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-HES
Mayo 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 Aspergillosis
Coccidioidomycosis(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)
9
Hypereosinophilic syndromes (HES) classification
FIP1L1-PDGFRA FIP1L1-PDGFRA
positive
Myeloproliferative HES Lymphocytic HES
Undefined
HES
Associated
HES
With a defined
diagnosis
Churg-
Strauss,
mastocytosis,
inflammatory
bowel disease,
sarcoidosis,
HIV and other
diseases
Overlap
HES
Associated
with organ-
restricted
eosinophilic
disorders (may
not meet all 3
criteria),
eosinophil-
associated
gastrointestinal
disorders,
eosinophilic
pneumonia,
eosinophilia
myalgia
syndrome
Familial
HES
Family
history of
documented
persistent
eosinophilia
of unknown
cause
Benign
No
organ
involve-
ment
negative
Episodic
Cyclical
angioedema
and
eosinophilia
Complex
Organ dysfunction
but not
myeloproliferative
or lymphocytic
variant
Aetiology unknown
Clonal eosinophils* or 4
or more of:
Dysplastic eosinophils,
High serum B12,
High serum tryptase,
Anaemia,
Thrombocytopenia,
Hepatosplenomegaly,
Marrow hypercellularity,
Spindle-shaped mast cells
and/or myelofibrosis
Monitor for T-cell clonality or other cytogenetic abnormalities
Chronic
eosinophilic
leukaemia
(CEL)
Cytogenic
abnormalities
and/or blasts
Eosinophils ≥ 1.5 × 109/l
Persistent eosinophilia and/or end organ damage/dysfunction
Exclusion of secondary causes of eosinophilia
Clonal T cells
*Clonality analysis based on the digestion of genomic
DNA with methylation-sensitive restriction enzymes
followed by PCR amplification of the CAG repeat at the
human androgen receptor gene (AR) locus on the X
chromosome
Review

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.
10
British 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;103:2879-2891
2次性好酸球増多を除外
FIP1L1-PDGFRαチェック
陽性; FIP1L1-PDGFRα Clonal Eosinophilia
Chronic Eosinophilic Leukemia
Systemic mastocytosis with Eosinophilia
陰性
CEL, Unclassified
T-cell associated HES
HES
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.Review
British Journal of Haematology, 2009;145:271–285
PDGFRβ (+): PDGFRB-rearranged eosinophilic leukemia/
Chronoic Myelomonocytic leukemia
FGFR1 (+): FGFR1-rearranged (stem cell leukemia and
lymphoma 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 eosinophilia
MDS associated with eosinophilia
他のMPD associated with eosinophilia
Table 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 Thrombocytosis
Positive total score denotes FIL1L1/PDGFRA-associated hypereosinophilic syndrome or chronic eosinophilic leukaemia. Negative total score denotes
KIT 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 and
FIP1L1/PDGFRA-associated chronic eosinophilic leukaemia are distinct entities, 680-687. Copyright 2007, with permission from Elsevier. The absolute
eosinophil count is given as eosinophils/mm3
and 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, 271–285 275
British Journal of Haematology, 2009;145:271–285
Cancer J 2007;13: 384–391

