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MD Consult: Books: Goldman: Cecil Medicine: Chapter 176 – EOSINOPHILIC SYNDROMES

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


Marc E. Rothenberg


Eosinophilic syndromes are a heterogeneous group of disorders that involve eosinophilia, which is defined as the accumulation of eosinophils in peripheral blood or tissues, or both. Circulating eosinophils normally account for only 1 to 3% of peripheral blood leukocytes, and the upper limit of the normal range is 350 cells/mm3 of blood. Eosinophilia occurs in a variety of disorders ( Table 176-1 ) and is usually arbitrarily classified according to the degree of blood eosinophilia: mild (351 to 1500 cells/mm3), moderate (>1500 to 5000 cells/mm3), or severe (>5000 cells/mm3). Tissue eosinophilic disorders, such as eosinophil-associated gastrointestinal disorders and eosinophilic fasciitis, are not necessarily associated with blood eosinophilia, so their diagnosis is based on the microscopic identification of eosinophil-rich inflammatory infiltrates associated with tissue damage.

TABLE 176-1   — 

Allergic diseases—asthma, atopic dermatitis, allergic rhinitis
Drug reactions—including cytokine infusions
Infection—viral (human immunodeficiency virus) or fungal (allergic bronchopulmonary aspergillosis, coccidioidomycosis)
Parasitic infection—mostly helminths
Eosinophil-associated gastrointestinal disorders—eosinophilic esophagitis, gastroenteritis
Skin—bullous pemphigoid, urticaria, eosinophilic cellulitis, episodic angioedema
Pulmonary—eosinophilic pneumonia, allergic bronchopulmonary aspergillosis
Neurologic—eosinophilic meningitis
Autoimmune—Churg-Strauss syndrome, eosinophilic fasciitis
Primary immunodeficiency—hyper-IgE syndrome, Omenn’s syndrome
Post-transplantation status—liver (in association with immunosuppression)
Transplant rejection—lung, kidney, liver
Malignancy—Hodgkin’s disease, solid tumors
Hypoadrenalism—Addison’s disease, adrenal hemorrhage
Renal—drug-induced interstitial nephritis, eosinophilic cystitis, dialysis
Chronic eosinophilic leukemia
Acute eosinophilic leukemia
Acute myelogenous leukemia with eosinophilia
Acute lymphoblastic leukemia with eosinophilia
Myeloblastic disorders with eosinophilia
Myeloproliferative disorders with eosinophilia
Systemic mastocytosis with eosinophilia
FIP1L1-PDGFRA fusion gene–positive disease

Historically, hypereosinophilic syndromes were generally classified as idiopathic and were defined by (1) the presence of eosinophilia (>1500 cells/mm3 for at least 6 months) that remained unexplained despite a comprehensive evaluation for known causes of eosinophilia (such as drug reactions and infections) and (2) evidence of organ dysfunction directly attributable to the eosinophilia. Now, however, it is known that in some patients a chromosome 4 microdeletion results in the generation of an activated tyrosine kinase (FIP1L1–platelet-derived growth factor receptor α [PDGFRA]) that causes a clonal hematologic disorder now better classified as chronic eosinophilic leukemia. Identification of FIP1L1-PDGFRA–positive disease has important therapeutic implications because PDGFRA-associated disease can be treated with imatinib, a tyrosine kinase inhibitor.


The most common cause of eosinophilia worldwide is helminth infections, which affect hundreds of millions of people worldwide. The most frequent cause in industrialized nations is atopic disease, which affects 10 to 30% of the population ( Chapter 270 ). Hypereosinophilic disorders such as FIP1L1-PDGFRA–associated disease and Churg-Strauss syndrome ( Chapter 291 ) are very rare. For example, Churg-Strauss syndrome affects 4 to 6 cases per million per year, whereas true idiopathic hypereosinophilic syndromes may affect only 4000 to 5000 people worldwide. Other syndromes such as eosinophil-associated gastrointestinal disorders are more common, with an incidence of approximately 1 in 10,000 children.


