Approach to the patient with unexplained eosinophilia

Approach to the patient with unexplained eosinophilia

1 Approach to the Patient with Eosinophilia Mohammad Faranoush Faranoush,Eosinophilia 02/28/2020 2 Eosinophils First described in 1879 by Dr. Ehrlich Stained with acidic dyes, eosin Recognized early that they are associated with helminthic infections, asthma, malignancy Differentiate from hematopoietic stem cells

Blood half-life of 18 hrs Faranoush,Eosinophilia 02/28/2020 3 Eosinophils Eosinophil counts are higher in neonates than in adults and the values gradually fall in the elderly. There is no sex or ethnic variation in the eosinophil count. Faranoush,Eosinophilia 02/28/2020 4 Eosinophils

The normal bone marrow contains between 1% and 6% eosinophils and these produce an eosinophil count in the peripheral blood of 0.050.5 x 109/l (Valent et al, 2012). Eosinophil production in the marrow is tightly controlled by a network of transcription factors (McNagny & Graf, 2002) Faranoush,Eosinophilia 02/28/2020 5 Eosinophils Reactive Clonal IL5

tyrosine kinase gene fusions are common IL3 granulocyte-macrophage colonystimulating factor (GM-CSF) typically involving the genes coding for platelet-derived growth factor receptor alpha (PDGFRA) activated T lymphocytes, stromal cells and mast cells, triggering differentiation and activation platelet-derived growth factor receptor beta (PDGFRB)

broblast growth factor receptor 1 (FGFR1) (Gotlib et al, 2006) (Ackerman & Bochner, 2007) Faranoush,Eosinophilia 02/28/2020 6 Eosinophils Eosinophilia represents an increased number of eosinophils in the tissues and/or blood Faranoush,Eosinophilia 02/28/2020

7 INTRODUCTION Peripheral blood eosinophilia (500 eosinophils/microL) may be caused by numerous conditions, including allergic, infectious, inflammatory, and neoplastic disorders The evaluation should seek to identify the cause of eosinophilia and assess the patient for associated organ involvement. Faranoush,Eosinophilia 02/28/2020 8 TERMINOLOGY Absolute eosinophil count (AEC) The number of eosinophils in peripheral blood, calculated as follows:

White blood cell (WBC) count/microL X percentage of eosinophils = AEC (eosinophils/microL) Eosinophilia AEC 500 eosinophils/microL in most clinical laboratories . Eosinophilia is not defined by the percentage of eosinophils (typically <5 percent in healthy individuals), because the percentage varies with the total WBC count and the proportion of other WBC lineages (eg, neutrophils, lymphocytes). Hypereosinophilia 1500 eosinophils/microL (with or without end-organ damage). Hypereosinophilic syndromes (HES) AEC 1500/microL (on two occasions 1 month apart) plus organ dysfunction attributable to eosinophilia. Faranoush,Eosinophilia 02/28/2020 9 CAUSES OF EOSINOPHILIA Eosinophilia may be caused by numerous conditions , including allergic, infectious, inflammatory, and neoplastic disorders. Faranoush,Eosinophilia 02/28/2020 10 Allergy Mild degree of eosinophilia Allergic rhinitis Asthma Atopic dermatitis Eosinophilic esophagitis Drug allergy Moderate to severe degree of eosinophilia Chronic sinusitis (especially polypoid and aspirin-exacerbated respiratory disease) Allergic bronchopulmonary aspergillosis Chronic eosinophilic pneumonia Drug allergy (drug rash with eosinophilia and systemic symptoms [DRESS] syndrome) Faranoush,Eosinophilia

02/28/2020 11 Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome Antibiotics : Penicillins, cephalosporins, dapsone, sulfa-based antibiotics Xanthine oxidase inhibitor : Allopurinol Antiepileptics : Carbamazepine, phenytoin, lamotrigine, valproic acid Antiretrovirals : Nevirapine, efavirenz Nonsteroidal antiinflammatory drugs : Ibuprofen Faranoush,Eosinophilia

