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Eosiniphiles biology disorders
- 1. Eosinophils and eosinophilia Amy Klion
- 2. Disclosure Employment – National Institutes of Health Financial Interests – None Research Interests – GlaxoSmithKline, MedImmune Organizational Interests – Member of ASTMH, IES, IDSA Gifts – Nothing to Disclose Other Interests – Nothing to Disclose
- 3. Case 1 57year old man with history of mild asthma, eczema, allergic rhinitis and eosinophilia of >20 year’s duration – wbc 10,000 - 40,000 with 30-40% eosinophils (4,000- 8,000/mm3) – numerous extensive evaluations since 1982, including bone marrow examinations, parasite serologies, rheumatologic evaluation, CT scans, echocardiograms, PFTs,… reveal only mild reversible obstructive pulmonary disease and mild eczema
- 4. Case 2 28 year old man with no past medical history who presented with signs and symptoms of severe right-sided congestive heart failure in the setting of marked eosinophilia – wbc 14,400 with 63% eosinophils (9,072/mm3), aneia, platelets 90k – echocardiogram: dilated cardiomyopathy, fibrotic material filling the right ventricle, moderate to severe MR and TR, small pericardial effusion – endomyocardial biopsy: focal fibrosis – bone marrow: hypercellular with marked eosinophilia, no blasts, mild fibrosis
- 5. Case 2 (continued) A diagnosis of hypereosinophilic syndrome was made and he was treated with high dose steroids and hydrea without response Approximately 10 months after he presented, imatinib mesylate therapy was started with complete hematologic remission One month later he developed hemoptysis, fever and chills and died of presumed sepsis
- 6. Questions What areeosinophils? What do eosinophils do? What are the causes of eosinophilia? Why do some people develop problems from eosinophilia and others not?
- 7. What are eosinophils? Eosinophils are terminally differentiated cells of the myeloid lineage that stain red with negatively charged eosin PMN cytokines IL3, GM-CSF, IL5 IL5 CD34+ HSC CMP GMP No or low GATA-1 GATA-1, FOG, GATA-1, PU.1, PU.1, C/EBPα C/EBPα transcription factors MΦ
- 8. Eosinophil life cycle 1-2% of peripheral blood leukocytes; t1/2 in blood = 18 hours >90% of eosinophils are found in the tissues, particularly those tissues which interface with the environment (BM, lymphoid tissue, lower GI tract, and uterus) (from Rothenberg 1998 NEJM)
- 9. Normal eosinophil morphology secondarygranules bilobed (core and matrix) nucleus cationic proteins (EDN, MBP, ECP, EPO) enzymes (lysozyme, elastase, cathepsin D,…) lipid bodies cytokines (IL4, IL5, IL6,…) cyclooxygenase, lipoxygenase, primary leukotrienes, granules EPO,…) Charcot- Leyden protein
- 10. Questions What areeosinophils? What do eosinophils do? What causes eosinophilia? Why do some people develop problems from eosinophilia and others not?
- 11. What we canlearn from ? there are no reported cases of a congenital lack of eosinophils in humans, although eosinophil-free mice have recently been engineered (EPO-DTN mice, Lee et al. Science 2004; Δdbl GATA Humbles et al. Science 2004) eosinophil-free mice appear normal, but have altered responses to allergen challenge effect in helminth infection depends on model schistosomiasis – no effect (Swartz et al. Blood 2006) strongyloidiasis – impaired resistance to seocndary infection (Knott et al. Int J Parasitol 2007)
- 12. What about humans? – Host defense against helminth infection – Anti-tumor effector cells – Reproduction/mammary gland development – Wound repair and tissue remodeling – MHC class I-restricted thymocyte depletion – Modulation of the immune response Antigen presentation Cytokine secretion …..
- 13. Questions What areeosinophils? What do eosinophils do? What causes eosinophilia? Why do some people develop problems from eosinophilia and others not?
- 14. Eosinophilia Peripheral bloodeosinophil count > 450/μl Occurs in 5-10% of travelers May be suppressed by: – bacterial and viral infections – fever – corticosteroids Diurnal variation
- 15. Eosinophilia: differential diagnosis Allergy/Asthma Drug hypersensitivity Connective tissue disorders (Churg-Strauss vasculitis, SLE, RA) Parasitic infection Neoplasm Other (idiopathic hypereosinophilic syndrome, eosinophilic gastroenteritis, Loeffler’s syndrome, hypoadrenalism, HIV...)
