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  • 1. 好酸球増多を、見たときに
  • 2. 好酸球増多を来す疾患 先ずFamilial vs Acquiredで分類され,AcquiredはさらにSecondary, Primaryに分類.PrimaryはClonal, Idiopathicで分類される.Secondary Primary感染症 組織侵襲性の寄生虫 細菌, ウイルス感染症Clonal;  Acute leukemia(AML, ALL) 慢性骨髄性疾患* MDS/MPD (別スライド)非感染症 薬剤性, 毒素性, アレルギー性 自己免疫性*, 悪性腫瘍, 内分泌(Addison病など)Idiopathic  HES, Pre-HESMayo Clin Proc 2005;80:75-83自己免疫性疾患では,血管炎, Kimura病, SSc, Polyarteritis,CTD, Sarcoidosis, IBD. 慢性骨髄性疾患では,Bcr/Abl+ CML,PDGFRα-rearranged eosinophilic disorder,PDGFRβ-rearranged eosinophilic disorder,Kit-mutated systemic mastocytosis,8p11 syndromeが挙げられる.
  • 3. 好酸球増加患者へのアプローチ 1st Step; HES以外に好酸球増加を来す疾患の鑑別 HES: Hypereosinophilic syndrome  好酸球増多による臓器障害 もしくは 特定の疾患に由来する好酸球増加 HES以外; 薬剤性, 感染症に由来する好酸球増加 → 薬剤の中止, 感染症の検索が重要. 2nd Step; HES以外の疾患らしくない場合, → HESの原因を評価.3
  • 4. 好酸球増多を来すもの
  • 5. 薬剤性薬剤性反応 薬剤例サイトカイン由来 GM-CSF, IL-2肺浸潤 NSAID肺, 胸膜由来 ダントロレン間質性腎炎 合成ペニシリン, セファロスポリン壊死性心筋炎 ラニチジン肝炎 合成ペニシリン, テトラサイクリン反応性血管炎 アロプリノール, フェニトイン胃腸炎 NSAID薬剤性 β阻害薬Eosinophilia-myalgia syndrome L-tryptophan contaminant喘息, 鼻ポリープ アスピリン無症候性 アンピシリン, ペニシリン, セファロスポリン
  • 6. 感染性 感染症では寄生虫が有名 だが, それが好酸球増多(-)でも否定はできない 寄生虫の種類も特定はできない アニサキス症は胃内分泌液の好酸球UP, 血中は不変 通常, 寄生部位の組織内好酸球増多がメイン血液中好酸球増多はその次に起こる 真菌性; Allergic bronchopulmonary AspergillosisCoccidioidomycosis(25%) その他; HIV感染症(相対的増加, 薬剤アレルギー, 副腎不全,Eosinophilic folliculitis, Hyper IgE syndrome)
  • 7.  その他 副腎不全 アテローム性血栓症; ESR亢進, 低補体血症, 血小板低下好酸球増多, 好酸球尿症, 腎障害, Livedoを来す 免疫不全; Hyper-IgE syndrome,Omenn’s syn.(Combined Immunodeficiency with Hyper-Eo)
  • 8. 補足; ためになる話 相対的副腎不全 術後ICUにてEo > 3%の患者の25%がACTH刺激試験にて異常を示した その内8/10名が副腎不全(+)
  • 9. HESの分類 (Hypereosinophilic Diseases Working Group 2005)9Hypereosinophilic syndromes (HES) classificationFIP1L1-PDGFRA FIP1L1-PDGFRApositiveMyeloproliferative HES Lymphocytic HESUndefinedHESAssociatedHESWith a defineddiagnosisChurg-Strauss,mastocytosis,inflammatorybowel disease,sarcoidosis,HIV and otherdiseasesOverlapHESAssociatedwith organ-restrictedeosinophilicdisorders (maynot meet all 3criteria),eosinophil-associatedgastrointestinaldisorders,eosinophilicpneumonia,eosinophiliamyalgiasyndromeFamilialHESFamilyhistory ofdocumentedpersistenteosinophiliaof unknowncauseBenignNoorganinvolve-mentnegativeEpisodicCyclicalangioedemaandeosinophiliaComplexOrgan dysfunctionbut notmyeloproliferativeor lymphocyticvariantAetiology unknownClonal eosinophils* or 4or more of:Dysplastic eosinophils,High serum B12,High serum tryptase,Anaemia,Thrombocytopenia,Hepatosplenomegaly,Marrow hypercellularity,Spindle-shaped mast cellsand/or myelofibrosisMonitor for T-cell clonality or other cytogenetic abnormalitiesChroniceosinophilicleukaemia(CEL)Cytogenicabnormalitiesand/or blastsEosinophils ≥ 1.5 × 109/lPersistent eosinophilia and/or end organ damage/dysfunctionExclusion of secondary causes of eosinophiliaClonal T cells*Clonality analysis based on the digestion of genomicDNA with methylation-sensitive restriction enzymesfollowed by PCR amplification of the CAG repeat at thehuman androgen receptor gene (AR) locus on the XchromosomeReview
