A. Physiology of Eosinophils
[Figure] "Hematopoietic Lineages"

1. Normally acount for 1-3% of peripheral blood leukocytes (PBL), <350 cells/µL
2. Derived from granulocyte/macrophage precursor cells
   1. Pluripotent stem cells differentiate to hybrid precursors
   2. These precursors give rise to eosinophils and basophils
   3. Interleukin 3 (IL3), IL5 and GM-CSF are important for eosinophil development [10]
   4. IL5 is the most specific inducer of eosinophil production and differentiation
   5. Overproduction of one or more of these cytokines leads to eosinophilia
   6. Monoclonal anti-IL5 antibodies (Abs) can induce prolonged reductions in eosinophil counts [13,14] and have activity in hypereosinophilic syndrome (HES) [18]
   7. Subcutaneous IL-12 administration can substantially reduce eosinophil counts [15]
3. Classification of Eosinophilia
   1. Normal eosinophil count: 350-650/µL
   2. Mild: 651-1500 cells/µL
   3. Moderate: 1500-5000 cells/µL
   4. Severe: >5000 cells/µL
4. Eosinophils must migrate into tissue to perform functions (and cause damage)
5. Eosinophil Migration to Tissue [11]
   1. Eosinophils are attracted to tissues by chemokines
   2. Eotaxins (1,2,3) are most specific chemokines for eosinophil recruitment
   3. RANTES, MCP-3 and -4, MIP-1a, TARC MDC, and I-309 are also eosinophil attractants
   4. Platelet activating factor (PAF) is also an eosinophil chemoattractant
   5. Eosinophils weakly adhere to endothelium through P-selectin (rolling)
   6. Eosinophils then adhere strongly through integrins (CD18 family and VLA-4)
   7. ICAM-1 and VCAM-1 are important coreceptors on endothelium for these proteins
   8. VCAM-1 is primarily induced by IL4
   9. ICAM-1 is induced by many pro-inflammatory cyokines including TNFa and IL1
6. Mast cells and Th2 lymphocytes stimulate eosinophil production and recruitment
7. Eosinophil Induced Damage
   1. Mediated primarily by eosinophil granule contents
   2. Contents include major basic protein, eosinophil peroxidase, eosinophil cationic protein
   3. Major basic protein triggers smooth muscle constriction and mast cell and basophil degranulation
   4. Eosinophils also produce hydrogen peroxide and halide acids, as well as superoxide
   5. Generate large amounts of leukotriene C4, which is highly inflammatory
8. No clear effect of very low numbers of eosinophils in developed countries
   1. Eosinophils are believed to play a role in controlling parasite infections
   2. In developed countries, hypo-eosinophilia has shown no detrimental effects

B. Differential Diagnosis of Eosinophilia [3,7]

1. Mnemonic = "NAACP"
   1. Neoplasm
   2. Allergy / Asthma
   3. Addison's Disease (Adrenal Insufficiency)
   4. Collagen-Vascular Disease / Cholesterol Emboli Syndrome
   5. Parasitic Infection
2. Neoplastic
   1. Eosinophilic Leukemia
   2. Associated with Lymphoma / Leukemia [3]
   3. Occult solid tumor
   4. Myelodysplastic Syndromes
   5. Myeloproliferative Syndrome
3. Allergy / Asthma
   1. Atopic Individuals
   2. Drug Reactions
   3. Some patients with disseminated tuberculosis develop a hypereosinophilia
4. Adverse Drug Reactions
   1. Most are idiosyncratic
   2. Peripheral hypereosinophilia
   3. Severe eosinophilia with organ involvement including heart, lung, liver, kidney [19]
   4. Interstitial nephritis
   5. Eosinophilia-myalgia syndrome has clear pathogenic toxic contaminant,
5. Collagen Vascular Disease
   1. Churg-Strauss Syndrome
   2. Eosinophilia Myalgia Syndrome / Eosinophilic myositis
   3. Eosinophilic Fasciitis
   4. Wegener's Granulomatosis
6. Cholesterol Emboli Syndrome
7. Parasitic Infections with High-Level Eosinophilia [7,20]
   1. Strongyloidiasis
   2. Filariasis
   3. Hookworm
   4. Schistosomiasis
   5. Trichinellosis
   6. Ascaris pneumonia
   7. Toxocara (visceral larva migrans)
   8. Paragonimiasis (striking eosinophilia)
   9. Protozoal - Isospora belli, Dientameba fragilis
8. Addison's Disease
9. Kimura Disease [2]
   1. Lymphadenopathy
   2. Hypereosinophilia
10. Organ Specific Inflammation
    1. Eosinophilic Gastroenteritis
    2. Eosinophilic Pneumonitis
    3. Eosinophilic Myocarditis [19]
    4. Eosinophilic Myositis
11. Idiopathic Hypereosinophilic Syndrome (HES)

C. Treatment of Eosinophilia

1. Treat only for symptoms or known organ damage
2. Goal is usually chronic maintenance therapy, not remission
3. Treat underlying disease if determined
4. Glucocorticoids
   1. Very potent agents, induce apoptosis of eosinophils
   2. Very effective in asthma and allergic disorders
   3. Caution in patients with possible parasitic infections
   4. In general, parasitic infections should be ruled out prior to initiating therapy
5. Other Primary Agents
   1. Interferon alpha
   2. Myelosuppressive Drugs - hydroxyurea, vincristine, alkylating agents (see below)
6. Experimental Agents
   1. VLA4 - VCAM-1 blocking agents
   2. Anti-selectin antibodies
   3. Chemokine blockers
   4. IL-5 inhibitors including antibodies [13,14]
   5. IL-12 administration [15]
   6. Phosphodiesterase IV inhibitors