02/28/2020 12 parasitic infections Helminthic infections Nematodes Angiostrongyliasis costaricensis Ascariasis Filariases Tropical pulmonary eosinophilia

Loiasis Onchocerciasis Flukes Schistosomiasis Fascioliasis Strongyloidiasis Clonorchiasis Trichinellosis

Paragonimiasis Visceral larva migrans Fasciolopsiasis Hookworm infection Gnathostomiasis Protozoan infections

Isospora belli Cysticercosis Dientamoeba fragilis Echinococcosis Sarcocysti Faranoush,Eosinophilia 02/28/2020 Connective tissue, rheumatologic, and autoimmune disease 13 Eosinophilic fasciitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis) Granulomatosis with polyangiitis (Wegener syndrome) Systemic lupus erythematosus Dermatomyositis Behet syndrome Severe rheumatoid arthritis IgG4-related disease

Progressive systemic sclerosis Inflammatory bowel disease Sjgren syndrome Sarcoidosis Thromboangiitis obliterans with eosinophilia of the temporal arteries Bullous pemphigoid Dermatitis herpetiformis (celiac disease)

Faranoush,Eosinophilia 02/28/2020 14 Primary eosinophilias Idiopathic hypereosinophilic syndrome : sustained peripheral eosinophilia at greater than 1500 cells/L with associated end-organ damage. Lymphoproliferative hypereosinophilic syndrome : sustained peripheral eosinophilia at greater than 1500 cell/L, often associated with rash, aberrant T-cell immunophenotypic profile, often steroid responsive. Faranoush,Eosinophilia

Myeloproliferative hypereosinophilic syndrome : sustained peripheral eosinophilia at greater than 1500 cell/L, often features of splenomegaly, heart related complications, and thrombosis. Can have associated FIP1L1-PDGFRA and other mutations and are often steroid resistant. Patients can be considered to have a diagnosis of chronic eosinophilic leukemia. Episodic eosinophilia associated with angioedema (G syndrome) : cyclical fevers, swelling, hives, pruritus, marked eosinophilia, and IgM elevation. Aberrant Tcell phenotypes often associated 02/28/2020 15 Malignancy Blood-related neoplasms Acute or chronic eosinophilic leukemia

Lymphoma (T cell and Hodgkin) Chronic myelomonocytic leukemia Faranoush,Eosinophilia Solid organassociated neoplasms Adenocarcinomas of the gastrointestinal tract (gastric, colorectal) Lung cancer Squamous epithelium related cancers (cervix, vagina, penis, skin, nasopharynx, bladder)

Thyroid cancer 02/28/2020 16 Other Rejection of a transplanted solid organ Graft-versus-host disease after hematopoietic stem cell transplantation Kimura disease and epithelioid hemangioma Eosinophilia-myalgia syndrome/toxic oil syndrome

Adrenal insufficiency Irritation of serosal surfaces Cholesterol embolus Faranoush,Eosinophilia 02/28/2020 17 IMPORTANT CONCEPTS The cause of eosinophilia is best identified by the patient's history, clinical presentation, and specific laboratory testing, and it is important to be aware of the following concepts. Faranoush,Eosinophilia 02/28/2020 18

Importance of AEC Keep in mind the following concepts regarding the absolute eosinophil count (AEC) AEC does not accurately predict organ damage Organ involvement cannot be accurately predicted by the AEC alone because eosinophils are primarily tissue-dwelling cells. Although complications of eosinophilia are more common in patients with higher AEC (eg, >1500/microL), some patients with persistent hypereosinophilia do not develop organ damage and, conversely, a patient with mild eosinophilia may have significant organ involvement. Organ damage must be evaluated by clinical evaluation and laboratory testing. Faranoush,Eosinophilia 02/28/2020 19 Cont,

AEC does not identify the cause The degree of eosinophilia may help to narrow the differential diagnosis, but the AEC is not sufficient to establish the diagnosis. As an example, marked eosinophilia (eg, 20,000/microL) can be seen in drug hypersensitivity reactions or myeloid neoplasms, but is unlikely to be associated with asthma, allergic rhinitis, or atopic dermatitis. Importantly, all patients with an AEC >1500/microL should be evaluated for hypereosinophilic syndrome Faranoush,Eosinophilia 02/28/2020 20 Diagnostic vigilance

