CE Update

Received 11.14.05 | Revisions Received 2.5.06 | Accepted 2.7.06 Peripheral and Diagnosis of Hypereosinophilic Syndrome

Kenneth L. Sims, MD Downloaded from https://academic.oup.com/labmed/article/37/7/440/2504503 by guest on 01 October 2021 (American University of the Caribbean School of Medicine, Sint Maarten, Netherlands Antilles)

DOI: 10.1309/RK234QMGLX0JPG0E

Abstract classification of peripheral blood eosinophilia the “hypereosinophilic syndromes” based on This article first reviews the mechanisms, disorders as well as the relative frequency of the their molecular biology and their relationship to frequency, and diagnostic criteria for peripheral various disorders. The remainder of the article clonal disorders involving esosinophils (eg, blood eosinophilia. Subsequent emphasis is on highlights recent advances in classification of chronic esosinophic leukemia).

The reader should better understand first the mechanisms, causes, and Immunology exam 40602 questions and corresponding answer form are classification of peripheral blood esosinophilia. After achieving this basic located after the CE Update section on p. 443. understanding of peripheral blood eosinophilia, the reader can then understand the diagnosis and clinical relationship of eosinophilia to the uncommon clonal and highly aggressive disorders known collectively as hypereosinophilic syndrome (HES).

Paul Ehrlich first observed the (terming it an in blood is 18 hours.7 quickly exit the blood via the acidophil) in 1879 because of the affinity of its granules for post-capillary venule in response to action of various chemokines eosin as part of his overall observations with staining peripheral (eotaxin-1 and eotaxin-2 are relatively specific for eosinophils).6 blood constituents.1 In Ehrlich’s textbook in 1900,2 the blood The intravascular compartment is by far the smallest of the 3 and tissue appearance of the eosinophil using Romanowsky stain compartments with only 1 peripheral blood eosinophil per 100 is depicted as the bilobed circulating granulocyte with pink tissue eosinophils.5 The ratio of tissue eosinophils to blood granules, which is now well known to all medical professionals eosinophils markedly increases in disease states such as in and investigators. The clinical association between peripheral the bronchopulmonary mucosa where eosinophils are not nor- blood eosinophilia and parasitic (helminthiasis) disease, allergic mally present in significant numbers.8 The primary tissue loca- conditions, and various malignancies was noted in the first half tion of eosinophils under non-disease conditions is in the of the 20th century. However, the definitive physiologic func- gastrointestinal tract and gall bladder where they are localized tions of the eosinophil remain poorly understood other than its almost exclusively with the lamina propria of the mucosa.3,9 essential role in response to parasitic infections.”3 In the last 15 Eosinophil survival in tissue is highly dependent on years, there has been renewed interest in the eosinophil and (interleukins IL-3 and IL-5) that inhibit activation and subse- both its physiologic functions and its destructive role in various quent apoptosis. Under normal non-disease conditions, disease states, particularly those characterized collectively as the eosinophils may survive in tissue for 12 to 14 days.5,6 “hypereosinophilic syndromes.”4 Measurement—Peripheral Blood Eosinophilia Normal Distribution and Dynamics of the With the advent of modern automated analyzers which Eosinophil sample 10,000 cells or greater per determination and the 5- The eosinophil is fundamentally a tissue-based cell with 3 part differential in automated cell counters, the measurement major compartments; bone marrow, blood, and tissue.5 of eosinophils is highly precise.10 Measurements of eosinophils Eosinophils are derived from hematopoietic stem cells that dif- are expressed either as % of the total white cell count (“differ- ferentiate via the basophil-eosinophil lineage, and their produc- ential count”)—common reference range 0% to 5% total gran- tion in the bone marrow is tightly regulated by various cytokines ulocytes or as an absolute eosinophil count expressed as (value) with the most important being interleukin-5.6 Mature x 109cells/L blood (multiply % eosinophils by total granulo- eosinophils are neither accumulated nor stored or reserved in cyte count). The preferred measurement is the absolute significant numbers in the bone marrow, but are released into eosinophil count that has an upper limit of the reference range the blood as they are produced. Their average survival (half-life) varying from 0.5 to 0.7 x 109/L, depending on testing location