Eosinophils are produced in the bone marrow from pluripotential stem cells under regulation of the transcription factor GATA-1 and the cytokines interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) ( Fig. 176-1 ). Eosinophils are under the regulation of helper type 2 T cells (TH2) that secrete IL-4, IL-5, and IL-13. Notably, IL-5 is a cytokine that specifically regulates the selective differentiation of eosinophils, their release from bone marrow into the peripheral circulation, and their survival. A humanized anti–IL-5 drug markedly lowers circulating eosinophilia and reduces tissue eosinophilia more modestly. Early studies in patients with asthma have shown that anti–IL-5 therapy does not appear to improve airway function but improves markers of lung remodeling (associated with decreases in transforming growth factor β1 [TGF-β1] levels); humanized anti–IL-5 therapy is currently in clinical testing for a variety of indications, including hypereosinophilic syndromes. IL-4 and IL-13 induce eosinophil recruitment and survival, expression of critical adhesion molecules on the endothelium that bind to the β1 and β2 integrins on eosinophils (such as intercellular adhesion molecule 1 [ICAM-1] and vascular cell adhesion molecule 1 [VCAM-1]), and eosinophil-active chemokines such as the eotaxins. The eotaxins are three structurally related eosinophil chemoattractant and activating proteins that signal exclusively through the eosinophil-selective receptor CCR3. In addition to regulating the baseline homing of eosinophils into various tissues, such as the gastrointestinal tract, wherein most eosinophils reside, the eotaxins are induced by TH2-associated inflammatory triggers (e.g., IL-13) and thereby promote tissue accumulation of eosinophils. Humanized antibodies against the eotaxins and small-molecule inhibitors against CCR3 are promising new approaches for treating eosinophilic disorders that are in clinical development.

FIGURE 176-1  Schematic representation of eosinophil development, tissue recruitment, and therapeutic intervention. Eosinophil lineage development is specified by the GATA-1 transcription factor and promoted by the cytokines interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-5 is most selective to the eosinophil lineage and regulates eosinophil movement from bone marrow into peripheral blood. Eosinophil adhesion is mediated by β1, β2, and β7 integrins and their interaction with the endothelial adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal address in cell adhesion molecule 1 (MAdCAM-1). Recruitment of eosinophils into tissue is regulated by the eotaxin chemokines that stimulate eosinophilic chemoattraction and activation via their receptor CCR3. Hypereosinophilic syndromes can develop after an 800-kilobase microdeletion on chromosome 4 results in fusion of the FIP1L1 and PDGFRA genes, thereby resulting in activation of a imatinib-sensitive tyrosine kinase. Targeted therapeutic intervention for eosinophilic syndromes includes anti–IL-5 and anti-CCR3/eotaxins, which are currently in clinical development.

Eosinophil granules contain a crystalloid core composed of major basic protein (MBP-1 and MBP-2), as well as a matrix composed of eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase (EPO). MBP, EPO, and ECP have cytotoxic effects on a variety of tissues in concentrations similar to those found in biologic fluids from patients with eosinophilia. Additionally, ECP and EDN belong to the ribonuclease A superfamily and possess antiviral and ribonuclease activity. ECP can insert voltage-insensitive, ion-nonselective toxic pores into the membranes of target cells, and these pores may facilitate the entry of other toxic molecules. MBP directly increases smooth muscle reactivity by causing dysfunction of vagal muscarinic M2 receptors, and this process has been postulated to contribute to the airway hyperresponsiveness associated with asthma. MBP also triggers degranulation of mast cells and basophils. Triggering of eosinophils by engagement of receptors for cytokines, immunoglobulins, and complement can lead to the generation of a wide range of inflammatory cytokines, including IL-1, IL-3, IL-4, IL-5, IL-13, GM-CSF, TGF-α/β, tumor necrosis factor α (TNF-α), RANTES, macrophage inflammatory protein 1α (MIP-1α), and the eotaxins, thus indicating that eosinophils have the potential to modulate multiple aspects of the immune response. Additionally, eosinophils can directly activate T cells by antigen presentation. Further eosinophil-mediated damage is caused by toxic hydrogen peroxide and halide acids generated by EPO and by superoxide generated by the respiratory burst oxidase enzyme pathway in eosinophils. Eosinophils also generate large amounts of cysteinyl leukotriene C4 (LTC4), which is metabolized to LTD4 and LTE4. These three lipid mediators increase vascular permeability and mucus secretion and are potent stimulators of smooth muscle contraction. Finally, bipyramidal Charcot-Leyden crystals are derived from a nongranule lysophospholipase in eosinophils and are frequently found in sputum, feces, and tissues infiltrated by eosinophils.

Clinical Manifestations

Hypereosinophilia is often recognized on a routine blood count in a patient who is asymptomatic or being evaluated for unrelated or nonspecific signs or symptoms. On other occasions, the possibility of eosinophilia may be specifically investigated in a patient with gastrointestinal or respiratory symptoms because helminthic disease or allergic causes are suspected. The clinical signs and symptoms of hypereosinophilic syndromes are heterogeneous because of the diversity of the causes and potential organ involvement. Common signs and symptoms include dermatitis, heart failure, neuropathy, and abdominal pain. One of the most serious complications of hypereosinophilia is cardiac disease secondary to endomyocardial thrombus formation and restrictive fibrosis ( Chapter 59 ). Mitral and tricuspid valve regurgitation may result from progressive fibrotic damage to the chordae tendineae, and resultant heart failure can develop from valvar insufficiency and endomyocardial fibrosis. Cardiac involvement can occur in association with eosinophilia from diverse causes, including parasitic infections. Hypereosinophilic syndromes can result in cerebral emboli from cardiac disease, diffuse encephalopathy, and peripheral neuropathy.


