndrome supplement; manifestations range from asymptomatic eosinophilia to life-threatening complications Infection and infestation Helminth infection (especially those with a Most common etiology tissue invasive phase) worldwide; Strongyloides infection Fungal infections should always be considered due to Viral infection (HIV, COVID-19) worldwide distribution and the Ectoparasite infestation potential for fatal dissemination with Protozoal infection (limited steroid therapy to Sarcocystis and Cystoisospora) Tuberculosis (rare) Autoimmune and Inflammatory bowel disease, sarcoidosis, IgG4 Clinical sequelae of eosinophilia immunodysregulatory disease may or may not be present and can disorders be difficult to distinguish from the manifestations of the underlying disorder Category Examples Comments Neoplasia Leukemia, lymphoma, solid Although any tumors (especially leukemia/lymphoma can adenocarcinoma) present with HE/HES, pre–B- cell acute lymphoblastic leukemia can be particularly difficult to diagnose Inborn errors of immunity Omenn syndrome, DOCK8 Usually diagnosed in childhood, deficiency, Loeys-Dietz recurrent or unusual infections syndrome common Rare hypereosinophilic Eosinophilic myeloid syndromes neoplasms, lymphocytic variant HE/HES, idiopathic HE/HES, familial HE/HES, single-organ HE/HES, and other overlap disorders Other Radiation, hypoadrenalism, cholesterol emboli, administration of IL-2 ABPA:alergic broncopulmunary aspergillosis CEP:chronic eosinophilic pneumonia EGID:eosinophilic gastrointestinal disorder EGPA:eosinphilic granulomatosis with polangitis (3)  Definitions of hypereosinophilic syndrome WHO definition of HES Consensus definition 9 9 AEC >1.5 × 10 /L for greater than 6 months AEC >1.5 × 10 /L on 2 examinations at least 1 month apart and/or tissue HE Evidence of end-organ manifestations Organ damage and/or dysfunction attributable to tissue HE and exclusion of other conditions as a major reason for organ damage “Idiopathic”—exclusion of reactive HE, Includes multiple clinical classifications, lymphocytic variant HES, CEL-NOS, WHO- including idiopathic, primary defined malignancies, eosinophilia- (clonal/neoplastic), secondary (presumed associated MPNs, or AML/ALL with cytokine driven—including lymphocytic rearrangements variant), and hereditary of PDGFRA, PDGFRB, FGFR1, or PCM1- JAK2 ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CEL-NOS, chronic eosinophilic leukemia- not otherwise specified; MPN, myeloproliferative neoplasm; WHO, World Health Organization. Clinical manifestation (2) ❖ Patients can present with constitutional symptoms such as fatigue, muscle aches or fevers. Pruritus, angioedema, diarrhoea and cough ❖ Many tissues can be involved, but cardiac disease is the major cause of mortality. The heart can be affected by endomyocardial fibrosis, pericarditis, myocarditis and intramural thrombus formation. Death is usually due to dilated cardiomyopathy. ❖ Involvement of the central and peripheral nervous systems can result in mononeuritis multiplex, paraparesis, encephalopathy and even dementia. ❖ Pulmonary involvement can take the form of pulmonary infiltrates, fibrosis or pleural disease with effusions. ❖ Gastrointestinal involvement can manifest as diarrhea, gastritis, colitis, hepatitis or the Budd–Chiari syndrome. ❖ The skin can be affected by pruritus, angioedema, papules or plaques. Rarely, other tissues such as the kidneys and bones can be involved.  Much of the tissue damage in eosinophilia is believed to be secondary to eosinophil degranulation and release of mediators such as eosinophil cationic protein and major basic protein. Eosinophil mediators act mainly locally in tissues infiltrated by eosinophils to cause tissue damage. The recent finding that a raised serum tryptase in a subset of cases with clonal eosinophilia hints at a role for other cells (mast cells) in some cases Classification: I. Myeloid HE/HES (suspected or proven eosinophilic myeloid neoplasm, including those associated with rearrangements of PDGFRA and other recurrent molecular abnormalities). II. Lymphocytic variant HE/HES (presence of a clonal or phenotypically Aberrant T-cell population that produces cytokines that drive the eosinophilia). III. Overlap HES (single-organ-restricted eosinophilic disorders and clinically defined eosinophilic syndromes that overlap in presentation with idiopathic HES; ie, eosinophilic gastrointestinal disorders, eosinophilic granulomatosis with polyangiitis), IV. Associated HE/HES (in the context of a defined disorder, Such as a helminth infection, neoplasm, immunodeficiency, or hypersensitivity reaction) V. Familial HE/HES (occurrence in >1 family member excluding associated HE/HES), VI. Idiopathic HE/HES (unknown cause and exclusion of