Eosinophilia

Eosinophilia

What every physician needs to know:

“Eosinophilia” refers to an increased absolute number of eosinophils in the peripheral blood. Both peripheral eosinophilia and tissue eosinophilia (infiltration of the body tissue by an abnormally high number of eosinophils) can occur as secondary manifestations of a wide range of allergic, infectious, and malignant conditions, or as a primary manifestation of a hypereosinophilic syndrome.

Strict definitions of eosinophilia vary slightly across laboratories, but the most commonly accepted cutoff is an absolute eosinophil count greater than 500 eosinophils/microliter of blood. Many experts further stratify the degree of eosinophilia as follows:

• Mild eosinophilia: 500 to 1,500 eosinophils/μl
• Moderate eosinophilia: 1500 to 5,000 eosinophils/μl
• Severe eosinophilia: greater than 5,000 eosinophils/μl

An additional term, “hypereosinophilia,” has been used to refer to an absolute eosinophil count of greater than 1500/microl, thereby encompassing moderate and severe eosinophilia. In contrast, the term “hypereosinophilic syndrome” is usually reserved for hypereosinophilia (generally severe) occurring in the absence of an obvious underlying process.

What features of the presentation will guide me toward possible causes and next treatment steps:

Acuity of presentation

Although not specific, rapidly developing eosinophilia is often seen in the presence of an allergic reaction, aggressive infection or malignancy. On the other hand, long-standing eosinophilia can be seen in chronic infections, autoimmune diseases, and indolent malignancies.

Severity of eosinophilia

Some diseases (most notably asthma and adrenal insufficiency) rarely present with more than a mild eosinophilia, and the presence of severe eosinophilia makes this less likely. Otherwise, however, the severity of eosinophilia is rarely helpful for distinguishing among its possible causes.

Associated symptoms

Pruritis is a common finding in many patients with eosinophilia, and may indicate the presence of an allergic process, a parasitic infection, or a hematologic malignancy. Certain dermatologic findings, especially urticaria (wheals), are also common in patients with eosinophilia and pruritis.

Prominent constitutional symptoms such as fatigue, fevers, night sweats, or weight loss, although nonspecific, may accompany eosinophilia due to chronic infections (especially HIV and intestinal parasites), adrenal insufficiency, autoimmune diseases, or malignancy.

Dyspnea or wheezing may indicate the presence of asthma, allergic bronchopulmonary aspergillosis (ABPA), or the Churg-Strauss syndrome. Dyspnea without prominent wheezing may occur with a theroembolic pulmonary emboli.

Diarrhea or abdominal pain can occur in several syndromes associated with eosinophilia, especially parasitic infections.

Arthralgias, myalgias, joint inflammation, Raynaud’s phenomenon, Sicca syndrome, or a malar skin rash may indicate the presence of underlying autoimmune disease.

Physical examination

Signs that may help guide work-up and management include:

• Orthostatic changes in vital signs (adrenal insufficiency)
• Wheezing (asthma, ABPA, Churg-Strauss syndrome)
• Abdominal tenderness (helminthic infections)
• Hepatosplenomegaly, lymphadenopathy (hematologic malignancy, chronic infections)
• Diminished peripheral pulses (thromboangiitis obliterans, atheroembolic renal disease)
• Inflamed joints (rheumatologic disease)
• Dermatographia (allergic reaction, primary mastocytosis)
• Foot drop, or other evidence of mononeuritis multiplex (Churg-Strauss syndrome)

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Laboratory studies required:

• Full chemistry panel

– Hyponatremia can indicate adrenal insufficiency or volume contraction from diarrhea.- Hyperkalemia can indicate adrenal insufficiency.- Non-anion gap metabolic acidosis can indicate adrenal insufficiency.- Impaired renal function is non-specific, but can be seen in acute interstitial nephritis.