  • 10. 骨髄増殖性のHES Chronic Eosinophilic Leukemia, SM with Eosinophiliaが代表的 圧倒的に男性例が多い.FIP1L1-PDGFRA陽性例は極 かな例外を除いて全て男性例. iHESと同じように心血管障害も多い. Loefflar endocarditisを呈する. CELはCMLの1 typeでありImatinibが有効.特にFIP1L1-PDGFRA陽性例は著効し, 投与量も100mg/dの低用量でOK HESのうち, FIP1L1-PDGFRA陽性例は4-12.5%と母集団により様々.10British Journal of Haematology, 2009;145:271–285
  • 11. Myeloproliferative HES variant iHESとCELは病態, 経過が似ている. 両者の鑑別にはFIP1L1-PDGFRα [del(4)(a12a12]の検出が重要 Hypereosinophiliaを呈する血液疾患との鑑別Blood. 2004;103:2879-28912次性好酸球増多を除外FIP1L1-PDGFRαチェック陽性; FIP1L1-PDGFRα Clonal EosinophiliaChronic Eosinophilic LeukemiaSystemic mastocytosis with Eosinophilia陰性CEL, UnclassifiedT-cell associated HESHES異常T cell検出ClonalなEo増加, 細胞異常骨髄芽球 5-19%Clonalな異常無し異常T cell無し
  • 12. 骨髄 刺所見による鑑別.ReviewBritish Journal of Haematology, 2009;145:271–285PDGFRβ (+): PDGFRB-rearranged eosinophilic leukemia/Chronoic Myelomonocytic leukemiaFGFR1 (+): FGFR1-rearranged (stem cell leukemia andlymphoma syndrome with 8p11 translocations)Cancer J 2007;13: 384–391
  • 13.  CEL vs SM with Eoの鑑別. Score >0ではFIP1L1/PDGFRA陽性 CELを示唆,Score <0ではKIT D816V陽性 SM with Eoを示唆する. 他にEo上昇をしめす骨髄増殖性疾患は, Acute leukemia associated with eosinophiliaMDS associated with eosinophilia他のMPD associated with eosinophiliaTable II. Risk factor scores to distinguish eosinophilia due to separate mutations.Score Risk factor for FIP1L1/PDGFRA eosinophilia Score Risk factor for KIT D816V eosinophilia+3 Absolute eosinophil count/tryptase > 100 )3 Absolute eosinophil count/tryptase £100+3 Dense mast cell aggregates in bone marrow absent )3 Dense mast cell aggregates in bone marrow present+3 Peak absolute eosinophil count > 10,000+2 Serum B12 increased)2 Gastrointestinal symptoms)2 Urticaria pigmentosa+1 Pulmonary symptoms)1 Female gender+1 Cardiac symptoms)1 ThrombocytosisPositive total score denotes FIL1L1/PDGFRA-associated hypereosinophilic syndrome or chronic eosinophilic leukaemia. Negative total score denotesKIT D816V-associated systemic mastocytosis with eosinophilia.Modified from J Allergy Clin Immunol, 120, Maric, I., Robyn, J., Metcalfe, D.D., Fay, M.P., Carter, M., Wilson, T., Fu, W., Stoddard, J., Scott, L.,Hartsell, M., Kirshenbaum, A., Akin, C., Nutman, T.B., Noel, P. & Klion, A.D. KIT D816V-associated systemic mastocytosis with eosinophilia andFIP1L1/PDGFRA-associated chronic eosinophilic leukaemia are distinct entities, 680-687. Copyright 2007, with permission from Elsevier. The absoluteeosinophil count is given as eosinophils/mm3and the tryptase level is given as ng/ml to maintain the correct ratios presented in the original article.ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 271–285 275British Journal of Haematology, 2009;145:271–285Cancer J 2007;13: 384–391
  • 14. SystemicMastcytosis WHOではSMを7つに分類. WHOのSM診断Criteria Major 1つ+ Minor 1つもしくはMinor 3つで診断.14Cancer J 2007;13: 384–391TABLE 3. “B” Findings: Indication of High Mast Cell Burden1. Infiltration grade (mast cells) in Ͼ30% in bone marrow on histologic examination and serum total tryptase levels Ͼ200 ng/mL2. Hypercellular marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias or WHO criteria forsyndrome or myeloproliferative disorder3. Organomegaly: palpable hepatomegaly, splenomegaly, or lymphadenopathy (on computed tomography scan or ultrasound) Ͼ2 cmfunctionData from Ref. 65.TABLE 4. “C” findings: Indication of Impaired Organ Function Attributable to Mast Cell Infiltration661. Cytopenia(s): absolute neutrophil count Ͻ1,000/␮L, or hemoglobin Ͻ10g/dL, or platelets Ͻ100,000/␮L2. Hepatomegaly with ascites and impaired liver function3. Palpable splenomegaly with hypersplenism4. Malabsorption with hypoalbuminemia and weight loss5. Skeletal lesions: large-sized osteolysis or severe osteoporosis causing pathologic fractures6. Life-threatening organopathy in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic mast cData from Ref. 66.TABLE 5. WHO Criteria for Diagnosis of SM*MajorMultifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organ sections (Ͼ15 mast cells aggregating)Minora. Ն25% mast cells in tissue sections or bone marrow aspirate smear are spindle shaped or have atypical morphologyb. c-kit point mutation at codon 816Vc. Expression of CD2 and/or CD25 by mast cellsd. Baseline serum tryptase persistently Ͼ20 ng/mL (not valid in presence of another non–mast cell clonal disorder)al residual disease after imatinib therapy can be as-by quantitative molecular analysis.44PDGFRB rearrangement was first characterized in theof a fusion tyrosine kinase encoding regions ofRB and the ets-like gene, ETV6 [ETV6-PDGFRB,(q33;p13)].46 At present, several other PDGFRB fu-anscripts are known to exist and are associated withnt myeloproliferative neoplasm (MPN) phenotypested with eosinophilia.47–55 As has been seen in indi-with PDGFRA-rearranged MPNs, imatinib therapyes complete hematologic remission in PDGFRB-rear-clonal eosinophilia.48,49,51,55–57FGFR1 translocations