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Hypereosinophilic Syndrome

HES

Hypereosinophilic syndromes (HES) are a collection of disorders defined by persistent and significantly elevated levels of eosinophils in the blood, in addition to evidence of direct damage to at least one organ. The increase in the eosinophilic count should not be a result of other definitive causes of hypereosinophilia, such as allergic reactions or parasitic infections.

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Presentation

Hypereosinophilic syndrome has the potential to disrupt every organ in the body and, although it more frequently presents insidiously, sudden and acute deterioration is not uncommon and affects mostly the nervous and cardiovascular system. HES can also be discovered incidentally in up to 12% of patients [11].

Cardiac damage is the major cause of death and pathogenesis generally proceeds along three stages. The first stage is characterized by acute necrosis; clinical manifestations are usually absent. The second stage leads to the formation of thrombi and, in the final stage, there is widespread endomyocardial fibrosis. Patients usually complain of chest pain, dyspnea and orthopnea.

HES can also result in widespread hematologic complications. Anemia associated with the disease can manifest in fatigue and other non-specific symptoms. Thrombosis can result either from cardiac disease or hypercoagulability and targets especially the nervous system. Splenomegaly occurs in 40% of patients and should be suspected in patients complaining of left upper quadrant pain

Neurologic involvement manifests with embolic or thrombotic events, which are frequently the initial presenting symptoms of HES. In addition, up to 50% of patients report peripheral neuropathy. The latter has a variable expression and can be symmetric or asymmetric, sensory, pure motor or mixed. 

Lung involvement results from infiltration of eosinophils along the base and periphery and manifests with a nonproductive, chronic and persistent cough. Patients may also develop pleural effusions, secondary to congestive heart failure and can result in dyspnoic symptoms. Other common respiratory complications include angioedema and rhinitis.

Joint and skin involvement are common and patients frequently complain of non-specific skin changes, dermatographism, angioedema, arthralgia and myalgia. Raynaud's phenomenon can also occur, but is uncommon.

Gastrointestinal involvement manifests principally with diarrhea, nausea and abdominal pain. Thrombosis seldom results in small bowel necrosis and some patients develop sclerosing cholangitis.

Finally, patients can develop symptoms that are not organ-specific, such as fever, night sweats, anorexia and weight loss. The latter two seem to occur mostly with cardiac disease although reports are variable.