D. Hypereosinophilic Syndrome (HES) [4]

1. Sustained blood eosinophil count >1500/µL for >6 months
   1. No other identifiable cause of Eosinophilia
   2. Internal organ involvement
2. Male : Female 9:1
3. Age 20-50 years
4. Pathophysiology [4,8]
   1. About 50% of patients carry FIP1L1-PDGFRalpha fusion gene
   2. FIP1 like gene 1 (FIP1L1) fusion to PDGFa leads to constitutive activation of PDGFa
   3. This fusion protein produced is a constitutively active tyrosine kinase
   4. The fusion protein can transform hematopoietic cells
   5. This fusion protein is also inhibited by imatinib (Gleevec®; see below)
   6. The 50% of cases without fusion genes are likely dependent on IL5 [18]
   7. These non-FIP1 cases respond to anti-IL5 monoclonal Ab (see below) [21]
5. Presenting Characteristics [2]
   1. Incidental detection ~12% of patients
   2. Fatigue ~26%
   3. Cough ~24%
   4. SOB ~16%
   5. Angioedema / Muscle Pain
   6. Rash or Fever
   7. Ocular symptoms
6. T Lymphocytes [9,12]
   1. T lymphocytes are the major producers of interleukin 5 (IL-5)
   2. Abnormal clones of T cells are found in ~25% of patients with idiopathic eosinophilia
   3. In most patients, these T cells had cell surface markers consistent with activation
   4. These T cells produced increased amounts of IL-5
   5. Other patients with HES have different T cell abnormalities
   6. Abnormal T cell populations including CD3-CD4+8- and CD3+CD4-8- populations found
   7. T cells with natural killer phenotype (CD16+56+) and elevated IL2 and IL15 found [12]
   8. Possible that infectious and/or autoimmune stimulation of T cells underlies HES

E. Organ Involvement in HES

1. Cardiovascular ~60%
   1. Fibrosis (Loeffler's Syndrome) - endomyocardial fibrosis
   2. Thrombus formation, intracardiac
   3. Thromboembolic Disease
   4. Dilated Cardiomyopathy
   5. Valve abnormalities
2. Skin ~55%
   1. Angioedema + urticaria
   2. Erythematous pruritic papules
3. Neurologic ~55%
   1. Thromboembolic disease
   2. Primary CNS Dysfunction - encephalopathy, ataxia, confusion, etc.
   3. Peripheral Neuropathy - sensory or sensorimotor type
4. Pulmonary ~40%
   1. Cough and shortness of breath are most common
   2. Interstitial infiltrates (~20% of patients)
5. Ocular Disease ~20%
   1. Visual symptoms, especially blurring
   2. Keratoconjunctivitis sicca and episcleritis
   3. Usually treat with topical glucocorticoids
6. Rheumatologic Diseases
   1. Churg-Strauss Syndrome - asthma with eosinophilia - must be ruled out
   2. Systemic eosinophilic disease may occur on glucocorticoid tapers in severe asthma [5]
   3. Erosive and non-erosive polyarthritis
   4. Effusions not uncommon
   5. Raynaud's Phenomenon
7. Gastrointestinal ~20% [4]
   1. Eosinophilic gastroenteritis
   2. Diarrhea most common symptom in HES

F. Therapy for HES

1. Treat only for symptoms or known organ involvement
2. Goal is usually chronic maintenance therapy, not remission
3. Glucocorticoids
   1. Mainstay of therapy
   2. Induce apoptosis of eosinophils
   3. Usual initial dose is 40-60mg predisone po qd
   4. Taper slowly, monitoring for relapse
   5. Bone marrow examination is very important to rule out leukemia
   6. Testing for parasites is critical if glucocorticoids are used
4. Imatinib Mesylate (Gleevec®) [8,16]
   1. Tyrosine kinase inhibitor specific for c-kit, PDGF, bcr-abl fusion, and abl
   2. Oral agent with remarkable activity in chronic myelogenous leukemia
   3. Active against PDGFalpha and its fusion proteins found in ~50% of HES patients [8]
   4. ~50% of patients with HES have a FIP1L1-PDGFRalpha fusion protein in HES cells
   5. These cells are highly sensitive to imatinib
   6. HES cells which became resistant to imatinib had T674I mutation in PDGF-RA
5. Imatinib also active in chronic myeloproliferative diseases with rearranged platelet derived growth factor receptor ß gene (chromosome 12p13) [17]
   1. Patients with anemia, leukocytosis, eosinophilia
   2. Histiocytosis may also occur
   3. Skin involvement is common
   4. Imatinib very effective with minimal side effects
6. Anti-IL5 Antibody (Mepolizumab) [18,21]
   1. Given every 4 weeks, reduces peripheral eosinophil levels in various eosinophilic states
   2. Cases of HES without FIP1L1 fusion protein are likely dependent on IL5
   3. Several patients with resistant HES had good responses to one to several doses anti-IL5 antibody
   4. Treatment of non-FIP fusion HES with mepolizumab q4 weeks allowed prednisone taper to 10mg qd or less in 80% of patients, and eosinophil counts <600/µL in 95% [21]
   5. Generally well tolerated with side effects similar to placebo
7. Hydroxyurea (Hydrea®)
   1. Second line agent, often combined with steroids
   2. May cause anemia or thrombocytopenia
8. Interferon Alpha
   1. Appears to be effective in resistant disease (1.5-8MU/day sc)
   2. Thrombocytopenia and flu-like syndromes are major side effects
9. Vincristine
10. Alkylating Agents
    1. Chlorambucil
    2. Cyclophosphamide

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