other subtypes). Clinical subtypes of hypereosinophilic syndrome: Frequency distribution of 554 patients referred to the National Institutes of Health for unexplained eosinophilia Myeloproliferative variant HES (2) ❖ Myeloproliferative variant of HES are characterized by male predominance, end organ damage, elevated serum tryptase, splenomegaly, anaemia, thrombocytopenia and bone marrow myeloproliferation with reticulin fibrosis. ❖ Unresponsive to steroid therapy. ❖ It’s often associated with an interstitial deletion on chromosome 4q12, resulting in a FIP1L1–PDGFRA fusion gene. The protein product of this fusion gene is a tyrosine kinase with enhanced activity and particular sensitivity to low-dose imatinib therapy. Lymphocytic variant HES ❖ Lymphocytic variant HES (LHES) are characterized by a large CD2+ CD3– CD4+ T-cell population that produced interleukin (IL) 4 and IL-5 in response to stimulation. ❖.Equally frequent in males and females. ❖ LHES most often presents with dermatologic manifestations. but, any organ system can be involved, and some patients with asymptomatic HE have clonal aberrant T-cell populations indistinguishable from those with symptomatic LHES. ❖ Serum IgM, IgE, and serum and thymus and activation-regulated chemokine levels are elevated in most patients with LHES and can provide useful diagnostic clues. ❖ Whereas the gold standard for diagnosis of LHES is identification of a clonal and/or aberrant population of T cells producing type 2 cytokines, intracellular flow cytometry is not available at most centers, and the diagnosis most often relies on a compatible clinical picture and demonstration of a clonal and/or aberrant T-cell population in the peripheral blood. Expanded surface phenotyping is often necessary to demonstrate and/or confirm the aberrant population. ❖ It is important to recognize that the surface phenotype of the clonal population in LHES can be indistinguishable from that seen in T-cell malignancies (especially angioimmunoblastic T-cell lymphoma and cutaneous T-cell lymphoma). Thus, LHES is a diagnosis of exclusion. Moreover, progression of LHES to a lymphoid malignancy occurs in approximately 10% of patients, sometimes after many years of stable disease.  Consequently, at a minimum, patients with LHES should undergo assessment for occult lymphoma at diagnosis and in the setting of an increase in size of the clonal T-cell population or development of resistance to previously effective therapy.  Diagnostic Workup All patients with confirmed HE Comments Comprehensive history and physical Including prior eosinophil counts, medications, examination travel/exposure history Complete blood count with differential and Dysplastic eosinophils, other lineage * smear involvement, and/or presence of myeloid precursors are suggestive of (but not diagnostic for) MHES Routine chemistries, including liver function To assess end organ involvement * tests Quantitative serum immunoglobulin levels IgE levels are typically elevated in a variety of conditions (ie, LHES, EGPA, parasitic infections, and some immunodeficiencies); IgM levels are elevated in LHES and episodic angioedema and eosinophilia Serum tryptase and B12 levels Elevated serum B12 levels can be seen in many myeloid neoplasms; elevated serum tryptase is near universal in PDGFRA and KIT-associated disease T- and B-cell receptor rearrangement Clonal and/or aberrant T-cell populations are * studies ; lymphocyte phenotyping by flow characteristic of LHES and some types of * cytometry lymphoma. Clonal B cells are suspicious for B-cell neoplasm, including pre–B-cell acute lymphoblastic leukemia in children/adolescents. * Serum troponin, electrocardiogram, and If abnormal, cardiac MRI should be echocardiogram considered * Chest/abdomen/pelvis CT To assess for splenomegaly, lymphadenopathy, asymptomatic pulmonary involvement, and occult neoplasms * Biopsy of affected tissues (if possible) Cardiac tissue involvement can be patchy, limiting the utility of cardiac biopsy Selected patients with HE/HES * Pulmonary function tests Any patient with suspected pulmonary involvement or abnormal findings on chest CT * 9 Bone marrow aspirate and biopsy All patients with AEC >5.0 × 10 /L and/or features suggestive of LHES or MHES; patients with clear diagnoses, such as EGPA or parasitic infection, may not need bone 9 marrow testing despite AEC >5.0 × 10 /L Testing for BCR::ABL1, FIP1L1::PDGFRA, and Testing should be guided by results of initial translocations/mutations testing and bone marrow examination; all involving PDGFRB, JAK2, FGFR1, and KIT patients with elevated serum tryptase and/or B12 levels should be tested for FIP1L1::PDGFRA NGS myeloid panel; targeted or whole-exome Depending on initial evaluation sequencing; other