Splenomegaly
  • 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.[ncbi.nlm.nih.gov]
  • Of the 20 patients, 14 initially received prednisolone treatment, which resulted in rapid improvement and normalization of eosinophilia within 8 weeks; however, 2 patients with splenomegaly showed poor control of eosinophilia in response to corticosteroid[ncbi.nlm.nih.gov]
  • Among 6 children with idiopathic HES; 2 had pulmonary involvement; 1 had cardiac and pulmonary involvement and splenomegaly; 1 had cardiac involvement and hepatosplenomegaly; 1 had cardiac and central nervous system involvement; and 1 had skin involvement[ncbi.nlm.nih.gov]
  • High-dose intravenous steroid (methylprednisolone 500 mg/day) alleviated the neurological symptoms within a few weeks, and the administration of imatinib (200 mg/day) resulted in an impressive regression of the hypereosinophilia and splenomegaly within[ncbi.nlm.nih.gov]
  • A man in his 30s presented to our hospital with fever, hypereosinophilia, widespread lymphadenopathy, and splenomegaly. Laboratory tests showed hypereosinophilia, increased soluble interleukin-2 receptor, and increased vitamin B12.[ncbi.nlm.nih.gov]
Fever
  • She was admitted in 2008 with fever, headache, confusion and visual loss. Diagnostic workup uncovered an eosinophilia of 3.1 10⁹/L and major ECG abnormalities.[ncbi.nlm.nih.gov]
  • The patient experienced fever, cough, abdominal pain, massive hematemesis, and hematochezia that developed in succession. Abdominal computed tomography showed portal vein and superior mesenteric vein thromboses.[ncbi.nlm.nih.gov]
  • A 43year old food vendor referred to the Haematology Department, University College Hospital, Ibadan on account of a 6-week history of cough productive of mucoid, brownish, foul smelling sputum with associated breathlessness, high grade intermittent fever[ncbi.nlm.nih.gov]
  • A man in his 30s presented to our hospital with fever, hypereosinophilia, widespread lymphadenopathy, and splenomegaly. Laboratory tests showed hypereosinophilia, increased soluble interleukin-2 receptor, and increased vitamin B12.[ncbi.nlm.nih.gov]
  • In adults, the frequencies of symptoms found on presentation are: fatigue (26%), cough (24%), dyspnea (16%), rash (12%), and fever (12%). Fever (58.8%), arthralgias (23%), and rash (23.5%) were more common in pediatric cases.[pediatrics.aappublications.org]
Fatigue
  • Four years later she re-presented with headache, fatigue and an eosinophilia of 13.4 10⁹/L. This occurred 3 months after cessation of immunosuppression and within 12 months of total colectomy for fulminant ulcerative colitis.[ncbi.nlm.nih.gov]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019[patientslikeme.com]
  • I have many skin allergies and other symptoms ( severe sinus, been in sugery 2 times) fatigue and short breathing.[inspire.com]
  • It usually presents with fever, weight loss, fatigue, and rash. An enlarged liver and spleen and liver is often present. The lungs, kidneys, heart, and nervous system can also be affected.[checkorphan.org]
  • Constitutional symptoms of fever, myalgia and fatigue may occur. Other common complications include central or peripheral nervous system involvement, hepato- and/or splenomegaly, and coagulation disorders.[orpha.net]
Weight Loss
  • Finally, patients can develop symptoms that are not organ-specific, such as fever, night sweats, anorexia and weight loss. The latter two seem to occur mostly with cardiac disease although reports are variable.[symptoma.com]
  • It usually presents with fever, weight loss, fatigue, and rash. An enlarged liver and spleen and liver is often present. The lungs, kidneys, heart, and nervous system can also be affected.[checkorphan.org]
  • The case report involved a 15-year-old male who presented with abdominal pain, diarrhea, and a 10-lb weight loss. Colonoscopy revealed colitis. A nonproductive cough, night sweats, and a diffuse pruritic, papular rash developed.[pediatrics.aappublications.org]
  • Case Presentation: A 41‐year‐old man with no medical history presented for a second opinion for chest pain, cough, fevers, and an 80‐pound weight loss in 2 months. Previous evaluation revealed peripheral eosinophilia, pericarditis, and pneumonia.[shmabstracts.com]
Congestive Heart Failure
  • The most dangerous complication involves the heart and involves myocardial fibrosis, congestive heart failure and, ultimately, death.[symptoma.com]
  • The five-year survival rate is 80% with congestive heart failure being the most common cause of death. Leukaemic change is a risk in prolonged disease.[patient.info]
  • Patient with clonal HES develops congestive heart failure in response to imatinib Patients with significant cardiac infiltration with eosinophils may develop acute cardiac problems upon initiation of imatinib.[cancertherapyadvisor.com]
  • In the heart, the infiltration by eosinophils results in endomyocardial fibrosis, with subsequent development of congestive heart failure (CHF) and death.[emedicine.medscape.com]
Lymphadenopathy
  • OBJECTIVE: To compare the clinical and laboratory features of IgG4-related disease (IgG4-RD) and lymphocyte-variant hypereosinophilic syndrome (L-HES), two rare diseases that often present with lymphadenopathy, gastrointestinal symptoms, eosinophilia,[ncbi.nlm.nih.gov]
  • A man in his 30s presented to our hospital with fever, hypereosinophilia, widespread lymphadenopathy, and splenomegaly. Laboratory tests showed hypereosinophilia, increased soluble interleukin-2 receptor, and increased vitamin B12.[ncbi.nlm.nih.gov]
  • Physical examination showed mild hepatosplenomegaly without peripheral lymphadenopathy, and vital signs were normal.[journals.plos.org]
  • […] tricuspid regurgitation with cough, dyspnea, heart failure, arrhythmias, endomyocardial disease, pulmonary infiltrates, and pleural effusions Dermatologic 50% Angioedema Dermatographism Pruritus Rashes (including eczema and urticaria) Hematologic 50% Anemia Lymphadenopathy[merckmanuals.com]
  • A case of dermatopathic lymphadenopathy associated with hypereosinophilic syndrome. Ann Acad Med Singapore. 2012 Jan. 41(1):35-6. [Medline]. Kahn JE, Bletry O, Guillevin L. Hypereosinophilic syndromes.[emedicine.medscape.com]
Cough
  • The patient experienced fever, cough, abdominal pain, massive hematemesis, and hematochezia that developed in succession. Abdominal computed tomography showed portal vein and superior mesenteric vein thromboses.[ncbi.nlm.nih.gov]
  • A 43year old food vendor referred to the Haematology Department, University College Hospital, Ibadan on account of a 6-week history of cough productive of mucoid, brownish, foul smelling sputum with associated breathlessness, high grade intermittent fever[ncbi.nlm.nih.gov]
  • A nonproductive cough, night sweats, and a diffuse pruritic, papular rash developed. His initial absolute eosinophil count was 1890/mm 3 (reference: 3 ), which increased to 52 000/mm 3 .[pediatrics.aappublications.org]
