Hospital Medicine

Eosinophilia

Eosinophilia

I. Problem/Condition.

Eosinophilia indicates elevated levels of eosinophils in the peripheral blood, usually related to an infectious, neoplastic, or allergic process. Often, high numbers of eosinophils may be present in other body fluids or tissues, but the term typically refers to peripheral blood eosinophilia. It is often defined as an absolute eosinophil count of ≥500 eosinophils/microliter (cells/microL) of blood. 500-1500 cell/microL is considered mild, 1500-5000 cells moderate, and >5000 severe.

Hypereosinophilia refers to the presence of an absolute eosinophil count of ≥1500 eosinophils/microL and does not signify whether end organ manifestations have occurred.

Hypereosinophilic syndrome is a non-specific term to describe the presence of an absolute eosinophil count of ≥1500 eosinophils/microL on two separate occasions in addition to end organ manifestations but does not specify a primary hematologic disorder or a secondary reactive etiology. In some cases, if an etiology is not identified, then the terms Idiopathic hypereosinophilia (hypereosinophilia of undetermined significance, see below) or Idiopathic hypereosinophilic syndrome (hypereosinophilic syndrome of undetermined significance) are used. In both cases, there must be a presence of ≥1500 eosinophils/microL but the former is used if there is no evidence of end organ manifestations.

In 2012, a panel of experts published recommendations on terminology of eosinophilia and introduced the term “hypereosinophilia of undetermined significance” in lieu of “idiopathic hypereosinophilia” (similar for idiopathic hypereosinophilic syndrome).

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Acquired blood eosinophilia (much more prevalent than familial eosinophilia) may be of primary etiology or secondary to a wide variety of disorders.

Primary eosinophilia: Occurs mostly in males in patients with myeloproliferative variants or PDGFRA/PDGFRB gene aberrations. Otherwise, no sex predominance is seen in other associated diseases.

  • Clonal: Neoplastic proliferation of eosinophils in a stem cell-derived myeloid malignancy.

    • Acute myeloid leukemia: Particularly acute eosinophilic leukemia which is a variant of the French American British (FAB) M4 acute myelomonocytic leukemia.

    • Chronic myeloid disorders: Myelodysplastic syndromes (MDS), classic myeloproliferative disorders (MPN) such as chronic myeloid leukemia, polycythemia vera, etc., MDS/MPN overlap syndromes such as chronic myelomonocytic leukemia, and systemic mastocytosis.

    • Other World Health Organization classification: In 2008, WHO added two new categories to classify myeloid and lymphoid neoplasms with eosinophilia.

      • Chronic eosinophilic leukemia not otherwise specified.

      • Myeloid or lymphoid neoplasms associated with eosinophilia and genetic abnormalities PDGFRa, PDGFRb, FIP1L1 (i.e., genes for tyrosine kinase platelet-derived growth factor receptors or fibroblast growth factor receptor rearrangements).

  • Idiopathic: No secondary or clonal cause identified.

    • Hypereosinophilic syndrome (HES), characterized by persistent eosinophilia >1500 cells/microL (typically on two separate occasions), no other identifiable etiology, and signs or symptoms of organ involvement. Evidence suggests that HES may actually represent an underlying myeloid malignancy and may progress to myeloid neoplasm. Some patients with FIP1L1-PDGFRa-positive clonal eosinophilia were previously diagnosed with HES before the mutation was discovered.

  • Familial: Rare cause and existing studies have shown typically no progression to end organ manifestations, though some case studies have. Studies have shown autosomal dominance inheritance with one family genetic analysis showing aberrations in the chromosome 5q31-33.

Secondary eosinophilia: In tropical areas, this is mostly due to parasitic infections, while in developed nations eosinophilia is mostly the result of non-infectious causes. Selected causes are shown below.

Allergic causes:

  • Asthma

  • Atopic dermatitis

  • Allergic rhinitis

  • Allergic bronchopulmonary aspergillosis

Medications:

  • Antibiotics (penicillins, cephalosporins, quinolones, sulfonamides).

  • Nonsteroidal anti-inflammatory drugs (NSAIDS).

  • Antiepileptics (phenytoin, carbamazepine, valproate).

  • Antihypertensives (angiotensin converting enzyme [ACE] inhibitors, hydrochlorothiazide, beta blockers).