Differential Diagnosis

The differential diagnosis of eosinophilia includes reactive eosinophilia, eosinophilia associated with other primary disorders, and eosinophilia associated with clonal hematopoiesis (see Table 176-1 ). Evaluation of patients is based on their history and clinical characteristics ( Fig. 176-2 ). The initial goal is to determine whether the eosinophilia is secondary to a reactive cause (i.e., in response to another primary trigger such as allergy, infection, solid tumor, vasculitis). If reactive causes are not identified, further evaluation should determine whether the eosinophilia is secondary to a clonal hematologic disorder. If no evidence of clonality is determined, the patient is considered to have an idiopathic hypereosinophilic syndrome.

FIGURE 176-2  Diagnostic evaluation of persistent eosinophilia. CBC = complete blood count; CT = computed tomography; ECG = electrocardiogram; IgE = immunoglobulin E; IHES = idiopathic hypereosinophilic syndrome; HIV = human immunodeficiency virus; PDGFRA = platelet-derived growth factor α; PFTs = pulmonary function tests.

The differential diagnosis of eosinophilia requires a review of the patient’s history, which may reveal wheezing ( Chapter 83 ), rhinitis ( Chapter 272 ), or eczema (indicating atopic causes); travel to areas where helminth infections (e.g., schistosomiasis [ Chapter 376 ]) are endemic; the presence of a pet dog (indicating possible infection with Toxocara canis [ Chapter 378 ]); symptoms of cancer; or drug ingestion (indicating a possible hypersensitivity reaction [ Chapter 275 ]). Eosinophilia caused by drugs ( Chapter 275 ) is usually benign but can sometimes be accompanied by tissue damage, as in hypersensitivity pneumonitis ( Chapter 92 ). In most cases, the eosinophilia resolves when use of the drug ceases, but in some cases, such as eosinophilia-myalgia syndrome secondary to the ingestion of contaminated L-tryptophan, the disease can persist despite withdrawal of the drug.

The presence of abnormal morphologic features of eosinophils, an increase in immature and dysplastic cells in the bone marrow or blood, elevated levels of vitamin B12, and splenomegaly raises suspicion of a clonal hypereosinophilic syndrome. In such cases, evidence of clonality (e.g., by analysis of X chromosome inactivation patterns in female patients), an elevated level of mast cell tryptase (elevated in myelodysplastic variants of hypereosinophilic syndrome), the presence of aberrant lymphocyte phenotypes (elevated in lymphocytic variants of hypereosinophilic syndrome), abnormal cytogenetics, and the possible presence of specific fusion genes such as FIP1L1-PDGFRA should be investigated.

Other eosinophilic syndromes such as Churg-Strauss syndrome ( Chapter 291 ) should be considered in patients with a history of worsening asthma, sinus disease, neuropathy, or blood eosinophilia and the presence of abnormal laboratory findings associated with autoimmunity, such as an elevated erythrocyte sedimentation rate, C-reactive protein, and antineutrophil cytoplasmic antibodies.

An accumulation of eosinophils that is limited to specific organs is characteristic of particular diseases, such as eosinophilic cellulitis (Wells’ syndrome), eosinophilic pneumonias (e.g., Löffler’s syndrome [ Chapter 59 ]), and eosinophilic fasciitis (Shulman’s syndrome).

Diagnostic Evaluation

Diagnostic studies that should be performed in patients with moderate to severe eosinophilia and considered in patients with persistent mild eosinophilia include morphologic examination of a blood smear, human immunodeficiency virus (HIV) screen, serial stool examinations for ova and parasites, parasite serology, and plasma immunoglobulin E (IgE) level. Parasitic infections that cause eosinophilia are usually limited to helminthic parasites, with the exception of two enteric protozoans, Isospora belli ( Chapter 374 ) and Dientamoeba fragilis ( Chapter 374 ). Strongyloides stercoralis ( Chapter 378 ) infection is important to diagnose because it can cause disseminated fatal disease in immunosuppressed patients; detection of such infection often requires serologic testing. Other infections to consider include trichinosis ( Chapter 378 ), T. canis infection ( Chapter 378 ), and HIV infection ( Chapter 407 ).