  • You have chills, a cough, or feel weak and achy. You have questions or concerns about your condition or care. When should I seek immediate care or call 911? You have severe chest or abdominal pain. You have sudden trouble breathing.[drugs.com]
  • Target-organ damage mediated by eosinophils is highly variable among patients, and consists of dermatological involvement (urticaria, eczema, angioedema, pruriginous papules, nodules, erythroderma) in more than 50% of cases, followed by involvement of lungs (cough[orpha.net]
Pneumonia
  • The changing pattern of heroin use to inhalation/sniffing leading to an increasing abuse may cause a rise in the prevalence of Heroin induced eosinophilia, as it has been reported in a case of eosinophilic pneumonia associated with heroin inhalation.[ncbi.nlm.nih.gov]
  • Hypereosinophilic syndrome; extensive thrombosis in the portal venous system; acute eosinophil-associated pneumonia; gastrointestinal bleeding; intestinal necrosis.[ncbi.nlm.nih.gov]
  • Definition / general Diagnosis of exclusion; also called idiopathic hypereosinophilic syndrome See also discussions in these chapters: Gallbladder-eosinophilic cholecystitis, Lung - nontumor: eosinophilic pneumonia, Pancreas - eosinophilic pancreatitis[pathologyoutlines.com]
  • In this article, we discuss acute and chronic eosinophilic pneumonias, eosinophilic granulomatosis with polyangiitis, and the hypereosinophilic syndromes.[ncbi.nlm.nih.gov]
  • Previous evaluation revealed peripheral eosinophilia, pericarditis, and pneumonia. On presentation to our facility, his WBC count was 28,000/μL with an eosinophil count of 12,600 cells/μL.[shmabstracts.com]
Pleural Effusion
  • Respiratory - pneumonitis, pulmonary emboli, pleural effusion and eosinophilic infiltrates. Skin - dermatitis, urticaria, papular rashes. Ear, nose and throat - sinusitis.[patient.info]
  • Chest radiographs may indicate pleural effusions and/or fibrosis, and neurological tests such as CT scans can show strokes and increased cerebrospinal fluid pressure.A proportion of patients have a mutation involving the PDGFRA and FIP1L1 genes on the[en.wikipedia.org]
  • effusions Dermatologic 50% Angioedema Dermatographism Pruritus Rashes (including eczema and urticaria) Hematologic 50% Anemia Lymphadenopathy Splenomegaly Thromboembolic phenomena Thrombocytopenia Neurologic 50% Cerebral emboli with focal deficits Diffuse[merckmanuals.com]
Dyspnea
  • One year after remission she presented malar rash, hair loss, arthralgias, conjuntival redness, dyspnea and thoracic oppression.[ncbi.nlm.nih.gov]
  • Common manifestations include brain or lung hypoxia (eg, encephalopathy, dyspnea or respiratory failure).[merckmanuals.com]
  • In adults, the frequencies of symptoms found on presentation are: fatigue (26%), cough (24%), dyspnea (16%), rash (12%), and fever (12%). Fever (58.8%), arthralgias (23%), and rash (23.5%) were more common in pediatric cases.[pediatrics.aappublications.org]
  • Common symptoms in these phases include chest pain, dyspnea, or orthopnea. Hematologic manifestations are largely nonspecific and may include fatigue, which may be due to the anemia that is occasionally observed with hypereosinophilic syndrome.[emedicine.medscape.com]
  • Patients usually complain of chest pain, dyspnea and orthopnea. HES can also result in widespread hematologic complications. Anemia associated with the disease can manifest in fatigue and other non-specific symptoms.[symptoma.com]
Rhinitis
  • rhinitis with eosinophilia Peritoneal eosinophilia Secondary eosinophilia Traumatic ulcerative granuloma of tongue with stromal eosinophilia Clinical Information Abnormal increase of eosinophils in the blood, tissues or organs Disordered formation of[icd9data.com]
  • Featured topics include asthma, rhinitis, sinusitis, food allergies, allergic skin diseases, diagnostic techniques, allergens, and treatment modalities.[ingentaconnect.com]
  • Other common respiratory complications include angioedema and rhinitis. Joint and skin involvement are common and patients frequently complain of non-specific skin changes, dermatographism, angioedema, arthralgia and myalgia.[symptoma.com]
  • Non-allergic nasal rhinitis with eosinophilia Clinical Information Abnormal increase of eosinophils in the blood, tissues or organs.[icd10data.com]
  • […] syndrome Dyspnea may occur due to CHF or pleural effusions (which are not always secondary to CHF) Less frequently, pulmonary fibrosis occurs after prolonged disease and often accompanies cardiac fibrosis Bronchospasm and asthmatic symptoms are infrequent Rhinitis[emedicine.medscape.com]
Abdominal Pain
  • 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.[ncbi.nlm.nih.gov]
  • The patient experienced fever, cough, abdominal pain, massive hematemesis, and hematochezia that developed in succession. Abdominal computed tomography showed portal vein and superior mesenteric vein thromboses.[ncbi.nlm.nih.gov]
  • Alcohol intolerance with abdominal pain, flushing, and nausea. Organ involvement in HES [ 6 ] This can be manifold and the following are some examples: Blood - thrombocytopenia, hypercoagulability.[patient.info]
  • You have severe chest or abdominal pain. You have sudden trouble breathing. Care Agreement You have the right to help plan your care. Learn about your health condition and how it may be treated.[drugs.com]
  • pain, diarrhea, ascites) in roughly 40%.[orpha.net]
Nausea
  • Alcohol intolerance with abdominal pain, flushing, and nausea. Organ involvement in HES [ 6 ] This can be manifold and the following are some examples: Blood - thrombocytopenia, hypercoagulability.[patient.info]
  • […] among patients, and consists of dermatological involvement (urticaria, eczema, angioedema, pruriginous papules, nodules, erythroderma) in more than 50% of cases, followed by involvement of lungs (cough, breathlessness and wheezing) and digestive tract (nausea[orpha.net]
  • Gastrointestinal involvement manifests principally with diarrhea, nausea and abdominal pain. Thrombosis seldom results in small bowel necrosis and some patients develop sclerosing cholangitis.[symptoma.com]
Diarrhea
  • […] dermatological involvement (urticaria, eczema, angioedema, pruriginous papules, nodules, erythroderma) in more than 50% of cases, followed by involvement of lungs (cough, breathlessness and wheezing) and digestive tract (nausea, vomiting, abdominal pain, diarrhea[orpha.net]
  • Results: A previously healthy 52 year old woman experienced a 10 day history of insidiously progressive confusion with preceding GI upset and diarrhea. On examination, she was afebrile with normal vital signs and a normal neurological examination.[neurology.org]
  • The case report involved a 15-year-old male who presented with abdominal pain, diarrhea, and a 10-lb weight loss. Colonoscopy revealed colitis. A nonproductive cough, night sweats, and a diffuse pruritic, papular rash developed.[pediatrics.aappublications.org]
