Fw: Background: Idiopathic hypereosinophilic syndrome

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From: " Kathi " <pureheart@...>

Sent: Sunday, July 07, 2002 8:36 PM

Subject: Background: Idiopathic hypereosinophilic syndrome

>

> Background: Idiopathic hypereosinophilic syndrome (HES) refers to a

> group of leukoproliferative disorders characterized by an overproduction

> of eosinophils that results in organ damage. Peripheral eosinophilia

> with tissue damage has been noted for approximately 80 years, but Hardy

> and first described the specific syndrome in 1968. The 3

> features required for a diagnosis of HES were defined in 1975 by Chusid

> et al. First, a sustained eosinophil count greater than 1500/mm3

> persists for longer than 6 months. Second, no other etiologies for

> eosinophilia are present. Finally, patients must have signs and symptoms

> of organ involvement. Thus, this last requirement excludes benign

> eosinophilia, which may exist for years with no associated pathology.

>

> HES is likely a collection of several similar entities, but the

> important commonality is the disseminated nature of tissue involvement

> and damage. If blood eosinophilia is associated with other disorders,

> such as allergic diseases, parasitic infections, eosinophilia-myalgia

> syndrome, Churg-Strauss syndrome, or malignancy, then, by definition,

> idiopathic HES is not present.

>

> Eosinophil production is governed by several cytokines, including

> interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor

> (GM-CSF), and IL-5. IL-5 appears to be the most important and specific

> cytokine and is responsible for differentiation of the eosinophil line.

> The difference between mechanisms of eosinophil production in HES and in

> secondary eosinophilic syndromes is not known. An association has been

> reported between T-cell clonal proliferation and hypereosinophilia. In

> these cases, the T-cells were responsible for hypersecretion of IL-5.

>

> Some cases previously diagnosed as HES involved malignant transformation

> of eosinophils, but these constitute a minority. Most patients with HES

> do not have a subsequently identified neoplastic association to explain

> their disorder. The overlap between diseases referred to as eosinophilic

> leukemia and those called HES is confusing, and both sets of patients

> initially may appear to meet the criteria for HES. However, most

> patients with HES have a normal karyotype, though some series have

> identified clonal abnormalities. A US National Institutes of Health

> (NIH) study reported abnormalities in 8 of

> 33 patients. The cases with chromosomal abnormalities (rarely including

> Philadelphia chromosome) seem to fit a neoplastic profile, with a

> myeloproliferativelike picture, and patients may have anemia at

> diagnosis.

>

> Most reviews of HES include discussions of both malignant and

> nonmalignant disease. However, recent papers propose that patients with

> severe hematologic manifestations or clonal chromosomal abnormalities

> have chronic eosinophilic leukemia, which is distinct from HES. This

> approach is supported by long-established factors associated with the

> poorest prognoses, including a peripheral leukocyte count greater than

> 90,000 cells/mm3 and the presence of myeloblasts in the periphery.

>

> Pathophysiology: Under usual circumstances, eosinophils arrive at an

> area of inflammation and quickly undergo apoptosis after degranulation,

> though normal eosinophils live longer than neutrophils and can

> recirculate from the tissues. In HES, the cells stimulated by the

> above-mentioned cytokines may survive in the tissues for longer periods

> of time, thus increasing the amount of damage they can inflict.

>

> Eosinophils contain granules that store toxic cationic proteins, which

> are the primary mediators of tissue damage. These toxins include major

> basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and

> eosinophil cationic protein. Eosinophils also release specific cytokines

> that recruit additional eosinophils and advance the cycle of tissue

> damage and modulation of the immune response. Oxidative products

> produced by the respiratory burst pathway of the infiltrating

> eosinophils add more damage. Precisely how or why circulating

> eosinophils degranulate in HES remains unknown, but it seems to account

> for the organ toxicity associated with the disease.

>

> The most serious complication of HES is cardiac involvement that leads

> to myocardial fibrosis, congestive heart failure (CHF), and death. The

> mechanisms of cardiac damage are not entirely understood, but the damage

> is marked by severe endocardial fibrotic thickening of either or both

> ventricles resulting in restrictive cardiomyopathy due to inflow

> obstruction. Hypereosinophilia alone is not sufficient to cause cardiac

> damage.

>

> Frequency:

>

> In the US: Various sources indicate prevalence of true HES is rare. The

> most common cause of eosinophilia in the US is allergic reaction or

> allergic disease, but prevalence of HES is far less frequent.

>

> Internationally: The most common cause of eosinophilia worldwide is

> parasitosis. Prevalence of HES is far less frequent.

>

> Mortality/Morbidity:

>

> While often progressive and rapidly fatal if untreated, the disease also

> may take a much more indolent course. Patients with characteristics

> suggestive of a myeloproliferative/neoplastic disorder and those who

> manifest CHF have a worse prognosis.

>

> An older review of 57 patients with advanced disease reported a mean

> survival of 9 months and a 3-year survival of 12%.