14. Systemic
Mastcytosis
 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.
14
Cancer J 2007;13: 384–391
TABLE 3. “B” Findings: Indication of High Mast Cell Burden
1. Infiltration grade (mast cells) in Ͼ30% in bone marrow on histologic examination and serum total tryptase levels Ͼ200 ng/mL
2. Hypercellular marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias or WHO criteria for
syndrome or myeloproliferative disorder
3. Organomegaly: palpable hepatomegaly, splenomegaly, or lymphadenopathy (on computed tomography scan or ultrasound) Ͼ2 cm
function
Data from Ref. 65.
TABLE 4. “C” findings: Indication of Impaired Organ Function Attributable to Mast Cell Infiltration66
1. Cytopenia(s): absolute neutrophil count Ͻ1,000/␮L, or hemoglobin Ͻ10g/dL, or platelets Ͻ100,000/␮L
2. Hepatomegaly with ascites and impaired liver function
3. Palpable splenomegaly with hypersplenism
4. Malabsorption with hypoalbuminemia and weight loss
5. Skeletal lesions: large-sized osteolysis or severe osteoporosis causing pathologic fractures
6. Life-threatening organopathy in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic mast c
Data from Ref. 66.
TABLE 5. WHO Criteria for Diagnosis of SM*
Major
Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organ sections (Ͼ15 mast cells aggregating)
Minor
a. Ն25% mast cells in tissue sections or bone marrow aspirate smear are spindle shaped or have atypical morphology
b. c-kit point mutation at codon 816V
c. Expression of CD2 and/or CD25 by mast cells
d. 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.44
PDGFRB rearrangement was first characterized in the
of a fusion tyrosine kinase encoding regions of
RB 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 with
nt myeloproliferative neoplasm (MPN) phenotypes
ted with eosinophilia.47–55 As has been seen in indi-
with PDGFRA-rearranged MPNs, imatinib therapy
es complete hematologic remission in PDGFRB-rear-
clonal eosinophilia.48,49,51,55–57
FGFR1 translocations are usually associated with a clin-
enotype with features of both an aggressive, eosinophilia-
ted MPN and T cell lymphoblastic lymphoma.58 The
site syndrome is known as either the 8p11 myeloprolif-
syndrome or stem cell leukemia lymphoma syndrome
molecularly characterized by fusion of various 5Ј partner
o the 3Ј part of FGFR1, making it constitutively active.
utation is present in both myeloid and lymphoid lineage
–63 Clinically, 8p11 myeloproliferative syndrome/stem
kemia lymphoma syndrome has an aggressive clinical
with a rapid transformation into acute leukemia. At
, drug therapy is ineffective and allogeneic stem cell
antation should be considered as soon as the particular
sis is established.
ation and Management of
hoproliferative Variant Idiopathic
ophilia
The lymphoproliferative variant of HES is a poorly
number and/or function (Table 2).65 Accordingly, 7 disease
variants are considered, including cutaneous mastocytosis, indo
lent systemic mastocytosis (ISM), SM with an associated clona
hematologic non–mast cell disorder (SM-AHNMD), aggressive
systemic mastocytosis (ASM), mast cell leukemia, mast cel
sarcoma, and extracutaneous mastocytoma.
The WHO classification of mastocytosis mandates a
TABLE 2. WHO Variants of Mastocytosis65
1. Cutaneous mastocytosis (CM)
a. Maculopapular CM
b. Diffuse CM
c. Mastocytoma of skin
2. Indolent systemic mastocytosis (ISM)
a. Smoldering systemic mastocytosis (SSM)
b. Isolated bone marrow mastocytosis
3. Systemic mastocytosis with an associated clonal hematological non–
mast cell lineage disease (SM-AHNMD)
a. SM-myelodysplastic syndrome
b. SM-myeloproliferative disorder
c. SM-chronic eosinophilic leukemia
d. SM-chronic myelomonocytic leukemia
e. SM-non-Hodgkin lymphoma
4. Aggressive systemic mastocytosis (ASM)
With eosinophilia (SM-eo)
5. Mast cell leukemia (MCL)
Aleukemic MCL
6. Mast cell sarcoma
7. 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. 15
TABLE 3. “B” Findings: Indication of High Mast Cell Burden
1. Infiltration grade (mast cells) in Ͼ30% in bone marrow on histologic examination and serum total tryptase levels Ͼ200 ng/mL
2. Hypercellular marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias or WHO criteria for myelodysplastic
syndrome or myeloproliferative disorder
3. Organomegaly: palpable hepatomegaly, splenomegaly, or lymphadenopathy (on computed tomography scan or ultrasound) Ͼ2 cm without impaired organ
function
Data from Ref. 65.
TABLE 4. “C” findings: Indication of Impaired Organ Function Attributable to Mast Cell Infiltration66
1. Cytopenia(s): absolute neutrophil count Ͻ1,000/␮L, or hemoglobin Ͻ10g/dL, or platelets Ͻ100,000/␮L
2. Hepatomegaly with ascites and impaired liver function
3. Palpable splenomegaly with hypersplenism
4. Malabsorption with hypoalbuminemia and weight loss
5. Skeletal lesions: large-sized osteolysis or severe osteoporosis causing pathologic fractures
6. Life-threatening organopathy in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic mast cells
Data from Ref. 66.
TABLE 5. WHO Criteria for Diagnosis of SM*
Major
Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organ sections (Ͼ15 mast cells aggregating)
Minor
a. Ն25% mast cells in tissue sections or bone marrow aspirate smear are spindle shaped or have atypical morphology
b. c-kit point mutation at codon 816V
c. Expression of CD2 and/or CD25 by mast cells
d. 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 MCD
Cancer 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.
16
British 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 EOSINOPHILIA
Peripheral blood screening
for FIP1L1-PDGFRA
using FISH or RT-PCR
Bone marrow biopsy
with cytogenetics
Peripheral blood lymphocyte
phenotyping and TCR
gene rearrangement studies
First step
Second step
Third step
Mutation
present
Idiopathic eosinophilia
including HES
“Lymphocytic” variant
hypereosinophilia
5q33 translocation
present
8p11 translocation
present
Other abnormalities
or excess blasts present
All the above negative
FIP1L1-PDGFRA–
associated
clonal eosinoplilia
PDGFRB-rearranged
clonal eosinophilia
FGFR1-rearranged
clonal eosinophilia
CEL-NOS or
other WHO-defined
myeloid neoplasm
Abnormal or clonal
lymphocytes present
Mayo Clin Proc. 2010;85(2):158-164