  • Antidepressants (fluoxetine, amitriptyline).

Infections (varies according to geographic origin of patient):

  • Helminth parasites include Strongyloides stercoralis, hookworm, Toxocara canis, filariae, schistosomes, whipworms, flukes, and trichinella. Usually parasites that are isolated to the intestinal lumen or are intact cysts (Echinococcus) do not cause blood eosinophilia unless there is tissue invasion or cyst dysruption.

  • Protozoan parasites such as Giardia lamblia or Entamoeba histolytica do not typically cause peripheral eosinophilia. However, exceptions to this include Dientamoeba fragilis, Isospora belli, and Sarcocystis species.

  • Fungal infections such as coccidiomycosis or disseminated histoplasmosis.

  • Can be found in human immunodeficiency virus (HIV) patients, but not usually directly caused from HIV itself.

Lymphoid neoplasms (not part of neoplastic myeloid clonal disorder but due to dysregulation of eosinophilopoietic cytokines like interleukin-g [IL-5]):

  • B-cell lymphoma (Hodgkin and non-Hodgkin lymphomas).

  • Solid tumors (adenocarcinoma, squamous cell carcinoma).

  • Lymphoblastic lymphomas/leukemias.

Immune dysregulation/Inflammation

  • Connective tissue/rheumatologic diseases:

    • Eosinophilic granulomatosis with polyangitis (previously Churg-Strauss).

    • Less commonly in granulomatosis with polyangiitis, systemic sclerosis, dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus, immunoglobulin G4 (IgG4)-related disease, eosinophilic fasciitis, eosinophilic synovitis and polyarteritis nodosa.

  • Eosinophilic granuloma (also known as Langerhans cell granulomatosis or pulmonary histiocytosis X).

  • Immunodeficiency states: hyper-immunoglobulin E (IgE) syndrome which is characterized by chronic dermatitis and recurrent infections.

  • Toxins: eosinophilia-myalgia syndrome from ingestion of contaminated L-tryptophan, toxic oil syndrome from ingestion of adulterated oil with denatured rapeseed oil.

  • Sarcoidosis.

  • Inflammatory bowel disease.

Other:

  • Adrenal insufficiency, particularly in critically ill patients and Addison's disease.

  • Atheroembolic disease from cholesterol crystal embolism, presenting also with livedo reticularis, renal insufficiency, purple toes, eosinophiluria.

  • Chronic eosinophilic pneumonia.

  • Eosinophilic gastrointestinal disorders.

B. Describe a diagnostic approach/method to the patient with this problem.

  • Evaluate for secondary causes of eosinophilia:

    • Use patient history to target possible etiologies above and assess for possible culprit medications.

  • If work-up unrevealing and/or clinical picture points to a primary etiology of eosinophilia:

    • Hematologic studies and bone marrow examination must be performed to investigate a clonal cause.

  • Evaluate for organ damage, especially in those with severe hypereosinophilia.

1. Historical information important in the diagnosis of this problem.

  • Medication list

  • Allergy history

  • Travel history

  • Family history

  • Occupational exposures

  • Constitutional symptoms

  • Symptoms due to lymphadenopathy or hepatosplenomegaly

  • Rash or pruritus

  • Respiratory, cardiac or gastrointestinal symptoms

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

  • Skin: check for a generalized rash which may be seen in drug rash with eosinophilia and systemic symptoms (DRESS) or autoimmune conditions, livedo reticularis which may indicate an autoimmune process or atheroembolic disease, hyperpigmentation which one might find in Addison's disease, or petechiae/bruising which could indicate an underlying hematologic pathology.

  • Pulmonary: active wheezing, low oxygenation might be consistent with asthma or lung process.

  • Gastrointestinal: hepatosplenomegaly could suggest a neoplastic process.

  • Lymphadenopathy: could suggest a neoplastic process.

  • Musculoskeletal: joint inflammation and/or muscle tenderness could indicate an autoimmune inflammatory process.

  • Ear/Nose/Throat: nasal and sinus inflammation can point towards allergic rhinitis, eosinophilic granulomatosis with polyangitis (previously Churg-Strauss), or granulomatosis with polyangiitis (previously Wegener's disease).