are usually associated with a clin-enotype with features of both an aggressive, eosinophilia-ted MPN and T cell lymphoblastic lymphoma.58 Thesite syndrome is known as either the 8p11 myeloprolif-syndrome or stem cell leukemia lymphoma syndromemolecularly characterized by fusion of various 5Ј partnero the 3Ј part of FGFR1, making it constitutively active.utation is present in both myeloid and lymphoid lineage–63 Clinically, 8p11 myeloproliferative syndrome/stemkemia lymphoma syndrome has an aggressive clinicalwith a rapid transformation into acute leukemia. At, drug therapy is ineffective and allogeneic stem cellantation should be considered as soon as the particularsis is established.ation and Management ofhoproliferative Variant IdiopathicophiliaThe lymphoproliferative variant of HES is a poorlynumber and/or function (Table 2).65 Accordingly, 7 diseasevariants are considered, including cutaneous mastocytosis, indolent systemic mastocytosis (ISM), SM with an associated clonahematologic non–mast cell disorder (SM-AHNMD), aggressivesystemic mastocytosis (ASM), mast cell leukemia, mast celsarcoma, and extracutaneous mastocytoma.The WHO classification of mastocytosis mandates aTABLE 2. WHO Variants of Mastocytosis651. Cutaneous mastocytosis (CM)a. Maculopapular CMb. Diffuse CMc. Mastocytoma of skin2. Indolent systemic mastocytosis (ISM)a. Smoldering systemic mastocytosis (SSM)b. Isolated bone marrow mastocytosis3. Systemic mastocytosis with an associated clonal hematological non–mast cell lineage disease (SM-AHNMD)a. SM-myelodysplastic syndromeb. SM-myeloproliferative disorderc. SM-chronic eosinophilic leukemiad. SM-chronic myelomonocytic leukemiae. SM-non-Hodgkin lymphoma4. Aggressive systemic mastocytosis (ASM)With eosinophilia (SM-eo)5. Mast cell leukemia (MCL)Aleukemic MCL6. Mast cell sarcoma7. Extracutaneous mastocytoma
  • 15.  肥満細胞の活性化の評価には “B”症状の評価, 肥満細胞浸潤による臓器障害は “C”症状で評価する. SMによるEosinophiliaでは皮膚症状が多い. 肥満細胞クローンはCD25+ and/or CD2+最も多い.また, 血中Tryptase<20ng/mLはSMを除外し得る. KITD816V mutaionが代表的な遺伝子異常. 15TABLE 3. “B” Findings: Indication of High Mast Cell Burden1. Infiltration grade (mast cells) in Ͼ30% in bone marrow on histologic examination and serum total tryptase levels Ͼ200 ng/mL2. Hypercellular marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias or WHO criteria for myelodysplasticsyndrome or myeloproliferative disorder3. Organomegaly: palpable hepatomegaly, splenomegaly, or lymphadenopathy (on computed tomography scan or ultrasound) Ͼ2 cm without impaired organfunctionData from Ref. 65.TABLE 4. “C” findings: Indication of Impaired Organ Function Attributable to Mast Cell Infiltration661. Cytopenia(s): absolute