• Liver function tests
• Complete blood count with manual smear/differential

– Elevation in other types of white blood cells can indicate infection or malignancy.- Anemia, though non-specific, can indicate chronic disease, iron deficiency from a malignancy or infiltrative parasite, hemolysis, or bone marrow infiltration or failure related to an underlying malignancy.- Thrombocytopenia can accompany autoimmune diseases, infection, or malignancy.- Thrombocytosis can be reactive to an infection or autoimmune disease, or can occur in the setting of a malignancy or myeloproliferative disorder.

• Urinalysis for the presence of eosinophils, which may indicate acute interstitial nephritis

Additional laboratory testing should depend on the clinical circumstances and can include:

• Allergic:

– Immunoglobulin subclasses (especially immunoglobulin E [IgE]).- Tryptase.

• Infectious:

– HIV serology +/- viral load.- The human T-lymphotropic virus (HTLV) Types I and II serology.- Stool examination for ova and parasites.- Serology for strongyloides, Toxocara canis, Trichinella, Schistosoma, Echinococcus.- Serology for coccidiomycosis, Histoplasma, or Aspergillus.- Skin testing for reactivity to Aspergillus antigens.- Of note, galactomannan, which is fairly sensitive for the diagnosis of invasive aspergillus infections, is not helpful in the diagnosis of ABPA.

• Malignant:

– Peripheral flow cytometry for leukemia or lymphoma markers.- Lactate dehydrogenase (LDH) (non-specific, but can indicate increased cellular turnover).- Bone marrow examination for flow cytometry and cytogenetics.

• Autoimmune:

– Antinuclear antibodies.- As detailed below, however, rheumatologic disease is a rare cause of eosinophilia, so testing for more common diseases like rheumatoid arthritis or systemic sclerosis is usually not indicated, and if positive, is likely incidental.

What conditions can underlie eosinophilia:

Allergic disorders

• Atopic dermatitis
• Rhinitis syndromes (most commonly manifest as nasal eosinophilia):

– Nasal polyposis +/- asthma or aspirin sensitivity.- Nonallergic rhinitis with eosinophilia syndrome (NARES).

• Drug-related eosinophilia

Infectious diseases

• Retroviruses:

– HIV.- HTLV-I and -II.

• Parasites:

– Helminths: (hookworm, Strongyloides, cysticercosis, Echinococcus, gnathostomiasis).- Filariasis (Loa loa, onchocerciasis, mansonelliasis).- Flukes (schistosomiasis, Clonorchis, paragonimiasis).- Protozoa: Dientamoeba fragilis, Isospora belli (of note, most other protozoa do not cause eosinophilia)

• Fungi:

– ABPA- Coccidiomycosis (primary or disseminated)

Neoplastic disorders

• Primary:

– Hypereosinophilic syndromes.- Mastocytosis.- Acute eosinophilic leukemia (FAB M4Eo).

• Secondary:

– Precursor B-cell acute lymphoblastic leukemia (usually with t[5;14]).- Precursor T-cell acute lymphoblastic leukemia (usually with t[8;13]).- Hodgkin lymphoma.- Non-Hodgkin lymphoma.- Sezary syndrome.- Solid tumors (uncommonly seen).

Autoimmune/rheumatic disease

• Eosinophilia-myalgia syndrome (associated with contaminated L-tryptophan)
• Toxic oil syndrome (associated with ingestion of denatured rapeseed oil)
• Idiopathic eosinophilic synovitis
• Other diseases (rarely seen): rheumatoid arthritis, dermatomyositis, systemic sclerosis, Sjogren’s syndrome

Vasculitis

• Churg-Strauss syndrome
• Thromboangiitis obliterans (Buerger’s disease [eosinophilia seen rarely])
• Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis [eosinophilia seen rarely])

Primary immunodeficiency

• Hyper-IgE syndrome (Job’s syndrome)
• Combined immunodeficiency with hypereosinophilia (Omenn syndrome).

Adrenal insufficiency

Atheroembolic disease

When do you need to get more aggressive tests:

A rapidly increasing eosinophil count or overt constitutional symptoms may indicate the presence of an aggressive neoplastic process, while hemodynamic instability or signs of anaphylaxis may indicate an evolving serious allergic reaction. On the other hand, long-standing eosinophilia, especially if accompanied by some of the signs or symptoms described above, may still require more invasive or aggressive testing, if the cause of the eosinophilia is unclear after a basic work-up.