Consider diverse causes It is important to consider many possible causes for eosinophilia. Even in apparently straightforward cases (eg, a child who has long-standing mild eosinophilia and atopy, a traveler returning from a parasite-endemic area with new eosinophilia and gastrointestinal complaints), there may be other, less apparent causes of eosinophilia. Remain vigilant It is especially important to consider other diagnoses when eosinophilia does not respond as expected to an intervention (eg, treatment of an infection, withdrawal of a presumed offending agent). Furthermore, a high degree of suspicion and thoughtful evaluation may be required to identify certain syndromes, such as primary immunodeficiencies, autoimmune illnesses, and eosinophilic granulomatosis with polyangiitis (EGPA; formerly called Churg-Strauss syndrome). Faranoush,Eosinophilia

02/28/2020 21 URGENCY OF EVALUATION Urgency of evaluation is informed by the clinical status of the patient and the level of eosinophilia. Eosinophilia may be encountered in the course of evaluating other clinical conditions or as an incidental finding on a complete blood count (CBC) and differential. We use both the patient's clinical status and the level of absolute eosinophil count (AEC) to guide the urgency of evaluation. Faranoush,Eosinophilia 02/28/2020 22 Acutely ill or extremely high AEC

Hospitalization is generally warranted for patients who are acutely ill or who have an extremely high or rapidly rising AEC. Hospitalization permits management of medical emergencies while the cause of eosinophilia is being investigated. Importantly, management of medical emergencies should not be delayed by the diagnostic evaluation. Since therapy (eg, high dose glucocorticoids) can affect the results of diagnostic testing, every effort should be made to obtain appropriate studies before initiating emergency treatment Emergency treatment may be needed for hemodynamic instability, severe respiratory compromise, delirium, coma, mononeuritis multiplex, or other life-threatening or disabling conditions that may reflect irreversible eosinophil-associated tissue damage to the heart, lungs, nervous system, or other organs. A decision to treat on an emergency basis should be based on the severity of illness and the likelihood of eosinophilia as the cause, rather than the level of AEC alone.

Emergency management of the acutely ill patient with eosinophilia, including treatment with high dose steroids, leukapheresis, and/or cytoreduction An extremely high AEC alone (eg, 50,000/microL) or leukemic blasts on the blood smear should be evaluated urgently even if the patient is clinically stable, as it may reflect a potentially life-threatening disorder (eg, hematologic malignancy) or impending medical emergency. The decision to hospitalize should be made on a case-by-case basis. Faranoush,Eosinophilia 02/28/2020 23 Symptomatic, but clinically stable For the patient who is symptomatic but clinically stable, the urgency of evaluation depends on the clinical presentation, level of eosinophilia, and concern on the part of the clinician and/or patient.

In general, the AEC alone should not determine the urgency of evaluation in a clinically stable patient. However, patients with 5000 eosinophils/microLor rapidly rising AEC should be evaluated promptly. All patients with AEC 1500/microL should be evaluated for hypereosinophilic syndromes (HES) For other symptomatic but clinically stable patients, the urgency of evaluation is informed by findings that may reflect organ involvement and/or the cause of eosinophilia, and by concerns on the part of the clinician and patient. As examples, patients with chest pain, elevated cardiac troponin, or an unexplained abnormal chest X-ray should be evaluated promptly, regardless of the AEC. Conversely, it may be reasonable to conduct the evaluation over a period of weeks or longer for a patient with an AEC of 1400/microL and eczema, previously diagnosed asthma, or a recently treated helminth infection. Faranoush,Eosinophilia

02/28/2020 24 Asymptomatic or incidental eosinophilia All patients with AEC 1500/microL should have a CBC repeated in one to two weeks to determine if the eosinophilia is transient, stable, or rising; the CBC should be repeated even when eosinophilia is detected incidentally in an asymptomatic patient. Persistent AEC >5000/microL or a rising AEC should be evaluated promptly for HES, even though it is uncommon for such patients to be completely asymptomatic. For asymptomatic patients with eosinophilia <1500/microL, it may be reasonable to postpone a repeat CBC and evaluation for a month or longer. However, it is important to first ensure that there are no clinical findings suggestive of eosinophilic end-organ damage, no history of travel or residence in helminth-endemic areas, and no features suggestive of a malignancy (eg, significant anemia or thrombocytopenia, splenomegaly, lymphadenopathy) before deferring the evaluation.