  • Gastrointestinal involvement manifests principally with diarrhea, nausea and abdominal pain. Thrombosis seldom results in small bowel necrosis and some patients develop sclerosing cholangitis.[symptoma.com]
Vomiting
  • She also had asymptomatic severe hypokalaemia (1.9mmol/l) likely due to vomiting and reduced dietary intake.[ncbi.nlm.nih.gov]
  • […] patients, and consists of dermatological involvement (urticaria, eczema, angioedema, pruriginous papules, nodules, erythroderma) in more than 50% of cases, followed by involvement of lungs (cough, breathlessness and wheezing) and digestive tract (nausea, vomiting[orpha.net]
Abdominal Cramps
  • This past year I was in and out of the hospital several times with pleuritis, pheumonia, food allergies, severe abdominal cramps, veryyy low pressure and cardiac issues (disautonomy) and tachycardia.[inspire.com]
  • cramps Diarrhea Nausea Immunologic 40% Circulating immune complexes with serum sickness Elevated levels of immunoglobulins (especially IgE) Occasionally, patients with very severe eosinophilia (eg, eosinophil counts of 100,000/mcL) develop complications[merckmanuals.com]
Thrombosis
  • The clinical data of a patient with extensive thrombosis in his portal venous system (superior mesenteric, splenic, hepatic, and portal veins), renal artery thrombosis, and mesenteric thrombosis caused by HES with secondary gastrointestinal bleeding and[ncbi.nlm.nih.gov]
  • However there are no standard recommendations for the use of anticoagulant therapy of HES in the setting of thrombosis.[ncbi.nlm.nih.gov]
  • First, fresh or organized thrombosis with marked eosinophilic infiltration was observed in the cavity and walls of the thrombosed vessels.[ncbi.nlm.nih.gov]
  • Case reports link HES to prosthetic valve thrombosis (PVT), but the optimal type of prosthetic valve in HES is not known. Herein is reported the case of a young female HES patient with secondary mitral valve degeneration and severe regurgitation.[ncbi.nlm.nih.gov]
  • Antiplatelet drugs such as clopidogrel, aspirin or ticlodipine are used to prevent thrombosis. Anticoagulation is only indicated in cases of left ventricular thrombosis, as well as transient ischemic attacks that persist after aspirin treatment.[symptoma.com]
Chest Pain
  • We report a 46-year-old female who came to hospital with atypical chest pains and a known history of eosinophilia. After excluding other possible causes of eosinophilia, she underwent further cardiac investigations.[ncbi.nlm.nih.gov]
  • Patients usually complain of chest pain, dyspnea and orthopnea. HES can also result in widespread hematologic complications. Anemia associated with the disease can manifest in fatigue and other non-specific symptoms.[symptoma.com]
  • Chest pain, tiredness, general sickness, awful pain in my abdomen, joint pain and hot bruises all over my body, and I couldn’t even walk anymore. I had lost several pounds and now I could barely eat…. my body started to reject all food.[globalgenes.org]
  • Case Presentation: A 41‐year‐old man with no medical history presented for a second opinion for chest pain, cough, fevers, and an 80‐pound weight loss in 2 months. Previous evaluation revealed peripheral eosinophilia, pericarditis, and pneumonia.[shmabstracts.com]
Hepatomegaly
  • Idiopathic hypereosinophilic syndrome in a child with fever and hepatomegaly MORINAGA Shingo, TAKAKI Kazutaka, SADA Akiko, MATSUI Toshimitsu Rinsho Ketsueki 53(1) 83-86 2012 Idiopathic hypereosinophilic syndrome (IHES) in children is a rare disorder.[researchmap.jp]
  • Gastrointestinal findings are as follows: Hepatomegaly may occur with chronic active hepatitis due to hypereosinophilic syndrome Hepatomegaly may also occur with Budd-Chiari syndrome, which may infrequently be a thrombotic complication of hypereosinophilic[emedicine.medscape.com]
Blurred Vision
  • A 64-year-old man was brought to the emergency department because of sudden-onset blurred vision in both eyes and diplopia, as well as a frontal headache that had begun earlier that day.[doi.org]
  • vision and slurred speech have been reported Peripheral neuropathies account for about 50% of all neurologic symptoms in hypereosinophilic syndrome; their etiology is poorly understood, but they may present as symmetric or asymmetric sensory changes,[emedicine.medscape.com]
Myalgia
  • Constitutional symptoms of fever, myalgia and fatigue may occur. Other common complications include central or peripheral nervous system involvement, hepato- and/or splenomegaly, and coagulation disorders.[orpha.net]
  • Manifestations included rash, pruritus, headache, and myalgia. Systemic nonallergic reactions were reported by 2% of subjects who received Nucala and 3% of subjects in the placebo group. Manifestations included rash, flushing, and myalgia.[gsk.com]
  • Joint and skin involvement are common and patients frequently complain of non-specific skin changes, dermatographism, angioedema, arthralgia and myalgia. Raynaud's phenomenon can also occur, but is uncommon.[symptoma.com]
  • Symptoms and Signs Abnormalities in Patients With Hypereosinophilic Syndrome System Prevalence Manifestations Constitutional 50% Anorexia Fatigue Fever Myalgias Weakness Weight loss Cardiopulmonary 70% Mural thrombi with emboli Restrictive or infiltrative[merckmanuals.com]
  • […] frequently, pulmonary fibrosis occurs after prolonged disease and often accompanies cardiac fibrosis Bronchospasm and asthmatic symptoms are infrequent Rhinitis is sometimes a presenting symptom Rheumatologic manifestations are as follows: Arthralgias and myalgias[emedicine.medscape.com]
Arthralgia
  • One year after remission she presented malar rash, hair loss, arthralgias, conjuntival redness, dyspnea and thoracic oppression.[ncbi.nlm.nih.gov]
  • Fever (58.8%), arthralgias (23%), and rash (23.5%) were more common in pediatric cases. As with adults, involvement of the cardiovascular system is the major source of morbidity and mortality.[pediatrics.aappublications.org]
  • Joint and skin involvement are common and patients frequently complain of non-specific skin changes, dermatographism, angioedema, arthralgia and myalgia. Raynaud's phenomenon can also occur, but is uncommon.[symptoma.com]
  • CHF) Less frequently, pulmonary fibrosis occurs after prolonged disease and often accompanies cardiac fibrosis Bronchospasm and asthmatic symptoms are infrequent Rhinitis is sometimes a presenting symptom Rheumatologic manifestations are as follows: Arthralgias[emedicine.medscape.com]
Joint Effusion
  • effusions can occur Digital necrosis is rare but sometimes observed with associated Raynaud phenomenon The skin is among the most common organ systems involved in hypereosinophilic syndrome; more than half of all patients have cutaneous involvement.[emedicine.medscape.com]
Pruritus
  • Pruritus is a frequent occurrence in dermatology, and investigation is often unrevealing.[ncbi.nlm.nih.gov]
  • A 36-year-old male with no comorbidities presented progressive erythroderma, pruritus, peripheral neuropathy, and eosinophilia in the previous seven months. No mutations were found in FIP1L1/PDGFRA.[ncbi.nlm.nih.gov]