Some of these tests may include:

• Bone marrow biopsy or lymph node biopsy

– To look for signs of tissue eosinophilia or mast cell invasion, as may be seen in the hypereosinophilic syndromes or mastocytosis.

Muscle, skin, or other organ biopsy

– To look for signs of tissue eosinophilia or mast cell invasion, as may be seen in the hypereosinophilic syndromes or mastocytosis.

Bronchoscopy with lavage +/- transbronchial biopsy

– To look for eosinophils, aspergillus, or granulmoas that could indicate Churg-Strauss or granulomatosis with polyangiitis.

What imaging studies (if any) will be helpful?

There are no imaging studies that are universally applicable to all cases of eosinophilia. Localizing signs and symptoms may suggest appropriate imaging to help characterize the source of an infection or malignancy.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Appropriate therapy will almost always depend on identification of the underlying cause of eosinophilia.

Patients who present with lip or tongue swelling, laryngeal edema or acute bronchospasm, or signs of hemodynamic collapse suggestive of an acute anaphylactic reaction should be treated with steroids and/or epinephrine, as appropriate.

Patients with underlying infections or malignancies should be referred to appropriate subspecialists for additional diagnostic work-up, and for treatment once a diagnosis has been made. Patients with adrenal insufficiency usually require replacement therapy with corticosteroids.

What other therapies are helpful for reducing complications?

Patients with severe pruritis should be treated symptomatically with topical moisturizing creams or lotions and antihistamines, either first generation (diphenhydramine or hydroxyzine) or second-generation (loratidine, fexofenadine, or cetirizine).

What should you tell the patient and the family about prognosis?

As with treatment, the prognosis depends on the underlying cause of the eosinophilia.

“What if” scenarios.

Since eosinophilia has a broad differential diagnosis, there are many potential decision points in its work-up and treatment. The most important of these is the identification of imminently life-threatening conditions (especially anaphylaxis) and those that, while not emergent, require quick, decisive work-up.

The latter group includes fulminant adrenal failure, aggressive hematologic malignancies, and the vasculitides (Churg-Strauss and granulomatosis with polyangiitis), which can have an aggressive course if not promptly treated. A comprehensive initial work-up such as that described above will help determine the subspecialists who will be most helpful in identifying and treating these conditions.

Pathophysiology

Eosinophils are terminally differentiated members of the granulocyte lineage. They are descended from the same common myeloid progenitor that gives rise to other hematopoietic cells that mature within the bone marrow, including erythrocytes, platelets, neutrophils, and monocytes. They share a more differentiated common progenitor with basophils. Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 are all important in eosinophil development, with IL-5 playing a particularly important role in differentiation and activation. Once differentiated, eosinophils migrate from the bone marrow to the peripheral tissues, mainly the gut, where they reside until senescence or activation; thus the presence of eosinophils in the peripheral blood is uncommon in the absence of stimulating factors.

For the most part, eosinophils are synthetically inactive and mainly act through degranulation and the release of prestored mediators. Some of these, such as major basic protein (MBP), eosinophil cationic protein, and eosinophil-derived neurotoxin, are directly cytotoxic to parasites, while others (leukotrienes and prostaglandins) induce local changes like vasodilatation and increased vascular permeability, which assist in the development of a more robust immune response.

The most common and best understood mechanism for physiologic eosinophil activation occurs through the T helper (Th) 2 mediated pathway, which is important in both allergic and atopic reactions and as a response to helminthic infections. In this pathway, the antigenic stimulation of Th2 cells leads to the production of specific cyokines and chemokines, especially IL-5. These products lead to the recruitment of existing eosinophils to the site of Th2 activation and prime them to release their cellular contents, while also stimulating the production of new eosinophils in the bone marrow; the actual process of degranulation is then usually stimulated by the crosslinking of surface receptors by immunoglobulin. At the same time, the Th2 response also leads to mast cell recruitment and the production of IgE.