Faranoush,Eosinophilia 02/28/2020 25 INITIAL EVALUATION The initial evaluation should assess the patient for clinical findings that may be attributable to eosinophilia, and seek to determine the underlying cause Faranoush,Eosinophilia 02/28/2020 26 History The history should elicit symptoms that may reflect organ involvement by eosinophils, including a complete review of systems, because of the protean manifestations of organ involvement by eosinophils.

The history should seek to identify conditions that may cause eosinophilia, including asthma, atopy, rheumatologic conditions, infections, malignancy, potential exposures (eg, medications, diet, infections), and family history. It is important to determine if there has been a recent change in symptoms that might represent disease progression or a new diagnosis. Faranoush,Eosinophilia 02/28/2020 27 Patients should be questioned about the following symptoms: Constitutional: Fever, night sweats, unintentional weight loss, fatigue Cutaneous: Eczema, pruritus, urticaria, angioedema, rash, ulcers Cardiac: Dyspnea, chest pain, palpitations, symptoms of heart failure

Respiratory: Nasal/sinus symptoms, wheezing, cough, chest congestion Gastrointestinal: Weight loss, abdominal pain, dysphagia, nausea, vomiting, diarrhea, food intolerance, changes in stools Nervous system: Transient ischemic attack, cerebrovascular accident, behavioral changes, confusion, balance problems, memory loss, change in vision, numbness, weakness, pain Other: Including symptoms attributable to lymphadenopathy or hepatosplenomegaly (ie, new abdominal or chest discomfort, early satiety), ocular findings, genitourinary complaints, myalgia, arthralgia, and anaphylaxis Faranoush,Eosinophilia 02/28/2020 28 Important aspects of the history also include:

Medications Current and past medications should be reviewed in detail, since eosinophilia can be caused by almost any prescription or nonprescription drug, herbal remedy, or dietary supplement Diet Dietary history should explore ingestion of raw or undercooked fish or shellfish, meat, and vegetables as potential sources of parasitic infection (eg, Trichinella, Toxocara, Paragonimus), as discussed in more detail separately. Food allergies and self-imposed dietary restrictions should also be explored. Other exposures May include infectious exposures,including: Occupation (eg, Strongyloides infection in miners, ascariasis in slaughterhouse workers) Recreational activities (eg, schistosomiasis in river rafters in endemic areas)

Travel or residence in countries that may be associated with infectious exposures Family history may be informative in rare cases of familial hematologic syndromes Faranoush,Eosinophilia 02/28/2020 29 Physical examination A thorough physical examination should seek evidence of organ involvement and/or possible causes of eosinophilia. The examination should include a complete skin examination and evaluation for lymphadenopathy and hepatosplenomegaly. Relevant physical findings include, rash, nasal/sinus findings, signs of cardiac and/or respiratory abnormalities, lymphadenopathy, hepatomegaly/splenomegaly, or neurologic findings.

Faranoush,Eosinophilia 02/28/2020 30 Laboratory and diagnostic tests Routine laboratory tests A repeat complete blood count (CBC) with differential count to confirm the presence of eosinophilia, and a chemistry panel that includes electrolytes and liver function tests should be performed in all patients Review of prior CBCs (both normal and abnormal) can provide valuable information about the duration and trajectory of eosinophilia, but it should be recognized that eosinophilia can transiently decrease with steroid treatment or intercurrent bacterial or viral infections. Eosinophilia may be the sole abnormality on the CBC, or it may be accompanied by other abnormalities.