Patients with sustained hypereosinophilia should be monitored closely for the subsequent development of cardiac disease. A pathologically similar disease, Löffler’s endomyocarditis ( Chapter 59 ), has been noted in tropical regions, where antecedent parasite-elicited eosinophilia may be responsible for the cardiac damage.


Reactive Hypereosinophilia and Hypereosinophilia Associated with Other Diseases

Treatment of reactive hypereosinophilia and eosinophilia associated with other diseases centers around identifying the cause and then treating the underlying disease process. For example, reactive eosinophilia typically responds by removal of the inciting triggers (e.g., allergens, parasites, and medications). Eosinophilia associated with other disease processes typically improves after treatment of the underlying disease, such as dietary manipulation in patients with allergic eosinophilic gastroenteritis.

FIP1L1/PDGFRA-Positive Disease

Imatinib should be considered as first-line therapy in patients in whom the FIP1L1-PDGFRA fusion gene has been demonstrated and in selected patients with the characteristic clinical and laboratory features of this myeloproliferative subtype of hypereosinophilic syndrome (e.g., male gender, tissue fibrosis, elevated serum vitamin B12 and tryptase levels). Clinical responses to imatinib in FIP1L1/PDGFRA-positive patients are rapid, with normalization of eosinophil counts generally occurring within 1 week of initiation of treatment and reversal of the signs and symptoms occurring within 1 month. Doses of imatinib as low as 100 mg daily appear to be effective in controlling symptoms and eosinophilia in most patients, but some recommend beginning imatinib treatment at 400 mg daily to achieve molecular remission and then decreasing the dose slowly while monitoring the patient closely for evidence of molecular relapse. In imatinib-resistant patients, sorafenib may be effective. The utility of imatinib therapy in hypereosinophilic patients without a demonstrable FIP1L1-PDGFRA mutation remains controversial, although some patients have responded. Nonmyeloablative allogeneic bone marrow transplantation ( Chapter 184 ) has also been used successfully in several patients with hypereosinophilia.

Other Hypereosinophilic Syndromes

Corticosteroids, which have been used for decades for the treatment of idiopathic hypereosinophilic syndromes, remain the first-line treatment for most patients except those with PDGFRA-associated hypereosinophilia. The most appropriate initial corticosteroid dose and the duration of steroid therapy have not been subjected to randomized trials, but a general recommendation is to start with a moderate to high dose (≥40 mg prednisone equivalent) and taper very slowly while monitoring the eosinophil count closely. With this approach, most but not all patients will respond initially, and some will be able to be maintained on low doses of corticosteroids for prolonged periods. Of the cytotoxic therapies that have been used for steroid-refractory hypereosinophilia, hydroxyurea has been the most extensively studied at doses of 1 to 3 g/day. Vincristine at a dose of 1 to 2 mg intravenously can rapidly lower eosinophilia in patients with extremely high eosinophil counts (>100,000/mm3) and may be useful for the treatment of children whose aggressive disease is unresponsive to other therapies. In patients who have corticosteroid-refractory hypereosinophilic syndromes or in whom intolerable side effects of steroid treatment develop, immunomodulatory agents that are sometimes helpful include interferon alfa, cyclosporine, and alemtuzumab. Responses can often be achieved with relatively low doses of interferon alfa (1 to 2 × 106 U/day) and may persist for prolonged periods. Because the effects of interferon alfa on eosinophil numbers in peripheral blood may not become evident for several weeks, escalation to an effective dose may require several months. Rarely, patients have remained in remission for extended periods after cessation of interferon alfa therapy, thus suggesting that interferon alfa may be curative in a small subset of individuals. Low-dose (500 mg daily) hydroxyurea appears to act synergistically with interferon alfa to lower the eosinophil count without increasing side effects. Monoclonal anti–IL-5 antibody therapy (e.g., mepolizumab at monthly intravenous doses of 750 mg) for hypereosinophilia has a number of unique advantages related to the specificity of IL-5 for the eosinophil lineage. The safety and efficacy of anti–IL-5 therapy as a steroid-sparing agent in hypereosinophilia are currently being assessed in a large, double-blind, placebo-controlled study.

Future Directions

Treatments on the horizon for hypereosinophilic disorders include targeted therapy against the eotaxin chemokines and their receptor CCR3.


The prognosis of hypereosinophilic syndromes depends on the primary cause. Whereas FIP1L1-PDGFRA positive disease and other forms of clonal disorders have a poor prognosis (25 to 50% 5-year mortality if responsiveness to therapeutic intervention is not achieved), the prognosis of hypereosinophilia from reactive and other causes is usually better.

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