>

> A more recent analysis from France noted 80% 5-year survival and

> 42% 10-year survival among 40 patients.

>

> Race:

>

> No racial predilection is reported.

>

> Sex:

>

> A 9:1 male predominance exists. The reason for this difference is not

> known.

>

> Age:

>

> HES is diagnosed most commonly in patients aged 20-50 years.

>

> HES is rare in children.

>

> Incidence seems to decrease in the elderly population.

>

>

> CLINICAL

>

> Section 3 of 11

>

>

> History: HES is a heterogeneous disease process; thus, multiple

> manifestations may occur simultaneously or individually. The presenting

> symptoms can be sudden and dramatic, which sometimes occurs with

> cardiac, neurologic, or thrombotic complications, but more often, the

> onset is insidious. In one series,

> 12% of patients with HES discovered it as an incidental finding.

> Virtually any organ system may be involved. Major symptoms include the

> following:

>

> Cardiac

>

> This is one of the most frequently involved systems and a leading cause

> of mortality.

>

> Damage typically occurs in 3 stages.

>

> Initial acute necrosis early in the disease process that typically has

> no clinical manifestations but occasionally may be severe enough to

> cause symptoms

>

> Thrombotic phase

>

> Endomyocardial fibrosis

>

> Common symptoms in these phases include chest pain, dyspnea, or

> orthopnea.

>

> Hematologic

>

> Symptoms are largely nonspecific and may include fatigue, which may be

> due to the anemia occasionally observed with HES.

>

> Left upper quadrant pain may indicate splenomegaly, which occurs in

> about 40% of cases.

>

> Thrombotic episodes occur frequently and often present as neurologic

> symptoms. The thrombotic events may occur solely due to cardiac disease,

> or they may be caused by hypercoagulability. The mechanism of

> hypercoagulability is unknown.

>

> Neurologic

>

> Embolic or thrombotic strokes or transient ischemic episodes may occur

> and are often the initial manifestations of disease.

>

> Some patients experience an encephalopathy caused by CNS dysfunction.

>

> Blurred vision and slurred speech have been reported.

>

> Peripheral neuropathies account for about 50% of all neurologic

> symptoms. Their etiology is poorly understood, but the symptoms may

> present as symmetric or asymmetric sensory changes, pure motor deficits,

> or mixed sensory and motor complaints.

>

> Pulmonary

>

> One source indicates that the most benign variant of HES involves

> eosinophilic infiltrates in the bases and periphery of the lungs.

>

> Patients often have recurrent angioedema.

>

> A chronic, persistent cough, usually nonproductive, is the most common

> respiratory symptom reported.

>

> 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 sometimes presents.

>

> Rheumatologic

>

> Arthralgias and myalgias are frequent complaints.

>

> Raynaud phenomenon occurs but is infrequent.

>

> Dermatologic

>

> Skin involvement is common and nonspecific.

>

> The most common symptom is pruritus.

>

> Dermatographism and angioedema are also frequently present.

>

> Gastrointestinal

>

> Diarrhea is a relatively common complaint, occurring in approximately

> 20% of patients.

>

> Nausea and abdominal pain are also common.

>

> Occasionally, small bowel necrosis due to microthrombi can occur.

>

> Constitutional

>

> Many patients experience fever and night sweats.

>

> Some sources identify anorexia and weight loss as common presenting

> symptoms. However, other authors feel that these symptoms usually do not

> occur unless underlying cardiac disease is present.

>

> Physical: The physical findings also are varied and parallel the

> clinical history.

>

> Cardiac

>

> Evidence of CHF becomes prominent with advanced HES and is an ominous

> sign.

>

> Various murmurs may be heard, especially mitral or tricuspid

> regurgitation.

>

> Splinter hemorrhages often are observed with cardiac involvement.

>

> Physical findings typical of restrictive heart disease can be expected.

>

> Hematologic findings include splenomegaly in approximately 40% of

> patients.

>

> Neurologic

>

> 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 symmetric.

>

> Mononeuritis multiplex and muscle atrophy due to radiculopathy sometimes

> are encountered.

>

> Generalized weakness is observed but is less specific.

>

> Pulmonary

>

> Rales may accompany infiltrates and fibrosis.

>

> Findings typical of CHF with effusion also may be encountered.

>

> Angioedema is often a prominent feature associated with pulmonary

> involvement.

>

> Rheumatologic

>

> Large joint effusions can occur.

>

> Digital necrosis is rare but sometimes observed with associated Raynaud

> phenomenon.

>

> Dermatologic

>

> Skin is among the most common organ systems involved, with more than

> half of all patients having cutaneous involvement. In a minority of

> reports, skin involvement is the only manifestation.

>

> Most skin eruptions fall into two patterns. One is angioedematous or

> urticarial. This pattern is associated with benign prognosis. The other

> is erythematous, pruritic papules, plaques and nodules, with or without

> ulceration.

>

> A special form of urticaria is dermatographism. This occurs in upto 75%

> of affected patients.