As examples, concurrent neutrophilia may suggest an infection or inflammatory condition, basophilia may reflect a myeloid malignancy or allergic disorder, and lymphocytosis may be associated with a lymphoid malignancy. Faranoush,Eosinophilia 02/28/2020 31 Blood smear The peripheral blood smear should be reviewed by the clinician or the laboratory to assess eosinophil morphology and detect other hematologic abnormalities. Certain findings on the blood smear increase the likelihood of an underlying hematologic or malignant disorder, but aberrant morphology is not sufficient to diagnose a hematologic disorder or to exclude other causes As an example, immature eosinophils (eg, blasts, other immature forms, mononuclear eosinophils) or dysplastic eosinophils may be seen with certain hematologic malignancies ,

but may also be seen in other conditions, including helminth infection and drug hypersensitivity reactions Faranoush,Eosinophilia 02/28/2020 32 Blood tests Serum tryptase estimation should be performed if the differential diagnosis includes chronic eosinophilic leukaemia or systemic mastocytosis In the absence of an identiable cause and with negative peripheral blood analysis for FIP1L1-PDGFRA by FISH or nested RT-PCR, a bone marrow aspirate, trephine biopsy and cytogenetic analysis should be performed the possibility of an underlying lymphoma or of the lymphocytic variant of hypereosinophilic syndrome should be evaluated, including consideration of immunophenotyping of peripheral blood and bone marrow lymphocytes and analysis for Tcell receptor gene rearrangement

The possibility of systemic mastocytosis or other myeloid neoplasm should be considered. Faranoush,Eosinophilia 02/28/2020 33 Tests for selected patients Further testing should be individualized and informed by the clinical presentation and findings from the CBC and chemistry tests above. All patients with an absolute eosinophil count (AEC) >1500/microL should undergo evaluation for hypereosinophilic syndromes (HES) The choice of further initial testing in patients with AEC <1500 is nuanced, and there is no menu of additional tests that should be performed in all patients. Following are tests that we obtain for selected patients in the initial evaluation of eosinophilia: Cardiac troponin We suggest testing serum cardiac troponin in patients with AEC 1500/microL, cardiac symptoms, or suggestive abnormalities on physical examination (eg, dyspnea, palpitations, heart murmur, cardiac dysrhythmia). Patients with elevated cardiac troponin should have electrocardiography and echocardiography to assess potential cardiac involvement. Vitamin B12 and tryptase We suggest measuring serum vitamin B12 and tryptase in patients with AEC 1500/microL, abnormal blood smear, anemia or thrombocytopenia, splenomegaly, or symptoms consistent with systemic mastocytosis (eg, urticaria, anaphylaxis, flushing, or abdominal symptoms), as these findings may suggest an underlying hematologic/malignant disorder Imaging We suggest obtaining a chest X-ray for patients with respiratory symptoms (eg, dyspnea, cough, wheezing, rhinosinusitis). For patients with an unexplained infiltrate or AEC 1500/microL, we suggest high resolution computed tomography (CT) and pulmonary function tests. We also obtain high resolution CT for patients with possible eosinophilic granulomatosis with polyangiitis (EGPA; formerly called Churg-Strauss disease). Clinical findings suggestive of EGPA include asthma, upper airway/ear disease, rash or subcutaneous nodules, cardiomyopathy, pericarditis, mononeuritis multiplex, or unexplained renal disease, as described in detail separately Infectious evaluation Infectious causes should be considered for most patients with eosinophilia, and they may be overlooked in the history unless specifically queried. The likelihood of an infectious cause is greater in patients whose travel or residence suggests possible exposure to parasites or other infections, and the evaluation should be informed by clinical findings and possible exposure to parasites and other infections. Faranoush,Eosinophilia

02/28/2020 34 Assessment for possible eosinophilassociated end-organ damage End-organ damage should be assessed using chest radiography and/or computed tomography (CT) of the thorax, echocardiography, serum troponin T and pulmonary function testing An unprovoked thromboembolic event should be recognised as a possible manifestation of eosinophil associated tissue damage In patients with end-organ damage, the frequency of further serial evaluations of organ function should be determined by the severity and extent of organ compromise and/or by worsening of the eosinophilia Faranoush,Eosinophilia 02/28/2020 35

