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Eosinophils and eosinophilia




             Amy Klion
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
Case 1

 57 year 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
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
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
Questions

 What are eosinophils?
 What do eosinophils do?
 What are the causes of eosinophilia?
 Why do some people develop problems
 from eosinophilia and others not?
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
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)
Normal eosinophil morphology




secondary granules                        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
Questions

 What are eosinophils?
 What do eosinophils do?
 What causes eosinophilia?
 Why do some people develop problems
 from eosinophilia and others not?
What we can learn 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)
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
       …..
Questions

 What are eosinophils?
 What do eosinophils do?
 What causes eosinophilia?
 Why do some people develop problems
 from eosinophilia and others not?
Eosinophilia

 Peripheral blood eosinophil count > 450/μl
 Occurs in 5-10% of travelers
 May be suppressed by:
  –   bacterial and viral infections
  –   fever
  –   corticosteroids
 Diurnal variation
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...)
Eosinophilia and drug reactions

 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,…
Eosinophilia and nonparasitic
infectious diseases

 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
Eosinophilia and protozoan
infections

  Not characteristic with the exception of
  Isospora belli infection




                        (image courtesy of CDC DPDx)
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)
Helminth causes of eosinophilia

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
Eosinophilia of several years’
duration
 Cysticercosis         Flukes
 Echinococcosis         – schisto,
 Filariasis                fascioliasis,
  – loiasis,               clonochiasis,
     onchocerciasis,       paragonimiasis
     mansonellosis,    Hookworm
     TPE
                       Strongyloidiasis
 Gnathostomiasis


                              (image courtesy of CDC DPDx)
Unexplained eosinophilia

 ≥ 50% of cases of eosinophilia remain
 unexplained despite exhaustive
 diagnostic evaluation
 Empiric anthelmintic therapy vs.
 observation?
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
End Organ Involvement in HES
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
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
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
FIP1L1/PDGFRA-associated CEL

 Caused by 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
Tissue fibrosis is a 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
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
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
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
Overlap HES

 eosinophilic disorders 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
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
Associated HES

 Recognized primary 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
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
Familial eosinophilia

 Autosomal dominant
 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
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
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
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
Undefined

 Benign
 –   prolonged asymptomatic eosinophilia >1500/mm3
 Complex
 –  signs and
 symptoms of
 multiorgan
 involvement
 Episodic
Questions

 What are eosinophils?
 What do eosinophils do?
 What causes eosinophilia?
 Why do some people develop problems
 from eosinophilia and others not?
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,…
Activated eosinophils have altered
morphology



                                            Piecemeal degranulation




                               Lipid body




        Cytoplasmic clearing
        Dysplastic nucleus
Serum levels of eosinophil 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)
Eosinophil surface molecules

             CD23




                    Adapted from Rothenberg Ann Rev Immunol 2004
Eosinophil numbers do not 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
Surface expression of the 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
Eosinophil-mediated pathogenesis

 Direct cytotoxic effects
 –   Eosinophil granule proteins
 –   Reactive oxygen intermediates
 Recruitment of other inflammatory cells
 Fibrogenesis
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
Eosinophils and fibrosis




                           Munitz and Levi-Schaffer
                                    2004

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Eosiniphiles biology disorders

  • 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 57 year 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 are eosinophils? 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 secondary granules 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 are eosinophils? What do eosinophils do? What causes eosinophilia? Why do some people develop problems from eosinophilia and others not?
  • 11. What we can learn 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 are eosinophils? What do eosinophils do? What causes eosinophilia? Why do some people develop problems from eosinophilia and others not?
  • 14. Eosinophilia Peripheral blood eosinophil 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 drug reactions 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 infectious diseases 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 of eosinophilia 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 several years’ 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
  • 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 Caused by 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 is a 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 eosinophilic disorders 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 Recognized primary 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 Autosomal dominant 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 are eosinophils? 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 have altered morphology Piecemeal degranulation Lipid body Cytoplasmic clearing Dysplastic nucleus
  • 45. Serum levels of eosinophil 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 do not 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 of the 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 Direct cytotoxic 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