neutrophil count Ͻ1,000/␮L, or hemoglobin Ͻ10g/dL, or platelets Ͻ100,000/␮L2. Hepatomegaly with ascites and impaired liver function3. Palpable splenomegaly with hypersplenism4. Malabsorption with hypoalbuminemia and weight loss5. Skeletal lesions: large-sized osteolysis or severe osteoporosis causing pathologic fractures6. Life-threatening organopathy in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic mast cellsData from Ref. 66.TABLE 5. WHO Criteria for Diagnosis of SM*MajorMultifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organ sections (Ͼ15 mast cells aggregating)Minora. Ն25% mast cells in tissue sections or bone marrow aspirate smear are spindle shaped or have atypical morphologyb. c-kit point mutation at codon 816Vc. Expression of CD2 and/or CD25 by mast cellsd. Baseline serum tryptase persistently Ͼ20 ng/mL (not valid in presence of another non–mast cell clonal disorder)*Major plus one minor or three minor criteria.The Cancer Journal • Volume 13, Number 6, November/December 2007 HES, CEL, and MCDCancer J 2007;13: 384–391
  • 16. Lymphocytic HES variant TH1, TH2の増殖性疾患ではCytokine産生が亢進し,Eosinophiliaを合併する. IL-5が上昇し, Eo増加に関与するため, その点が鑑別となり得る.T cellはCD3-CD4+がIL-4,5産生に関与する. 他にはCD3+CD4-CD8-, CD3+CD4+CD7-のクローン増殖例の報告あり Myeloproliferative HESと比較して, 男女差はほぼなし.皮膚症状を呈する例が多い. 心筋障害を来す例は稀. Lymphomaでも好酸球増多は合併することがあり,Hogikinの15%, Non-Hの5%で好酸球増多を認める.16British Journal of Haematology, 2009;145:271–285
  • 17. 骨髄, リンパ増殖性のHES vs iHESの鑑別OSINOPHILIC SYNDROME AND CLONAL EOSINOPHILIAPeripheral blood screeningfor FIP1L1-PDGFRAusing FISH or RT-PCRBone marrow biopsywith cytogeneticsPeripheral blood lymphocytephenotyping and TCRgene rearrangement studiesFirst stepSecond stepThird stepMutationpresentIdiopathic eosinophiliaincluding HES“Lymphocytic” varianthypereosinophilia5q33 translocationpresent8p11 translocationpresentOther abnormalitiesor excess blasts presentAll the above negativeFIP1L1-PDGFRA–associatedclonal eosinopliliaPDGFRB-rearrangedclonal eosinophiliaFGFR1-rearrangedclonal eosinophiliaCEL-NOS orother WHO-definedmyeloid neoplasmAbnormal or clonallymphocytes presentMayo Clin Proc. 2010;85(2):158-164
  • 18. HESの分類 (Hypereosinophilic Diseases Working Group 2005)18Hypereosinophilic syndromes (HES) classificationFIP1L1-PDGFRA FIP1L1-PDGFRApositiveMyeloproliferative HES Lymphocytic HESUndefinedHESAssociatedHESWith a defineddiagnosisChurg-Strauss,mastocytosis,inflammatorybowel disease,sarcoidosis,HIV and otherdiseasesOverlapHESAssociatedwith organ-restrictedeosinophilicdisorders (maynot meet all 3criteria),eosinophil-associatedgastrointestinaldisorders,eosinophilicpneumonia,eosinophiliamyalgiasyndromeFamilialHESFamilyhistory