- 16. Eosinophilia and drugreactions Eosinophilia may be provoked by a wide variety of drugs Drug reactions may be asymptomatic or associated with characteristic signs and symptoms – Asymptomatic- quinine, PCNs, cephalosporins, quinolones – Pulmonary infiltrates-NSAIDs, sulfas, nitrofurantoin – Hepatitis - tetracyclines, semisynthetic PCNs – EMS - L-tryptophan contaminant – Interstitial nephritis- cephalosporins, semisyn. PCNs – Drug rash with eosinophilia and systemic symptoms (DRESS) - anti-epileptics, NSAIDs, antibiotics,…
- 17. Eosinophilia and nonparasitic infectiousdiseases Most acute bacterial and viral diseases are associated with eosinopenia Exceptions include: – Bacteria: resolving scarlet fever, chronic tuberculosis – Fungi: coccidiomycosis, allergic bronchopulmonary aspergillosis (APBA) – Viruses: HIV
- 18. Eosinophilia and protozoan infections Not characteristic with the exception of Isospora belli infection (image courtesy of CDC DPDx)
- 19. Eosinophilia and ectoparasites Scabies – sensitization to the mites and their eggs causes itching, erythema, rash, and may cause eosinophilia Myiasis – Infestation by fly larvae has rarely been associated with hypereosinophilic syndrome (images courtesy of CDC DPDx)
- 20. Helminth causes ofeosinophilia Angiostrongyliasis Echinostomiasis Metagoniamiasis Anisakiasis Enterobiasis Opisthorciasis Ascariasis* Fascioliasis* Paragonomiasis* Capillariasis Fasciolopsiasis* Schistosomiasis* Clonorchiasis* Filariasis Sparganosis Coenurosis Gnathostomiasis Strongyloidiasis* Cysticercosis Heterophyiasis Trichinosis* Dicrocoeliasis Hookworm* Trichuriasis Echinococcosis Hymenolepsiasis VLM marked hypereosinophilia (>3000/μl) * early in infection
- 21. Eosinophilia of severalyears’ duration Cysticercosis Flukes Echinococcosis – schisto, Filariasis fascioliasis, – loiasis, clonochiasis, onchocerciasis, paragonimiasis mansonellosis, Hookworm TPE Strongyloidiasis Gnathostomiasis (image courtesy of CDC DPDx)
- 22. Unexplained eosinophilia ≥50% of cases of eosinophilia remain unexplained despite exhaustive diagnostic evaluation Empiric anthelmintic therapy vs. observation?
- 23. Hypereosinophilic syndromes A group of heterogeneous disorders characterized by: – the presence of marked peripheral eosinophilia >1500 eosinophils/mm3 on at least two occasions 6 months apart – the lack of a secondary cause ex. drug reaction, parasite infection, neoplasm – evidence of end organ dysfunction attributable to the eosinophilia or otherwise unexplained in the clinical setting
- 24. End Organ Involvementin HES
- 25. Treatment of HES Prednisone Hydroxyurea Interferon-α Imatinib mesylate (monoclonal anti-IL5 antibody) Other agents for which there is data from case reports and small series –cyclosporin A, 2-CDA, vincristine, chlorambucil, bone marrow transplant, allogeneic stem cell transplant, alemtuzumab
- 26. HES subtypes Myeloproliferative Undefined Associated variant Lymphocytic variant Overlap Familial * Klion A et al, Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report, J Allergy Clin Immunol 2006
- 27. Myeloproliferative variant HES/CEL FIP1L1/PDGFRA-associated CEL Etiology unknown – FIP1L1/PDGFRA-negative – Clonal eosinophils OR > 4 of the following: dysplastic eosinophils on peripheral smear serum B12 >1000 pg/ml serum tryptase > 12 anemia and/or thrombocytopenia hepatosplenomegaly bone marrow cellularity > 80% spindle-shaped mast cells myelofibrosis Chronic eosinophilic leukemia – Demonstrable cytogenetic abnormalities and/or increased blasts
- 28. FIP1L1/PDGFRA-associated CEL Causedby an interstitial deletion in chromosome 4 that leads to a constitutively activated fusion tyrosine kinase Almost exclusively in men, 20-40 years of age 50% 5 year fatality rate prior to the discovery of the tyrosine kinase inhibitor, imatinib mesylate
- 29. Tissue fibrosis isa common sequela of F/P-HES F/P-HES HES* (n=14) (n=29) Endomyocardial 6/14 3/29 fibrosis (43%) (10%) Restrictive 5/14 2/29 pulmonary (35%) (7%) disease Myelofibrosis 6/11 rare (54%) * one patient presented with liver abnormalities; eosinophilia and bridging fibrosis was seen on biopsy biopsy
- 30. HES subtypes Myeloproliferative Undefined Associated HES Lymphocytic variant Overlap Familial * Klion A et al, Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report, J Allergy Clin Immunol 2006
- 31. Lymphocytic variant HES Associated with the presence of clonal lymphocyte populations with aberrant phenotypes (ex. CD3+CD4-CD8- and CD3- CD4+) that produce eosinophilopoietic cytokines Equally common in men and women Predominance of skin manifestations Often associated with elevated serum IgE, TARC levels May progress to lymphoma No response to imatinib