18. HESの分類 (Hypereosinophilic Diseases Working Group 2005)
18
Hypereosinophilic syndromes (HES) classification
FIP1L1-PDGFRA FIP1L1-PDGFRA
positive
Myeloproliferative HES Lymphocytic HES
Undefined
HES
Associated
HES
With a defined
diagnosis
Churg-
Strauss,
mastocytosis,
inflammatory
bowel disease,
sarcoidosis,
HIV and other
diseases
Overlap
HES
Associated
with organ-
restricted
eosinophilic
disorders (may
not meet all 3
criteria),
eosinophil-
associated
gastrointestinal
disorders,
eosinophilic
pneumonia,
eosinophilia
myalgia
syndrome
Familial
HES
Family
history of
documented
persistent
eosinophilia
of unknown
cause
Benign
No
organ
involve-
ment
negative
Episodic
Cyclical
angioedema
and
eosinophilia
Complex
Organ dysfunction
but not
myeloproliferative
or lymphocytic
variant
Aetiology unknown
Clonal eosinophils* or 4
or more of:
Dysplastic eosinophils,
High serum B12,
High serum tryptase,
Anaemia,
Thrombocytopenia,
Hepatosplenomegaly,
Marrow hypercellularity,
Spindle-shaped mast cells
and/or myelofibrosis
Monitor for T-cell clonality or other cytogenetic abnormalities
Chronic
eosinophilic
leukaemia
(CEL)
Cytogenic
abnormalities
and/or blasts
Eosinophils ≥ 1.5 × 109/l
Persistent eosinophilia and/or end organ damage/dysfunction
Exclusion of secondary causes of eosinophilia
Clonal T cells
*Clonality analysis based on the digestion of genomic
DNA with methylation-sensitive restriction enzymes
followed by PCR amplification of the CAG repeat at the
human androgen receptor gene (AR) locus on the X
chromosome
Review

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.
20
British 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.
22
Blood 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.
23
Arch Neurol. 2009;66(4):528-531
Arq Neuropsiquiatr 2009;67(2-B):510-512
Acta 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. 25
Immunol Allergy Clin N Am 27 (2007) 457–475

26. HESの分類 (Hypereosinophilic Diseases Working Group 2005)
26
Hypereosinophilic syndromes (HES) classification
FIP1L1-PDGFRA FIP1L1-PDGFRA
positive
Myeloproliferative HES Lymphocytic HES
Undefined
HES
Associated
HES
With a defined
diagnosis
Churg-
Strauss,
mastocytosis,
inflammatory
bowel disease,
sarcoidosis,
HIV and other
diseases
Overlap
HES
Associated
with organ-
restricted
eosinophilic
disorders (may
not meet all 3
criteria),
eosinophil-
associated
gastrointestinal
disorders,
eosinophilic
pneumonia,
eosinophilia
myalgia
syndrome
Familial
HES
Family
history of
documented
persistent
eosinophilia
of unknown
cause
Benign
No
organ
involve-
ment
negative
Episodic
Cyclical
angioedema
and
eosinophilia
Complex
Organ dysfunction
but not
myeloproliferative
or lymphocytic
variant
Aetiology unknown
Clonal eosinophils* or 4
or more of:
Dysplastic eosinophils,
High serum B12,
High serum tryptase,
Anaemia,
Thrombocytopenia,
Hepatosplenomegaly,
Marrow hypercellularity,
Spindle-shaped mast cells
and/or myelofibrosis
Monitor for T-cell clonality or other cytogenetic abnormalities
Chronic
eosinophilic
leukaemia
(CEL)
Cytogenic
abnormalities
and/or blasts
Eosinophils ≥ 1.5 × 109/l
Persistent eosinophilia and/or end organ damage/dysfunction
Exclusion of secondary causes of eosinophilia
Clonal T cells
*Clonality analysis based on the digestion of genomic
DNA with methylation-sensitive restriction enzymes
followed by PCR amplification of the CAG repeat at the
human androgen receptor gene (AR) locus on the X
chromosome
Review

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.
27
British 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.
28
British 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.
29
British 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Better
British Journal of Haematology, 2009;145:271–285
Mayo 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)
31
British Journal of Haematology, 2009;145:271–285
Mayo 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 causes
Drug history
Travel history
Stool for ova and parasites
Other tests if indicated
Clonal eosinophilia
with a molecular
target for imatinib
Clonal eosinophilia
without a molecular
target for imatinib
Hypereosinophilic
syndrome
Hydroxyurea
Vincristine
Cladribine
Allogeneic transplant
Imatinib, 100 mg / d Consider treatment
option that is optimal
to the underlying
clonal disorder
Interferon alfa with or
without prednisone
No response
No response Imatinib, 400 mg / d
Evaluate for clonal eosinophilia
Bone marrow examination with tryptase stains
Cytogenetic studies
FISH or RT-PCR to detect FIP1L1-PDGFRA mutation
Mayo Clin Proc. 2005;80(1):75-83

35. 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.
35
Cancer J 2007;13: 384–391