  • We report a hitherto undescribed unusual CD30 clonal T-cell proliferation in a 46-year-old man with the lymphocytic variant of hypereosinophilic syndrome with a 17-year history of pruritus, generalized persistent papulonodular skin lesions and peripheral[ncbi.nlm.nih.gov]
  • […] vendor referred to the Haematology Department, University College Hospital, Ibadan on account of a 6-week history of cough productive of mucoid, brownish, foul smelling sputum with associated breathlessness, high grade intermittent fever, and intense pruritus[ncbi.nlm.nih.gov]
  • Here we present a patient with a 27-year history of pruritus, urticarial lesions, recurrent diarrhoea, depression and a monoclonal gammopathy in the setting of HES. The patient presented with erythemas, disseminated plaques, papules and scaling.[ncbi.nlm.nih.gov]
Urticaria
  • Clinical description Target-organ damage mediated by eosinophils is highly variable among patients, and consists of dermatological involvement (urticaria, eczema, angioedema, pruriginous papules, nodules, erythroderma) in more than 50% of cases, followed[orpha.net]
  • These manifestations include:Skin rashes, for example, urticaria or angioedema, Dizziness, Memory misfortune or disarray, Cough, Shortness of inhale, Fatigue, Fever, Mouth wounds.[omicsonline.org]
  • Prominent skin findings include erythroderma, plaques, and/or urticaria.[unboundmedicine.com]
  • These symptoms include: Skin rashes such as urticaria or angioedema Dizziness Memory loss or confusion Cough Shortness of breath Fatigue Fever Mouth sores Diagnosis Symptoms of HES are also common in many other medical problems, making an initial diagnosis[aaaai.org]
  • Skin - dermatitis, urticaria, papular rashes. Ear, nose and throat - sinusitis. Central nervous system - acute cerebrovascular event and peripheral neuropathy.[patient.info]
Angioedema
  • Clinical description Target-organ damage mediated by eosinophils is highly variable among patients, and consists of dermatological involvement (urticaria, eczema, angioedema, pruriginous papules, nodules, erythroderma) in more than 50% of cases, followed[orpha.net]
  • These manifestations include:Skin rashes, for example, urticaria or angioedema, Dizziness, Memory misfortune or disarray, Cough, Shortness of inhale, Fatigue, Fever, Mouth wounds.[omicsonline.org]
  • Other hypereosinophilic syndrome variants include chronic eosinophilic leukemia, Gleich syndrome (cyclical eosinophilia and angioedema), familial hypereosinophilic syndrome mapped to 5q 31-33, and other organ-specific syndromes.[merckmanuals.com]
  • Other common respiratory complications include angioedema and rhinitis. Joint and skin involvement are common and patients frequently complain of non-specific skin changes, dermatographism, angioedema, arthralgia and myalgia.[symptoma.com]
  • These symptoms include: Skin rashes such as urticaria or angioedema Dizziness Memory loss or confusion Cough Shortness of breath Fatigue Fever Mouth sores Diagnosis Symptoms of HES are also common in many other medical problems, making an initial diagnosis[aaaai.org]
Dermatitis
  • A skin biopsy showed acute neutrophilic folliculitis with perivascular dermatitis with eosinophils. Bone marrow biopsy demonstrated a hypercellular marrow with predominantly eosinophils, which is consistent with idiopathic HES. Methods.[pediatrics.aappublications.org]
  • Skin - dermatitis, urticaria, papular rashes. Ear, nose and throat - sinusitis. Central nervous system - acute cerebrovascular event and peripheral neuropathy.[patient.info]
  • […] developed countries, allergic diseases are the most common cause. [1] Other causes include the following: Malignancies – Metastatic cancer, T-cell lymphoma, [13] colon cancer Connective tissue disorders – Scleroderma, polyarteritis nodosa Skin diseases – Dermatitis[emedicine.medscape.com]
Night Sweats
  • Finally, patients can develop symptoms that are not organ-specific, such as fever, night sweats, anorexia and weight loss. The latter two seem to occur mostly with cardiac disease although reports are variable.[symptoma.com]
  • A nonproductive cough, night sweats, and a diffuse pruritic, papular rash developed. His initial absolute eosinophil count was 1890/mm 3 (reference: 3 ), which increased to 52 000/mm 3 .[pediatrics.aappublications.org]
  • Generalised symptoms - fatigue, aches and pains, fever, night sweats and pruritus. Diarrhoea is common, as are abdominal pain and nausea.[patient.info]
  • sweats Some sources identify anorexia and weight loss as common presenting symptoms; however, other sources report that these symptoms do not usually occur unless underlying cardiac disease is present Physical The physical findings of hypereosinophilic[emedicine.medscape.com]
Peripheral Neuropathy
  • A 36-year-old male with no comorbidities presented progressive erythroderma, pruritus, peripheral neuropathy, and eosinophilia in the previous seven months. No mutations were found in FIP1L1/PDGFRA.[ncbi.nlm.nih.gov]
  • Neurological - acute cerebrovascular accident, confusion, ataxia, peripheral neuropathy. Eyes - episcleritis, retinal thrombi.[patient.info]
  • Neurologic manifestations are relatively rare in these conditions however encephalopathy, strokes and peripheral neuropathy can occur.[neurology.org]
  • Neurologic findings are as follows: Physical findings associated with stroke and transient ischemic attacks can be observed When peripheral neuropathy is present, findings may be purely sensory, entirely motor, or a combination of both Deficits are often[emedicine.medscape.com]
Dizziness
  • These manifestations include:Skin rashes, for example, urticaria or angioedema, Dizziness, Memory misfortune or disarray, Cough, Shortness of inhale, Fatigue, Fever, Mouth wounds.[omicsonline.org]
  • These symptoms include: Skin rashes such as urticaria or angioedema Dizziness Memory loss or confusion Cough Shortness of breath Fatigue Fever Mouth sores Diagnosis Symptoms of HES are also common in many other medical problems, making an initial diagnosis[aaaai.org]
  • You are dizzy and feel faint. You have chills, a cough, or feel weak and achy. You have questions or concerns about your condition or care. When should I seek immediate care or call 911? You have severe chest or abdominal pain.[drugs.com]
Slurred Speech
  • speech have been reported Peripheral neuropathies account for about 50% of all neurologic symptoms in hypereosinophilic syndrome; their etiology is poorly understood, but they may present as symmetric or asymmetric sensory changes, pure motor deficits[emedicine.medscape.com]
Dysesthesia
  • […] cutaneous diseases Arne Kanig and Rudolf Happle Ichthyoses erythrokeratodermas and related disorders Keratodermas Kro Dariers disease and HaileyHailey disease Daniel Hohl Theodora Mauro and leanPhilippe Gorog Mosaicism and linear lesions Pruritus and dysesthesia[books.google.com]