ofdocumentedpersistenteosinophiliaof unknowncauseBenignNoorganinvolve-mentnegativeEpisodicCyclicalangioedemaandeosinophiliaComplexOrgan dysfunctionbut notmyeloproliferativeor lymphocyticvariantAetiology unknownClonal eosinophils* or 4or more of:Dysplastic eosinophils,High serum B12,High serum tryptase,Anaemia,Thrombocytopenia,Hepatosplenomegaly,Marrow hypercellularity,Spindle-shaped mast cellsand/or myelofibrosisMonitor for T-cell clonality or other cytogenetic abnormalitiesChroniceosinophilicleukaemia(CEL)Cytogenicabnormalitiesand/or blastsEosinophils ≥ 1.5 × 109/lPersistent eosinophilia and/or end organ damage/dysfunctionExclusion of secondary causes of eosinophiliaClonal T cells*Clonality analysis based on the digestion of genomicDNA with methylation-sensitive restriction enzymesfollowed by PCR amplification of the CAG repeat at thehuman androgen receptor gene (AR) locus on the XchromosomeReview
  • 19. Hypereosinophilic syndrome 末梢血Eo>=1500/mcLが6ヶ月以上持続する稀な病態 Eo上昇の誘因となる疾患を認めなく,Eo上昇による臓器障害を認めるものをIdiopathic Hypereosinophilic syndromeと呼ぶ 6ヶ月間持続しなくても, 重大な臓器障害がある場合は診断する.(例; 心筋障害など) 原因に応じていくつかのTypeに分類される.骨髄増殖性, リンパ球性, 疾患随伴性, 家族性 などなど.J Allergy Clin Immunol 2009;124:1319-25 British Journal of Haematology, 2009;145:271–285
  • 20. HES 中枢神経, 心血管, 血球, 肺, 皮膚障害が多い. 心血管障害では血栓形成を生じ, 弁破壊, 心機能低下, 脳 塞のリスク.四肢末梢の点状出血は塞栓症を示唆する所見であり,Eo高値の患者でこの所見が認められた場合は緊急的な対応が必要. HESの50%が初期症状に皮膚所見を認める. 血管浮腫, じんま疹, 遠心性環状紅斑, 紅皮症, Livedo reticularis, 粘膜潰瘍, 爪床 塞, 壊死性血管炎, 紫斑, 点状出血, 湿疹, 血管炎, Well’s syndrome(好酸球性蜂窩織炎) の報告例あり.20British Journal of Haematology, 2009;145:271–285
  • 21. HES188名のRetrospective study Baseline; 平均年齢は45yr[6-85], 男性55%. Fip1-like1-plt-derived growth factor-R α(FP)は11%で陽性 異常T cellは17%で認められ, それらは L-HESと判断. 血清Tryptase値はFP変異陽性群では82%が上昇 vs 20%(非変異群) 血清TARC値はL-HES群で75%上昇 vs 36%(非L-HES群) HESの臓器症状臓器症状 初期頻度(%) 全体頻度(%)皮膚症状 37% 69%肺障害 25% 44%消化管障害 14% 38%心機能障害 <5% 20%初診時無症状 6%J Allergy Clin Immunol 2009;124:1319-25
  • 22. HESの症状, 侵襲臓器 貧血は53%, PLT低下は31%, PLT増多 16% 骨髄の好酸球増加は33%[7-57]で認められる所見. 米国, 仏, 英の105名の解析.22Blood 1994;83: 2759-2779侵襲臓器 %心血管 58%皮膚 56%神経 54%肺 49%脾臓 43%肝臓 30%眼 23%消化管 23%
  • 23. HESとStroke HESでは~65%で神経障害を伴う. その半分が末梢神経障害, 12%が脳血管障害, 10%が脳症. 脳血管障害では, 血管炎に伴う血管閉塞, 脳静脈洞血栓症以外に,心原性塞栓が原因となるCaseも報告されている. 分水嶺領域の多発性脳 塞で,剖検では心内膜の線維化, 内膜血栓を多数認め,Shower Emboliを呈していたと考えられる.23Arch Neurol. 2009;66(4):528-531Arq Neuropsiquiatr 2009;67(2-B):510-512Acta Neurol Taiwan 2008;17:184-188
  • 24. HESと心血管疾患 HESの40-50%に心血管疾患を合併. 最も特徴的なものはLoeffler endocarditis.“fibroplastic parietal endocarditis with blood eosinophilia” 好酸球増多, 心筋の線維性肥厚を特徴とする拘束性心筋症.内膜の巨大な血栓形成を多く認める. 他には心室内血栓形成, DVTなど血栓症頻度も高い. 鑑別疾患としては, Churg-Strauss syndrome, 薬剤, 寄生虫感染症,Tropical endomyocardial fibrosis, 悪性腫瘍. TEFとLoeffler’s endocarditisは似ているが,TEFではhelminth(寄生蠕虫)感染に伴う好酸球増多で,長期間熱帯地域に生活することがリスクとなる点で異なる. MIの併発, 突然死はCSSで多い.Immunol Allergy Clin N Am 27 (2007) 457–475