Faranoush,Eosinophilia 02/28/2020 Clonal Eosinnophilia 36 Faranoush,Eosinophilia 02/28/2020 37 Emergency treatment Patients requiring emergency treatment for severe or life-threatening eosinophilia should receive high-dose corticosteroids Patients receiving corticosteroids, in whom there is a risk of strongyloides infection, should receive concomitant ivermectin to prevent potentially fatal hyperinfection Faranoush,Eosinophilia

02/28/2020 38 Treatment of clonal eosinophilia Patients with clonal eosinophilia with FIP1L1PDGFRA (including patients presenting with acute leukaemia), should be treated with low dose imatinib Patients with clonal eosinophilia with PDGFRB rearrangement or ETV6-ABL1 fusion should receive standard dose imatinib Patients with clonal eosinophilia with ETV6-FLT3 fusion should be considered for sunitinib or sorafenib therapy Patients with clonal eosinophilia with JAK2 rearrangement should be considered for ruxolitinib therapy Patients with acute myeloid leukaemia (AML) with clonal eosinophilia and no molecular or cytogenetic abnormality suggesting likely response to a tyrosine kinase inhibitor should be offered standard AML

induction therapy Patients with other haematological neoplasms with clonal eosinophilia should have treatment directed at management of the neoplasm. If there is organ damage or dysfunction relating to the eosinophilia, treatment with corticosteroids should also be given Faranoush,Eosinophilia 02/28/2020 39 Treatment of lymphocytic variant of hypereosinophilic syndrome Patients with the lymphocytic variant of hypereosinophilic syndrome (HES) can be managed in the same manner as idiopathic HES Faranoush,Eosinophilia 02/28/2020 40 Treatment of idiopathic hypereosinophilic

syndrome Patients with idiopathic HES should be treated in the rst instance with corticosteroids Patients with idiopathic HES who do not respond adequately to corticosteroids, or who require prolonged corticosteroid therapy, or who are intolerant of corticosteroids,should be considered for a short trial (4 6 weeks) of imatinib, immunomodulatory agents (interferon alpha, ciclosporin or azathioprine), myelosuppressive therapy (hydroxycarbamide) or monoclonal antibody therapy with mepolizumab (anti-interleukin 5) Alemtuzumab, an anti-CD52 monoclonal antibody, should be considered for patients with severe idiopathic HES unresponsive to other therapies, and may be useful in patients with idiopathic HES-associated cardiac and cerebral dysfunction Faranoush,Eosinophilia 02/28/2020 41 Faranoush,Eosinophilia 02/28/2020

42 Role of haemopoietic stem cell transplantation (HSCT) HSCT should be considered for cases with clonal eosinophilia with FGFR1 rearrangement, patients with chronic eosinophilic leukaemia, not otherwise specied HES patients refractory to or intolerant of both conventional tyrosine kinase inhibitor (TKI) therapy and experimental medical therapy, where available, Progressive end-organ damage Faranoush,Eosinophilia 02/28/2020 43 Faranoush,Eosinophilia 02/28/2020

44 CLINICAL SCENARIOS Although many eosinophilic disorders are protean in their manifestations, the clinical presentation may inform the evaluation of unexplained eosinophilia Faranoush,Eosinophilia 02/28/2020 45 KEY POINTS Eosinophilia is an elevation in the total number of bloodstream eosinophils, can be transient or sustained, and can exist in milder versus more significant levels. Sustained and significant eosinophilia in the 1500 cells/L or above range, without clear cause, should prompt evaluation.

Processes known to cause modest eosinophilia include allergic disease, parasitic disease, drug allergy, and mastocytosis. More significant eosinophilia is often caused by drug allergy, aspirin exacerbated respiratory disease, sustained and significant atopic dermatitis, and some parasitic disorders. If no apparent cause of the eosinophilia is known and levels above 1500 cells/L exist for greater than 1 month, an exhaustive search guided by clinical presentation should ensue Faranoush,Eosinophilia 02/28/2020 46 Thank You Any Question Faranoush,Eosinophilia 02/28/2020

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