Conversely, some causes of both peripheral or tissue eosinophilia (most notably esophagitis and some forms of pulmonary eosinophilia) occur without prominent IgE production or mast cell activation, providing evidence that there are parallel mechanisms for eosinophil activation independent of the Th2 pathway.

The pathogenesis of the hypereosinophilic syndromes (HES) and other clonal diseases of eosinophils is distinct from these physiologic mechanisms. The best understood pathway develops in the context of the most common genetic abnormality underlying the hypereosinophilic syndromes, in which an interstitial deletion of chromosome 4q12 leads to the formation of the fusion gene product FIP1L1-PDGFRα, a constitutively activated tyrosine kinase that drives the production of terminally differentiated eosinophils.

The response of this subset of HES to tyrosine kinase inhibitors like imatinib, supports the hypothesis that this mutation is likely causative, though some HES without the mutation respond to the drug as well, implying the involvement of other tyrosine kinases in the disorder’s pathogenesis. A number of other genetic abnormalities have been observed in HES patients who lack 4q12 deletions, including mutations in binding partners of PDGFRα and PDGFRβ, rearrangements of FGFR1, and the same V617F point mutation in JAK2 that is frequently found in the classic bcr-abl-negative myeloproliferative disorders. The pathogenic significance of many of these abnormalities is not yet fully understood.

What other clinical manifestations may help me to diagnose eosinophilia?

This is discussed above.

What other additional laboratory studies may be ordered?

This is discussed above.

What’s the evidence?

Cools, J, DeAngelo, DJ, Gotlib, J. “A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome”. N Engl J Med. vol. 348. 2003. pp. 1201[Seminal description of the FIP1L1 translocation in hypereosinophilic syndrome and its response to imatinib.]

Golkar, L, Bernhard, JD. “Mastocytosis”. Lancet. vol. 349. 1997. pp. 1379[Review of mastocytosis.]

Gotlib, J, Cools, J, Malone, JM. “The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management”. Blood. vol. 103. 2004. pp. 2879[Review placing the discovery of the PDGFRA-FIP1L1 fusion gene in the context of hypereosinophilic syndromes.]

Kargili, A, Bavbek, N, Kaya, A. “Eosinophilia in rheumatologic diseases; a prospective study of 1000 cases”. Rheumatol Int. vol. 24. 2004. pp. 321[Review of eosinophilia in rheumatologic disease.]

Kaufman, LD, Krupp, LB. “Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia”. Curr Opin Rheumatol. vol. 7. 1995. pp. 560[Review of unusual eosinophilic syndromes.]

Löffler, H, Gassmann, W, Haferlach, T. “AML M1 and M2 with eosinophilia and AML M4Eo: diagnostic and clinical aspects”. Leuk Lymphoma. vol. 18 Suppl 1. 1995. pp. 61[Review of the subtypes of AML that can be associated with eosinophilia, and the importance of eosinophilia as a marker of a subtype of M4 AML.]

Paganelli, R, Scala, E, Mazzone, AM. “Th2-type cytokines, hypereosinophilia, and interleukin-5 in HIV disease”. Allergy. vol. 52. 1997. pp. 110[Discussion of the immunologic features of hypereosinophilia in HIV disease.]

Simon, HU, Rothenberg, ME, Bochner, BS. “Refining the definition of hypereosinophilic syndrome”. J Allergy Clin Immunol. vol. 126. 2010. pp. 45[Reassessment of the analysis of hypereosinophilic syndrome in the face of current understanding of clonality of specific hypereosinophilic syndromes.]

Weller, PF. “The immunobiology of eosinophils”. N Engl J Med. [Review of eosinophil biology.]

Weller, PF, Bubley, FJ. “The idiopathic hypereosinophilic syndrome”. Blood. vol. 83. 1994. pp. 2759[Descriptions of hypereosinophilic syndrome prior to the discovery of the FIP1L1-PDGFRA fusion.]

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