  • 25.  HESの心臓所見は大きく3つの病期がある. 急性壊死(5.5wk) → 血栓形成(10mo) → 線維化(24.5mo). 急性壊死期では, 好酸球の心筋浸潤を認める.この時期は無症候. ECG, エコーもはっきりしないことが多い.生検, MRIが検出に有用. 血栓形成期では心室内, 流出路, 弁下部, 特に左室心尖部に血栓形成を認める好酸球の顆粒内にTissue Factorが含まれており, 凝固を亢進させる.また好酸球蛋白が抗凝固作用を阻害する. 線維化期では心筋の線維化が進み, 拡張型心筋症, 拘束性心筋障害となる.この時期になると症状も出現し, 顕在化する. 臨床症状 呼吸苦, 動悸, 咳嗽など心不全症状が主. 塞栓症は4%程度. MR 42%, CHF 38%, AR 4%, AS 4% まれながら心外膜炎, 心筋 塞例の報告もあり. ECG所見は非特異的. LVH, ブロック, ST-T変化, CRBBBなど. 25Immunol Allergy Clin N Am 27 (2007) 457–475
  • 26. HESの分類 (Hypereosinophilic Diseases Working Group 2005)26Hypereosinophilic syndromes (HES) classificationFIP1L1-PDGFRA FIP1L1-PDGFRApositiveMyeloproliferative HES Lymphocytic HESUndefinedHESAssociatedHESWith a defineddiagnosisChurg-Strauss,mastocytosis,inflammatorybowel disease,sarcoidosis,HIV and otherdiseasesOverlapHESAssociatedwith organ-restrictedeosinophilicdisorders (maynot meet all 3criteria),eosinophil-associatedgastrointestinaldisorders,eosinophilicpneumonia,eosinophiliamyalgiasyndromeFamilialHESFamilyhistory ofdocumentedpersistenteosinophiliaof unknowncauseBenignNoorganinvolve-mentnegativeEpisodicCyclicalangioedemaandeosinophiliaComplexOrgan dysfunctionbut notmyeloproliferativeor lymphocyticvariantAetiology unknownClonal eosinophils* or 4or more of:Dysplastic eosinophils,High serum B12,High serum tryptase,Anaemia,Thrombocytopenia,Hepatosplenomegaly,Marrow hypercellularity,Spindle-shaped mast cellsand/or myelofibrosisMonitor for T-cell clonality or other cytogenetic abnormalitiesChroniceosinophilicleukaemia(CEL)Cytogenicabnormalitiesand/or blastsEosinophils ≥ 1.5 × 109/lPersistent eosinophilia and/or end organ damage/dysfunctionExclusion of secondary causes of eosinophiliaClonal T cells*Clonality analysis based on the digestion of genomicDNA with methylation-sensitive restriction enzymesfollowed by PCR amplification of the CAG repeat at thehuman androgen receptor gene (AR) locus on the XchromosomeReview
  • 27. Undefined HES Undefined HESはBenign, Episodic, Complexに分類 Benign Eosinophilia;  古典的なHESの基準を見たすが, 臓器障害を伴わないもの. ただし, 自然予後が不明であり, フォローは重要. Eo, T cellクローン, 他臓器障害の合併を慎重に見てゆく. Episodic angioedema and Eosinophilia; スライド参照. Complex Eosinophilia;  症候性のHESであるが, Myeloproliferative, Lymphocytic HESでは無い. 他のTypeでも合わない場合に診断. 以前に言われていたIdiopathic HESにあたる.27British Journal of Haematology, 2009;145:271–285