440 LABMEDICINE ᭿ Volume 37 Number 7 ᭿ July 2006 labmedicine.com CE Update and instrumentation. The degree of peripheral eosinophilia has Table 1_Secondary (Reactive) Causes of Peripheral arbitrarily been divided into 3 categories11,12: Eosinophilia* Mild 0.5 (0.7) – 1.4 x 109/L Moderate 1.5 – 4.9 x 109/L Allergic Diseases Immunologic Diseases Severe >5.0 x 109/L Asthma (extrinsic and intrinsic) Churg-Strauss syndrome Allergic rhinitis Eosinophilic myalgia syndrome Chronic sinusitis Wegener’s granulomatosis Etiology of Elevated Peripheral Blood Drug-induced hypersensitivity Polyarteritis nodosa Atopic dermatitis Serum sickness Eosinophil Counts Chronic urticaria Rheumatoid arthritis Peripheral blood eosinophilia is quite uncommon in the 13 Parasitic Diseases Neoplasms United States. Brigden and Graydon, in a study in the Pacific Helminthes Hodgkin lymphoma Northwest, examined 193,300 hematology profiles and found Schistosoma T-cell lymphomas 225 patients (0.1% of total patients sampled) that had >0.7 x Tapeworm (all types) Acute lymphoblastic leukemia/lymphoma 109/L peripheral eosinophil counts. Seventy percent were mild, Filiariasis Mastocytosis Liver and lung flukes Downloaded from https://academic.oup.com/labmed/article/37/7/440/2504503 by guest on 01 October 2021 25% to 28% were moderate, and fewer than 5% were severe. All Pinworm (Enterobius vermicularis) patients with eosinophilia were studied to determine etiology. Trichinosis Allergic disease (asthma, allergic rhinitis, eczema, and drug al- Viscera larva migrans lergy) accounted for 56%, “unknown” for 36%, and parasitic *Table assembled from information from Brito-Babapulle,11 Tefferi,12 Whitty,14 and Moore.15 disease for 2% of the cases of eosinophilia. In this entire group, The table is not comprehensive but representative of the major disorders in each group of there were no examples of hypereosinophilic syndrome as de- diseases associated with eosinophilia. fined in a subsequent section. The most common cause of eosinophila worldwide is para- sitic disease. In travelers returning to the United States or Eng- Table 2_WHO Classification Chronic Eosinophilic land from a prolonged stay in endemic areas for various types of Leukemia (CEL) and Hypereosinophilic Syndrome (HES)* parasitic disease, 20% to 25% of these patients had eosinophilia secondary to parasitic disease.14,15 1. Exclude all causes of reactive eosinophilia 2o to secondary causes such as or parasitic diseases. 2. Exclude all neoplastic disorders with secondary reactive eosinophilia: Classification of Peripheral Blood Eosinophilia T-cell lymphomas including mycosis fungoides, Sczary syndrome Hodgkin Lymphoma Familial versus Acquired: Virtually all eosinophilia is Acute lymphoblastic leukemia/lymphoma acquired. The entity, familial eosinophilia, represents “an Mastocytosis extremely rare autosomal dominant disorder.”12 3. Exclude other neoplastic disorders in which eosinophils are part of the Acquired: Secondary versus Primary11,12,20,21: The term neoplastic clone secondary is often used interchangeably with “reactive” to indi- CML (Philadelphia chromosome or BCR-ABL-positive) AML including those with inv(16), t(16;16)(p13:q22) cate eosinophilia caused by another clinical condition or disease. Other myeloproliferative diseases (polycythemia vera, essential Secondary (reactive) eosinophilia accounts for the vast majority thrombocytosis) of all instances of peripheral eosinophilia (>99%). The basic Myelodysplastic syndromes groups of diseases as well as a sampling of the common specific 4. Exclude T-cell population with aberrant phenotype and abnormal diseases in the groups are summarized in Table 1. What these population secondary causes have in common is that they (1) usually give 5. If there is no demonstrable disease that could cause eosinophilia, not rise to mild or moderate peripheral eosinophilia, (2) represent a abnormal T-cell population and no evidence of a clonal myeloid disorder, physiologic response by bone marrow to increased tissue diagnosis HES demand for eosinophils, and (3) eosinophilia ceases or declines 6. If requirements 1-4 have been met, and if the myeloid elements demonstrate a clonal cytogenetic abnormality or clonality is shown by other means, or if with cessation of the causative disease process. blasts are present in the peripheral blood (>2%) or marrow (>5% but less 11,12,20,21 Primary : The cause of the peripheral eosinophilia than 19%), diagnosis CEL is either a clonal (DNA-related) process involving progenitor *Modified from Gotlib21 cells involved in eosinophil production (regulation) or no cause or genetic (clonal) abnormality is identified. This second group is designated “idiopathic hypereosinophilic syndrome.” Clinical findings associated with this primary group are (1) male entity became known as “Loffler’s endocarditis.” Later, addi- predominance (90% patients), (2) onset during 3rd through 6th tional rare examples of greatly increased peripheral blood es- decades, and (3) overall poor prognosis without treatment—less osinophils associated with tissue damage to heart, skin, lungs, than 3 years survival from diagnosis. A subset of primary disor- and nervous system were described. The high levels of ders are further subclassified under a 2003 WHO classification eosinophils also raised the possibility of a spectrum of disease into chronic eosinophilic leukemia (CEL) and hypereosinophic blending with eosinophilic leukemia.11 In 1968, Hardy and syndrome (HES) (Table 2). Anderson introduced the term “hypereosinophilic syndrome” to describe these clinically disparate and unusual cases that shared the 2 basic characteristics of markedly elevated periph- Evolution of Term “Hypereosinophilic eral blood eosinophils coupled with end-organ infiltration with Syndrome” eosinophils and tissue damage.17 In 1975, Chusid and In 1936, Loffler reported 2 individuals with marked periph- colleagues proposed 3 essential diagnostic criteria to define the eral blood eosinophilia and prominent eosinophil infiltration of idiopathic HES and these criteria have been used until recently myocardial tissue that died of congestive heart failure.16 This to define the syndrome.18,