>

> Other less common cutaneous manifestations include erythroderma,

> erythema annulare centrifugum, erythema gyratum repens, and mucosal

> ulcerations.

>

> Gastrointestinal

>

> Hepatomegaly may occur with chronic active hepatitis due to HES.

>

> Hepatomegaly also may occur with Budd-Chiari syndrome, which

> infrequently may be a thrombotic complication of HES.

>

> Causes:

>

> HES likely represents a variety of similar disorders, and the underlying

> cause of eosinophil overproduction is not well understood.

>

> Eosinophilia due to some other disorder is not HES.

>

> Cytokine overproduction may account for some cases of HES.

>

>

> DIFFERENTIALS

>

> Section 4 of 11

>

>

> Chronic Myelogenous Leukemia Churg-Strauss Syndrome Eosinophilia

> Eosinophilia-Myalgia Syndrome Eosinophilic Fasciitis Eosinophilic

> Gastroenteritis Eosinophilic Leukemia Eosinophilic Pneumonia Hodgkin

> Disease Strongyloidiasis

>

>

> Other Problems to be Considered:

>

> Angiolymphoid hyperplasia with eosinophilia Dermatitis, Atopic Asthma

> Allergic diseases Collagen vascular diseases Drug reactions Eosinophilic

> toxocariasis Episodic angioedema with eosinophilia Hypersensitivity

> diseases Malignancy with secondary eosinophilia (eg, Hodgkin disease,

> Acute myeloid leukemia [AML-M4]) Parasitic infections

>

>

> WORKUP

>

> Section 5 of 11

>

>

> Lab Studies:

>

> Hematologic

>

> Eosinophilia is present (>1500/mL).

>

> The overall neutrophil count may be normal but often is elevated. Many

> patients have absolute neutrophilia.

>

> Infrequently, bands and other immature forms may be present. Mild

> basophilia may be observed. Increased numbers of eosinophilic or

> neutrophilic precursors may be indicative of neoplastic disease.

> Teardrops and nucleated red blood cells are common.

>

> Approximately 50% of patients are anemic on presentation, often because

> of chronic disease. Platelet counts are most often normal but may be

> high or low.

>

> The eosinophils as observed on the peripheral smear may be normal in

> appearance, but often some morphologic abnormalities, such as a decrease

> in granule number and size, are observed.

>

> Vacuoles may be prominent in some patients, and nuclear

> hypersegmentation also may be observed.

>

> The NIH series indicated that the presence of eosinophils with

> vacuolization and hypogranularity is associated more commonly with

> cardiac disease.

>

> Chemistries

>

> Serum vitamin B-12 levels may be elevated in some patients. This

> typically indicates the presence of a myeloproliferativelike picture.

>

> Immunoglobulin E (IgE) levels may be elevated, and

> hypergammaglobulinemia is common.

>

> Other expected blood chemistry abnormalities may accompany renal

> involvement, heart failure, liver involvement, or thrombotic insult to

> various tissues.

>

> Imaging Studies:

>

> Cardiac studies

>

> In the initial phase of endocardial damage, usually no echocardiographic

> or angiographic abnormalities are present. If HES is strongly suspected,

> then right ventricular biopsy can be performed to evaluate for

> endomyocardial involvement. If successful treatment can be initiated

> during this early period of cardiac damage, the later thrombotic and

> fibrotic stages might be avoided or delayed.

>

> In the later phases, which are usually symptomatic, echocardiography

> (ECG) is helpful. Intracardiac thrombi may be detected, as well as the

> fibrosis that appears not only as areas of increased echogenicity, but

> often as posterior mitral valve leaflet thickening. Because the

> papillary muscles often are involved in HES, mitral and tricuspid

> dysfunction also may be detected by echo. On ECG, T-wave inversion is a

> common finding, but more often, there are no abnormalities in the early

> stages of disease.

>

> CT scans may be helpful for evaluating suspected thrombotic or embolic

> complications.

>

> Procedures:

>

> If any question about the diagnosis exists, endocardial biopsy may be

> performed via cardiac catheterization.

>

> Perform bone marrow aspiration and biopsy and submit samples for

> cytogenetics.

>

> Occasionally, this may diagnose an atypical presentation of chronic

> myelogenous leukemia.

>

> Cytogenetic abnormalities or the presence of a myeloproliferative

> picture in the bone marrow may be indicative of more aggressive disease.

>

> If cutaneous involvement is present, skin biopsies may be carried out to

> rule out other diagnoses that have similar skin presentations, such as

> drug eruptions, cutaneous T cell lymphoma, Well's syndrome,

> immunobullous diseases and vasculitis.

>

> Histologic Findings: Eosinophil infiltrates are present in affected

> tissues. Cutaneous histology varies with the pattern of presentation. In

> patients with papular or nodular lesions, perivascular mixed cellular

> infiltrates (eosinophils and other cell types) are present. However,

> there is no vasculitis. See Lab Studies.

>

> full article: http://www.emedicine.com/med/topic1076.htm

>

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