Workup

The workup of hypereosinophilic syndrome is broad and extensive, given the range of organs and systems affected. Workup starts with hematologic studies, including a complete blood count, a peripheral smear, a bone marrow aspiration and a biopsy. Leukocytosis above 90,000 cells per microliter is a bad prognostic indication. The peripheral blood smear will generally show mature eosinophils with rare cell precursors, in addition to hypogranularity, hypergranularity and hypersegmentation. Usually, eosinophils with hypogranularity and vacuoles are more common in cardiac disease [12]. Signs of myleoproliferative disorder include leukocyte precursor anemia, thrombocytopenia or thrombocytosis, in addition to tear drops and nucleated red blood cells

Serum tryptase levels need to be assessed and elevated levels generally indicate either FIP1LI HES or systemic mastocytosis with chronic eosinophilic leukemia (SM-CEL). Genetic studies can also be done to detect FIP1LI-PDGFRA and C-KIT mutations and help in determining sensitivity to imatinib.

Assessment of organ damage is conducted with computed tomographhy (CT) of the chest, abdomen and pelvis, electrocardiography (ECG), echocardiography and pulmonary function tests. Elevation of troponin levels can signal the presence of cardiomyopathy and a risk of cardiogenic shock with the initiation of imatinib therapy. 

Pulmonary Infiltrate
  • infiltrates, and pleural effusions Dermatologic 50% Angioedema Dermatographism Pruritus Rashes (including eczema and urticaria) Hematologic 50% Anemia Lymphadenopathy Splenomegaly Thromboembolic phenomena Thrombocytopenia Neurologic 50% Cerebral emboli[merckmanuals.com]
  • .- ) pulmonary eosinophilia due to drugs ( J70.2- J70.4 ) pulmonary eosinophilia due to specified parasitic infection ( B50 - B83 ) pulmonary eosinophilia due to systemic connective tissue disorders ( M30-M36 ) pulmonary infiltrate NOS ( R91.8 ) J82 )[icd10data.com]
  • infiltration with eosinophilia (PIE)肺好酸球増多症 r radioallergosorbent tset (RAST)ラスト法、放射性アレルゲン吸着試験〈特異的IgE測定法〉 radioimmunosorbent test (RIST)リスト法、放射性免疫吸着法〈総IgE測定法〉 refractory1.難治[性]の、抗療性の、治療抵抗性の 2.治療不応性の、無反応性の respiratory alkalosis呼吸性アルカローシス respiratory epithelial[tokyo-med.ac.jp]
Eosinophils Increased
  • An elevated IL-8 level was observed only when eosinophils increased. On the other hand, serum IL-4 and IL-5 levels were under detectable limits during the course.[ncbi.nlm.nih.gov]
  • There was no clinical evidence of eosinophil increase induced by secondary factors; no obvious anomalies were observed with respect to the chromosomes or gene fusions.[austinpublishinggroup.com]
White Matter Lesions
  • MRI brain scan showed multiple white matter lesions consistent with acute infarcts. She recovered rapidly with corticosteroids and anticoagulation. Four years later she re-presented with headache, fatigue and an eosinophilia of 13.4 10⁹/L.[ncbi.nlm.nih.gov]
Pleural Effusion
  • Respiratory - pneumonitis, pulmonary emboli, pleural effusion and eosinophilic infiltrates. Skin - dermatitis, urticaria, papular rashes. Ear, nose and throat - sinusitis.[patient.info]
  • Chest radiographs may indicate pleural effusions and/or fibrosis, and neurological tests such as CT scans can show strokes and increased cerebrospinal fluid pressure.A proportion of patients have a mutation involving the PDGFRA and FIP1L1 genes on the[en.wikipedia.org]
  • effusions Dermatologic 50% Angioedema Dermatographism Pruritus Rashes (including eczema and urticaria) Hematologic 50% Anemia Lymphadenopathy Splenomegaly Thromboembolic phenomena Thrombocytopenia Neurologic 50% Cerebral emboli with focal deficits Diffuse[merckmanuals.com]

Treatment

Treatment of HES is classified into immediate therapy, definitive therapy directed specifically at the disorder and supportive therapy.