- 32. HES subtypes Myeloproliferative Undefined Associated HES Lymphocytic variant Overlap Familial * Klion A et al, Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report, J Allergy Clin Immunol 2006
- 33. Overlap HES eosinophilicdisorders in which tissue infiltration is restricted to a single organ peripheral eosinophilia >1,500/mm3 may be present – ex. eosinophilic gastrointestinal disorders, chronic eosinophilic pneumonia, eosinophilic cystitis, Churg-Strauss vasculitis may be difficult to distinguish from undefined HES
- 34. HES subtypes Myeloproliferative Undefined Associated HES Lymphocytic variant Overlap Familial * Klion A et al, Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report, J Allergy Clin Immunol 2006
- 35. Associated HES Recognizedprimary disorders associated with peripheral eosinophilia >1,500/mm3 most commonly as a result of immunodysregulation Eosinophilia resolves with treatment of underlying disorders Complications of eosinophilia are rare – ex. sarcoid, inflammatory bowel disease, ALPS
- 36. HES subtypes Myeloproliferative Undefined Associated HES Lymphocytic variant Overlap Familial * Klion A et al, Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report, J Allergy Clin Immunol 2006
- 37. Familial eosinophilia Autosomaldominant Gene mapped to chromosome 5q31-33 Eosinophilia begins at birth, but only a small subset develop end-organ damage Lack of clinical manifestations is associated with a relative lack of eosinophil activation compared to other eosinophilic disorders
- 38. HES subtypes Myeloproliferative Undefined Associated HES Lymphocytic variant Overlap Familial * Klion A et al, Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report, J Allergy Clin Immunol 2006
- 39. HES subtypes Myeloproliferative Undefined Associated HES Lymphocytic variant Overlap Familial * Klion A et al, Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report, J Allergy Clin Immunol 2006
- 40. HES subtypes Myeloproliferative Undefined Associated HES Lymphocytic variant Overlap Familial * Klion A et al, Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report, J Allergy Clin Immunol 2006
- 41. Undefined Benign – prolonged asymptomatic eosinophilia >1500/mm3 Complex – signs and symptoms of multiorgan involvement Episodic
- 42. Questions What areeosinophils? What do eosinophils do? What causes eosinophilia? Why do some people develop problems from eosinophilia and others not?
- 43. Eosinophil activation Altered phenotype Density -hypodense Light microscopy -dysplasia -cytoplasmic clearing EM Enhanced functions -piecemeal degranulation Prolonged survival -increased lipid bodies Adhesion Surface marker expression ADCC -increased CD69, CD44, CD25, Chemotaxis HLADR Mediator release -decreased CD23 -ECP, MBP, EDN, LTC4 Cytokine production -IL8, GM-CSF, IL5,…
- 44. Activated eosinophils havealtered morphology Piecemeal degranulation Lipid body Cytoplasmic clearing Dysplastic nucleus
- 45. Serum levels ofeosinophil granule proteins vary depending on the etiology of the eosinophilia 8790 4245 >1500 EDN 1000 500 0 NL FE HES PARA NL FE HES PARA (n=16) (n=15) (n=7) (n=8) GM eos/mm3 252 3314 5607 4639 (range) (95-520) (2184 - (1900-27492) (1508-10496) 5292)
- 46. Eosinophil surface molecules CD23 Adapted from Rothenberg Ann Rev Immunol 2004
- 47. Eosinophil numbers donot correlate with expression of surface activation markers 60 CD69 60 CD25 10 CD23 50 50 8 40 %CD69+ EOS 40 % CD25+ EOS %CD23+ EOS 6 30 30 4 20 20 2 10 10 0 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Eos/mm3 x 10^3 EOS/mm3 x10^3 EOSx10^3
- 48. Surface expression ofthe activation markers CD69 and CD25 on eosinophils is increased in patients with eosinophil- mediated tissue damage 60 50 %CD69+ eos 40 30 20 10 0 MHES HES PARA p < 0.01
- 49. Eosinophil-mediated pathogenesis Directcytotoxic effects – Eosinophil granule proteins – Reactive oxygen intermediates Recruitment of other inflammatory cells Fibrogenesis
- 50. Eosinophils and fibrosis Eosinophils have been associated with fibrotic conditions of various etiologies – Hypereosinophilic syndromes, tropical endomyocardial fibrosis, scleroderma, idiopathic pulmonary fibrosis, asbestos-induced lung fibrosis, retroperitoneal fibrosis, chronic asthma, eosinophilic esophagitis, chronic schistosomiasis Eosinophils possess a number of pre-formed mediators that are thought to be pro- fibrogenic – These include TGF-β, IL-4, IL-6, TNF-α, ECP, and MBP
- 51. Eosinophils and fibrosis Munitz and Levi-Schaffer 2004