labmedicine.com July 2006 ᭿ Volume 37 Number 7 ᭿ LABMEDICINE 441 CE Update

(1) Peripheral blood eosinophilia exceeding 1.5 x 109/L for 1. Ehrlich P. Uber die specifischen granulationen des blut. Arch Anat Physio (Lpz). more than 6 consecutive months. 1879;571-579. (2) Absence of underlying (secondary) cause of 2. Ehrlich P, Lazarus A. Histology of the Blood, Normal and Pathological. Translated hypereosinophilia despite extensive diagnostic evaluation. by W. Myers. Cambridge, England: University Press, 1900. 3. Straumann A, Simon H. The physiological and pathophysiological roles of (3) Presence of organ damage or dysfunction related to eosinophils in the gastrointestinal tract. Allergy. 2004;59:15-25. hypereosinophilia. 4. Roufosse F, Cogan E, Goldman M. The hypereosinophilic syndrome revisited. The entity of eosinophilic leukemia fell within the Annu Rev Med. 2003;54:169-184. spectrum of HES as defined above. During the last 30 years, 5. Walsh GM. Human eosinophils: their accumulation, activation and fate. Br J there have been dramatic increases in molecular diagnostic tech- Haematol. 1997;97:701-709. niques. In 1997, Brito-Babapulle suggested that these rare 6. Rothenberg ME. Eosinophilia. N Engl J Med. 1998;338:1592-1600. eosinophilic disorders be separated into clonal or non-clonal 7. Yamaguchi Y, Suda T, Ohta S, et al. Analysis of the survival of mature human groups.19 Clonality could be established by any number of diag- eosinophils: interleukin-5 prevents apoptosis in mature human eosinophils. nostic techniques including bone marrow cytogenetic analysis, Blood. 1991;78:2542-2547. fluorescent in situ hybridization, expression of a single alloen- 8. Broide D, Sriramarao P. Eosinophil trafficking to sites of allergic inflammation. Immunol Rev. 2001;179:163-172. Downloaded from https://academic.oup.com/labmed/article/37/7/440/2504503 by guest on 01 October 2021 zyme, and/or DNA analysis techniques. Implementation of this 9. Bishop JW. Quantification of tissue eosinophils and lymphocytes in histologic basic concept has changed the concept of HES from an inclusive sections. Mod Pathol.1998;11:1247-1251. umbrella “syndrome” diagnosis to a diagnosis of exclusion. 10. Morris MW, Davey FR. Basic examination of blood. In: Clinical Diagnosis and Management by Laboratory Methods, 20th ed. Henry JB, ed. Philadelphia: W.B. Saunders Company; 2001, 489-499. Current Use of Term “Hypereosinophilic 11. Brito-Babapulle F. The , including the idiopathic Syndrome” hypereosinophilic syndrome. Br J Haematol. 2003;121:203-223. As is seen in Table 2, the diagnosis of HES is now a diag- 12. Tefferi A. Blood eosinophilia: a new paradigm in disease classification, nosis of exclusion in patients with markedly elevated eosinophils diagnosis, and treatment. Mayo Clin Proc. 2005;80:75-83. 13. Brigden M, Graydon C. Eosinophilia detected by automated blood cell over a prolonged period time that do not have a reactive or sec- counting in ambulatory North American outpatients. Incidence and clinical ondary cause for the eosinophilia. Furthermore, if any evidence significance. Arch Pathol Lab Med. 1997;121:963-967. of clonality can be detected, then the basic disorder is considered 14. Whitty CJ, Carroll B, Armstrong M, et al. Utility of history, examination and an example of CEL and not HES.21,22 In a recent large multi- laboratory tests in screening those returning to Europe from the tropics for institutional (14 institutions), Cools and colleagues reported that parasitic infection. Trop Med Int Health. 2000;5:818-823. 9 of the16 patients with the diagnosis of HES in their study ex- 15. Moore TA, Nutman TB. Eosinophilia in the returning traveler. Infect Dis Clin hibited a gene fusion of the PDGFRA and FIP1L1 genes (chro- North Am. 1998;12:503-521. 16 Loffler W. Endocarditis parietalis fibroplastica mit Bluteosinophilie: ein mosome 4q12) resulting in constitutively activated tyrosine eigenartiges. Krankheitsbild. 1936;17:817 23 kinase. This knowledge prompted effective therapy with ima- 17. Hardy WR, Anderson RE. The hypereosinophilic syndromes. Ann Int Med. tinib in a majority of the patients with the gene fusion. Patients 1968;68:1220-1229. with this gene fusion are now considered to have CEL. 18. Chusid MJ, Dale DC, West BC, et al. The hypereosinophilic syndrome: Currently, all patients with CEL or HES are already considered Analysis of fourteen cases with review of the literature. Medicine (Baltimore). to have a chronic myeloproliferative disease and are treated on 1975;54:1-27. this basis.24-26 As a diagnosis of exclusion, HES (an already quite 19. Brito-Babapulle F. Clonal eosinophilic disorders and the hypereosinophilic rare disorder) now will become increasingly rare indeed, as new syndrome. Blood Rev. 1997;11:129-145. 20. Tefferi A. Modern diagnosis and treatment of primary eosinophilia. Acta markers or evidence of clonality or genetic alteration are uncov- Haematol. 2005;114:52-60. ered in those patients previously considered to have HES. 21. Gotlib J. Molecular classification and pathogenesis of eosinophilic disorders: 2005 update. Acta Haematol. 2005;114:7-25. 22. Bain BJ. Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis. Am J Hematol. 2004;77: 82-85. 23. Cools J, DeAngelo DJ, Gotlib J, et al. 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. 2003;348:1201-1214. 24. Coutre S, Gotlib J. Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. Semin Cancer Biol. 2004;14:307-315. 25. Sutton SA, Assa’ad AH, Rothenburg ME. Anti-IL-5 and hypereosinophilic syndromes. Clin Immunol. 2005;115:51-60.

442 LABMEDICINE ᭿ Volume 37 Number 7 ᭿ July 2006 labmedicine.com