Immediate therapy consists of high doses of IV corticosteroids in the context of severe eosinophilia or complications of hyperleukocytosis. If the patient responds and the eosinophil count decreases by more than 50% after 24 hours, the same dose of corticosteroid can be administered on a routine basis. If the response is negative, an alternative regimen with hydroxyurea can be attempted. Lowering the white blood cell count is critical and treatment targeting eosinophilia should be initiated immediately.

Definitive therapy is dependent on the subtype of HES. Tyrosine kinase inhibitors (TKIs) are particularly effective in patients with a positive FIP1L1/PDGFRA fusion gene. Imatinib is usually the first line drug administered and some studies indicate a response rate approaching 100%. Courses of other TKIs can be attempted in cases where imatinib is not effective or well-tolerated. Corticosteroids are the treatment of choice for patients with cardiac damage. 

On the other hand, symptomatic or asymptomatic patients who are FIP1L1/PDGFRA negative are treated with a 5 day course of corticosteroids, and positive response is usually immediate. Evidence of organ damage necessitates treatment with the same dose for two weeks, followed by a gradual tapering. In case there's no evidence of organ damage, patients are monitored for a period of 6 months. In cases where patients cannot tolerate a tapering of corticosteroids, alternative drugs such as hydroxyurea and interferon-α can be administered [13] [14].

Supportive therapy is mostly targeted at treating the complications and organ damage resulting from HES. Antiplatelet drugs such as clopidogrel, aspirin or ticlodipine are used to prevent thrombosis. Anticoagulation is only indicated in cases of left ventricular thrombosis, as well as transient ischemic attacks that persist after aspirin treatment. On the other hand, cardiac complications, such as inflitrative cardiomyopathy, valvular lesions and heart failure necessitate medical and sometimes surgical intervention. Asymptomatic HES patients do not require any continuous treatment, but need to be followed up for the development of any complications. In particular, serum troponin is measured every 3 to 6 months along with the performance of pulmonary function tests and echocardiography every 6 to 12 months [15]. 

Refractory cases that do not respond to the treatments mentioned above are usually managed with chemotherapeutic drugs such as chlorambuic, etoposide, vincristine, 2-chlorodeoxyadenosine and cytarabine or with hematopoietic stem cell transplantation (HSCT). These treatment modalities are particularly effective in patients resistant to imatinib [16].

Prognosis

Hypereosinophilic syndrome has a variable prognosis, depending on treatment response, severity of organ damage and the possibility to cause a myeloproliferative and neoplastic disorder. It follows a chronic and progressive path and is potentially fatal, especially when the heart is involved. Development into a myeloproliferative disorder can occur after many years and its risk increases when leukocytosis is above 90,000 cells per microliter. Although early studies report a 3 year survival rate of 12%, later studies show a marked improvement in prognosis with a mean of 80% 5-year survival rate and 42% survival rate at 15 years [1] [10].

Etiology

Studies on tissue from patients diagnosed with HES have so far determined two major causative mechanisms. The first one involves a sporadic mutation in myeloid progenitor cells of the bone marrow, leading to an increase in subpopulations of cells which differentiate into eosinophils. The second mechanism responsible for HES is termed L-HES or the "lymphocytic variant", whereby some lymphocytic T-cells increase their production of eosinophilic cytokines, leading to an expansion of the eosinophil cell line [5]. Granulocyte-macrophage colony stimulating factor (GM-CSF), IL-3 and IL-5 have all been shown to act as eosinophil growth factors, although only IL-5 is specific for eosinophils [3] [4] [8] [9].

Epidemiology

HES is a rare disorder and epidemiological reports remain scarce, making it difficult to estimate the exact prevalence. It is known, however, that the disease is more common among men than women, with a ratio of 9:1. All age groups can be affected, although the disease displays a peak in the fourth decade and, in general, has a predilection for patients in the age range of 20 to 50 years old. Studies based on annual hospital discharges and on claims database for outpatient management in the United States have estimated that up to a third of patients with chronic myelogenous leukemia have HES [6]. Improvements in the definition of HES diagnostic criteria, as well as detailed patient registries are required for a more accurate estimation of prevalence.

Sex distribution
Age distribution

Pathophysiology

Normal eosinophils are part of the myeloid cell lineage and play a critical role in the inflammatory cascade. Their cytoplasmic granules contain cationic molecules that are the most important mediators of tissue damage in the body. They also release free radicals and possess a respiratory burst oxidative pathway that further promotes damage in infiltrated tissue.

Organ damage resulting from hypereosinophilia is not directly related to the level of eosinophils in the blood and is thought to be mediated by eosinophilic infiltration of tissue. Eosinophils can also aggregate in blood vessels, particularly when levels are extremely elevated (>100,000 per microliter), resulting in widespread ischemia and tissue microinfractions. The most dangerous complication involves the heart and involves myocardial fibrosis, congestive heart failure and, ultimately, death. The fibrosis is severe and affects mostly the endocardium in either ventricles, leading to significant restrictive cardiomyopathy and inflow obstruction.