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

  • Complete blood count with differential

  • Peripheral blood smear to look for circulating blasts, dysplastic cells.

  • Serum chemistries, urinalysis

  • Serum B12

  • Stool ova and parasites.

  • Some parasites may not be stool-dwelling and serologies may be needed, particularly with a concerning travel history. Considerations include Schistosoma, Toxocara canis, Trichinella, Strongyloides serologies.

  • Other infectious serologies as determined by history such as HIV, Cryptococcus, Histoplasma.

  • Antinuclear antibody (ANA), Anti-neutrophil cytoplasmic antibody (ANCA), and other autoimmune testing as indicated by clinical picture.

  • Consider chest X-ray if history and physical exam point to lung abnormalities.

  • Consider serum Tryptase level to evaluate for systemic mastocytosis.

  • Bone marrow biopsy with morphologic, cytogenetic, and immunophenotypic tests.

  • Advanced hematologic testing includes peripheral blood mutation screening for FIP1L1-PDGFRA gene fusion using methods such as fluorescence in situ hybridization (FISH) or real time-polymerase chain reaction (RT-PCR) and peripheral blood lymphocyte testing.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

  • Infectious and autoimmune processes can be distinguished with positive testing and the clinical picture.

  • Bone marrow biopsy and cytogenetic studies can help differentiate between acute myeloid leukemias or chronic myeloid processes. Chronic eosinophilic leukemia is considered when the peripheral eosinophil count is >1500 cells/microL and there is a cytogenetic abnormality or greater than 2% peripheral blasts or greater 5% bone marrow blasts (but otherwise a non-classifiable myeloid malignancy).

  • FISH/ RT-PCR results can identify particular clonal eosinophilias with FIP1L1-PDGFR genetic rearrangements.

  • Peripheral blood lymphocyte testing can indicate the possibility of lymphocytic-variant eosinophilia.

  • When the above testing is negative, the cause may be characterized as idiopathic eosinophilia (eosinophilia of undetermined significance) or idiopathic hypereosinophilic syndrome (HES), based upon the level of eosinophils and presence of end-organ damage as described previously.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

A thorough history and physical exam should help guide the determination of what diagnostic tests will be most high-yield. A "shotgun" approach is not recommended.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Eosinophilia.

In an asymptomatic patient, treatment can generally be deferred until the diagnostic work-up is completed. However, one should be aware that moderate and severe hypereosinophilia from conditions such as hypereosinophilic syndrome can result in multiorgan damage and complications including cardiomyopathy, pneumonitis, neuropathy, gastrointestinal inflammation, or thromboembolic complications. Patients with severe hypereosinophilia and/or signs and symptoms of hyperleukocytosis may need rapid treatment with high-dose steroids and/or leukopheresis.

Once diagnostic work-up has been completed, treatment is tailored towards the etiology of the eosinophilia. For secondary causes of eosinophilia, attempt to treat the underlying condition or remove the offending agent. FIP1L1-PDGFRA clonal eosinophilias are best treated with the tyrosine-kinase inhibitor imatinib, and this should be promptly initiated, even in asymptomatic patients, given the propensity of these conditions to progress towards end-organ damage. Other myeloid malignancies should be treated as appropriate to that condition. Idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia can be treated with corticosteroids, interferon alfa, or hydroxyurea.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Asymptomatic patients need periodic monitoring to ensure that there has not been end-organ involvement, and testing may include blood chemistries, electrocardiogram, echocardiogram, and pulmonary function tests. Prednisone has a variety of side effects including immunosuppression. Imatinib treatment may result in myelosuppression, gastrointestinal side effects, rash, and peripheral/periorbital edema.

IV. What's the Evidence?

Curtis, C, Ogbogu, P. "Hypereosinophilic Syndrome". Clinic Rev Allerg Immunol. vol. 50. 2016. pp. 240-251.

Gotlib, J. "World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management". Am J Hematol. vol. 90. 2015. pp. 1077-89.

Klion, AD, Law, MA, Riemenschneider, W. "Familial eosinophilia: a benign disorder". Blood. vol. 103. 2004. pp. 4050-55.

Valent, P, Klion, AD, Horny, HP. "Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes". J Allergy Clin Immunol. vol. 130. 2012. pp. 607-12.

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