  • 28.  Overlap HES; 単一臓器を障害する好酸球増多症 Eosinophilic gastroentestinal disease(食道炎, 胃腸炎, 大腸炎)好酸球性肺炎, 好酸球性筋痛症, 膀胱炎など. Associated HES; 好酸球増多を伴う疾患による好酸球増多 Churg-Strauss syndrome, Systemic mastocytosis, HIV, サルコイドーシス,炎症性腸疾患など.28British Journal of Haematology, 2009;145:271–285
  • 29. HESの検査 血液検査でCheckすべきもの 炎症所見; ESR, CRP自己抗体; RF, ANCA, IgE, Strongyloides IgG抗体, IL-5値代謝; LFT, 腎機能, CPK, Vit B12, Mast cell/basophil tryptase level凝固系尿検査; 円柱, 蛋白, 血尿蛋白電気泳動, Ig 骨髄 刺にてクローン細胞, 遺伝子異常のCheck. 他には侵襲臓器の生検による好酸球浸潤, 血管炎評価など.29British Journal of Haematology, 2009;145:271–285
  • 30. HESの治療 Myeloproliferative HESの第一選択はImatinib. CML 400mg/dよりも低用量で治療可能な場合が多い.100-200mg/wkでの治療成功例も報告されている. FIP1L1-PDGFRA陽性例ではImatinibに対する反応良好を示唆するため,100mg/dでの治療開始でOK. FIP1L1-PDGFRβ陽性患者でもImatinibは有効. 400mg/dで開始する. FIP1L1-PDGFRA(+) CELに対するImatinibでは,投与後に好酸球顆粒大量放出による心原性ショックとなるリスクあり ステロイド全身投与に反応するため,Imanitib投与前はエコー, TropによるHESの心筋障害をCheck.リスクがあればImatinib投与開始前1-2wkはPSL 1mg/kg/dを使用し,Trop陰性化を確認した上でImatinib開始がBetterBritish Journal of Haematology, 2009;145:271–285Mayo Clin Proc. 2010;85(2):158-164, UpToDate
  • 31. HESの治療 Lymphocytic, Complex HESでは, ステロイド, INF-αが1st choice Lymphocytic HESに対してはMonoclonal IL-5抗体(mepolizumab)が有効である可能性があり, 今後に期待. ステロイドはPSL 1mg/kg/d を1-2wk継続し, その後2-3moかけてTapering.ステロイド受容体が欠落した好酸球増多では, ステロイド抵抗性となる. PSL>10mg/dで再発, 再燃した場合, Hydroxyurea 500mg bid,もしくはINF-α 100U SC 3回/wkをSteroid-sparing agentとして併用する. ステロイド不応例ではImatinib 400mg/dが有効だが,Case reportではiHESでも100mg/dの低用量で効果的との報告もあり,考慮して良いかもしれない. (Blood. 2004;103:2879-2891)31British Journal of Haematology, 2009;145:271–285Mayo Clin Proc. 2010;85(2):158-164
  • 32. 他の治療 Hydroxyurea 1000mg/d[500-2000] 188名中64名(34%)に使用され, 内18名は単剤治療. 単剤治療群において,33%で完全寛解, 39%で部分寛解を達成. 副作用での中断は21名 IFN-α 1400万U/wk[300-4000万] 188名中46名(25%)に使用. 12名は単剤治療 単剤治療群において,17%で完全寛解, 33%で部分寛解を達成. Cyclosporine 200mg/d[150-500] Imatinib 400mg/d[100-600] 抗IL-5抗体; Mepolizumab 750mg/mo, Reslizumab 1-3mg/kg/mo
  • 33. Evaluate for secondary causesDrug historyTravel historyStool for ova and parasitesOther tests if indicatedClonal eosinophiliawith a moleculartarget for imatinibClonal eosinophiliawithout a moleculartarget for imatinibHypereosinophilicsyndromeHydroxyureaVincristineCladribineAllogeneic transplantImatinib, 100 mg / d Consider treatmentoption that is optimalto the underlyingclonal disorderInterferon alfa with orwithout prednisoneNo responseNo response Imatinib, 400 mg / dEvaluate for clonal eosinophiliaBone marrow examination with tryptase stainsCytogenetic studiesFISH or RT-PCR to detect FIP1L1-PDGFRA mutationMayo Clin Proc. 2005;80(1):75-83
  • 34. HESの治療 無症候性のiHESの場合 統一された見解は無いが, 無症候性ならばEo値に関わらず治療は必要ないとの意見が多い. ただし慎重な経過観察が推奨される.特に心筋障害のCheck目的に, 3-6mo毎のTropのチェック,6-12mo毎の心エコーは行う必要がある.35Cancer J 2007;13: 384–391

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