Based on pathophysiological mechanisms responsible for hypereosinophilia, HES can be broadly classified into myeloproliferative and lymphoproliferative subtypes. An FIP1L1/PDGFRA fusion gene associated with tyrosine kinase activity and resulting from an interstitial deletion at the CHIC2 site on chromosome 4 is responsible for the myeloproliferative variant. Patients affected by this mutation tend to be predominantly male and respond to a low dose of imatinib. They rarely develop lymphoblastic or acute myeloid leukemia, although they frequently have endomyocardial fibrosis

The lymphoproliferative phenotype is characterized by a rearrangement of T-cell receptors, resulting in an aberrant population of T-cells with abnormal eosinophilic cytokine production. Patients with this subtype usually respond to corticosteroids and can develop T-cell lymphoma.

Prevention

Individuals with HES need to be followed up for early detection and prevention of the complications that can accompany the disease. Periodical assessment of the eosinophil count is recommended, as well as measurements of serum troponin every 3 months, pulmonary function tests and an echocardiogram every 6 months.

Summary

Hypereosinophilic syndromes (HES) describe a range of disorders chiefly characterized by persistent and unexplained elevation of eosinophil levels, in the presence of organ damage and absence of any evidence of a known cause, such as parasitic infections or allergic reactions [1] [2].

Because HES can affect almost every organ in the body, patients present with a broad range of symptoms: non-specific ones such as fever, weight loss or night sweats, alongside more organ-specific manifestations such as strokes, heart dysfunction or pleural effusions. Workup is broad and directed at providing evidence for organ involvement as well as hematologic tests to assess possible subtypes of HES. Initial treatment with steroids is targeted at lowering the eosinophil count and is followed by more specific regimens that address subtypes, as well as potential complications. HES can be fatal if not properly treated, but recent advances have significantly improved outcomes.

Patient Information

Hypereosinophilic syndrome is a rare disorder characterized by a significant elevation of eosinophil count above 1,500 cells per microliter in the absence of a well-defined cause. The condition can affect all age groups, but particularly targets men who are 20 to 50 years old. An increase in the number and action of eosinophils can potentially affect all organs including the heart, liver, nervous system, skin and lungs. The heart is especially vulnerable and its involvement can lead to heart failure, heart attacks and damaged heart valves.

Patients with hypereosinophilic syndrome can present with a wide range of symptoms including weight loss, night sweats, fatigue, swelling, rashes, weakness, confusion, coma, chest pain, cough and abdominal pain. Diagnosis is established after blood tests show a persistent elevation of eosinophil count in the presence of symptoms and without evidence of an allergic reaction, a parasitic infection or another definite cause.

Hypereosinophilic syndrome is fatal in patients who are not treated or properly monitored. Recent advances, however, have markedly improved survival among patients and, nowadays, more than 80% survive with adequate treatment. Patients who are asymptomatic are usually treated with a single dose of corticosteroids and then monitored closely for the next 3 to 6 months. Others need to be treated with steroids, hydroxyurea or cancer drugs.

References

Article

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  2. Klion AD, Bochner BS, Gleich GJ, Nutman TB, Rothenberg ME, Simon HU, Wechsler ME, Weller PF, The Hypereosinophilic Syndromes Working Group. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol. 2006 Jun;117(6):1292-302.
  3. Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147-74.
  4. Romagnani S. Th1 and Th2 in human diseases. Clin Immunol Immunopathol. 1996 Sep;80(3 Pt 1):225-35.
  5. Roufosse F, Cogan E, Goldman M. Recent advances in pathogenesis and management of hypereosinophilic syndromes. Allergy. 2004 Jul;59(7):673-89.
  6. Wilkins HJ, Crane MM, Copeland K, Williams WV. Hypereosinophilic syndrome: an update. Am J Hematol. 2005 Oct;80(2):148-57.
  7. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood. 1994 May 15;83(10):2759-79.
  8. Galli SJ, Goetzl EJ. Eosinophils, basophils, and mast cells. Handin RI, Stossel TP, Lux SE, Stossel TP, eds. Blood: Principles and Practice of Hematology. Baltimore, Md: Lippincott Williams & Wilkins; 1995. 621-40.
  9. Wardlaw AJ, Kay AB. Eosinopenia and eosinophilia. Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 5th ed. New York, NY: McGraw- Hill; 1995. 844-52.
  10. Lefebvre C, Bletry O, Degoulet P, et al. [Prognostic factors of hypereosinophilic syndrome. Study of 40 cases] [French]. Ann Med Interne (Paris). 1989. 140(4):253-7.
  11. Klion A. Hypereosinophilic syndrome: current approach to diagnosis and treatment. Annu Rev Med. 2009. 60:293-306.
  12. Fauci AS, Harley JB, Roberts WC, et al. NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med. 1982 Jul. 97(1):78-92.
  13. Luciano L, Catalano L, Sarrantonio C, et al. AlphaIFN-induced hematologic and cytogenetic remission in chronic eosinophilic leukemia with t(1;5). Haematologica. 1999 Jul. 84(7):651-3.
  14. Yamada O, Kitahara K, Imamura K, et al. Clinical and cytogenetic remission induced by interferon-alpha in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation. Am J Hematol. 1998 Jun. 58(2):137-41. [Medline].
  15. Malbrain ML, Van den Bergh H, Zachée P. Further evidence for the clonal nature of the idiopathic hypereosinophilic syndrome: complete haematological and cytogenetic remission induced by interferon-alpha in a case with a unique chromosomal abnormality. Br J Haematol. 1996 Jan. 92(1):176-83.
  16. Gotlib J. World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management. Am J Hematol. 2014 Mar. 89(3):325-37.

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Last updated: 2018-06-21 21:15