genetic testing * PET scan, EBV viral load Particularly in patients with suspected LHES Other testing for secondary causes As indicated by clinical history and physical examination  HEus: hypereosinophilia of unknown significance CEL: chronic eosinophilic leukemia MLN: Myeloid/Lymphoid Neoplasms with Eosinophilia MLN_TK:Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase (TK) Gene Rearrangements. Approach to therapy ❖ Since secondary causes of eosinophilia, such as helminth infection, typically require a different therapeutic approach, these should be considered early in the diagnostic process. ❖ The presence and severity of clinical manifestations should be assessed as this will affect both the nature and urgency of therapeutic intervention ❖ Prednisone remains the mainstay of therapy in the acute setting for severe and/or life-threatening manifestations of HES. If the eosino- philia does not dramatically decrease within 24 to 48 hours, additional therapy should be considered depending on the suspected clinical subtype (ie, imatinib for patients with clinical findings suggestive of a myeloid neoplasm, cyclophosphamide for patients with manifestations suggestive of eosinophilic granulomatosis with polyangiitis). ❖ Once the patient is stable, further evaluation should focus on the identification of the most likely clinical subtype). ❖ With the exception of patients with myeloid HES, most patients with symptomatic HES respond rapidly to corticoste- roid therapy, although toxicity and resistance limit the utility of this therapy in the long term. ❖ Conventional second-line agents, including hydroxyurea and interferon α.  Eosinophil-targeting biologics (eg: mepolizumab and Reslizumab ) are specialized therapeutic agents designed to reduce eosinophil levels in the blood and tissues by targeting pathways critical to their survival, activation, and recruitment. ❖ The use of eosinophil-targeting biologics in the acute setting remains controversial CLINICAL CASE ❖ A 38 years old previously healthy woman presented with intermittent but intense pruritus without rash. The pruritus initially involved only her ankles but subsequently spread up her legs with accompanying angioedema of the thighs and buttocks that prevented her from being able to wear pants. Antihistamines were ineffective, and a short course of solumedrol prescribed for sinusitis did not relieve the pruritus or swelling. A dermatologist prescribed oral and topical antibiotics for presumed folliculitis without improvement. One year after the onset of the symptoms, a complete blood count was performed and revealed anemia, thrombocytopenia (platelets 34 000), and eosinophilia (14.0. 10 9 / L). She was referred to hematology. ❖ A bone marrow biopsy specimen was hypercellular with increased eosinophils and plasma cells. Testing for FIP1L1::PDGFRA was negative. She was treated with prednisone 60 mg daily for presumed idiopathic thrombocytopenic purpura with clinical and hematologic improvement. However, as the prednisone was tapered, the eosinophilia, pruritus, and edema returned. She was referred to Mayo Clinic for further evaluation, which included an indeterminate serologic test for Strongyloides. She was treated with 2 doses of ivermectin and a 2-week course of albendazole. During this time, the prednisone was slowly tapered despite a rising AEC, peaking at 26.0. 109/L on prednisone 5 mg every other day, and recurrent symptoms.The prednisone dose was increased to 25 mg daily, and hydroxyurea therapy (500 mg twice daily) was initiated. This was ineffective, and she was referred to the National Institutes of Health for further evaluation. ❖ At the time of referral, she complained of fatigue, swelling, and extreme pruritus. Physical examination revealed symmetric nonpitting edema of the thighs and excoriations predominantly on the lower legs. Laboratory testing was notable for AEC 3.01. 109/L; platelets 114 000; markedly elevated IgG, IgM, and IgE; and normal serum B12 and tryptase. Computed tomography (CT) scan was notable for borderline splenomegaly and minimal diffuse lymphadenopathy. Repeat bone marrow again showed only increased eosinophils. Mast cells were not increased, and testing for D816V KIT was negative. T-cell receptor Testing by polymerase chain reaction showed a clonal pattern, and flow cytometry was notable for an aberrant CD3– CD4+CD10+ T-cell population, consistent with a diagnosis of lymphocytic variant hypereosinophilic syndrome (HES). B-cell clonality studies were negative. She was started on interferon α 1 mU daily with resolution of eosinophilia, platelets >50 k and symptomatic improvement ❖ Over the next 4 years, she remained relatively stable on interferon α therapy with partially controlled symptoms, AEC