犬伴水肿的急性嗜酸性皮炎（威尔斯样综合征）

王帆

犬伴水肿的急性嗜酸性皮炎（威尔斯样综合征）

Canine Acute Eosinophilic Dermatitis with Edema (Wells-Like Syndrome)

作者：Elizabeth A. Mauldin, DVM

译者：王帆（巴哥控）

关键词

•犬科•嗜酸性皮炎•犬威尔斯样综合征•无菌性中性粒细胞性皮肤病•犬斯威特综合征

重点

•犬伴水肿的急性嗜酸性皮炎(CAEDE)，在犬上是一种罕见的综合性疾病，具有独特的临床表现。

•大多数CAEDE患犬，在之前会有胃肠道病史，或与皮肤病变表现同时出现。

•CAEDE患犬会表现红斑或全身皮肤发红，在腹部无毛皮肤处最为明显。

•CAEDE的诊断基于临床表现和组织学特征，但有些病例可能很难与犬无菌性中性粒细胞性皮肤病(犬斯威特综合征)相区分。

•CAEDE的病因学尚不明确，但药物副反应或全身性I型过敏反应可能在发病机制中发挥作用。

KEYWORDS

•Canine
•Eosinophilic dermatitis
•Canine Wells-like syndrome
•Sterile neutrophilic dermatitis
•Canine Sweet’s syndrome

KEY POINTS

•Canine acute eosinophilic dermatitis with edema (CAEDE) is an uncommon syndromic disorder in dogs with a unique clinical presentation.

•Most dogs with CAEDE have a history of gastrointestinal upset preceding or concurrent with onset of skin lesions.

•Dogs with CAEDE present with macular or generalized erythema that is most evident on the glabrous skin of the abdomen.

•Diagnosis of CAEDE is based on clinical and histologic features, but some cases can be difficult to distinguish from canine sterile neutrophilic dermatosis (canine Sweet’s syndrome).

•The etiology of CAEDE is not known but an adverse drug reaction or a systemic type I reaction may play a role in the pathogenesis.

介绍

INTRODUCTION

犬伴水肿的急性嗜酸性皮炎(CAEDE)是一种罕见的犬综合性疾病，具有独特的临床表现。大多数但不是所有的犬都有中到重度胃肠道(GI)病史。在治疗胃肠道疾病期间或之后出现皮肤病变。患犬会出现明显红斑或全身性红斑，以腹部无毛皮肤最明显(图1)。诊断依据临床表现和组织学特征。虽然病因尚不明确，但可能与药物副反应或未知的全身过敏反应有关。有些病例很难与犬无菌性中性粒细胞性皮肤病(也称为犬斯威特综合征[CSS])相区分，因为两者的临床评估标准和组织切片中嗜酸性粒细胞脱颗粒表现相似。

Canine acute eosinophilic dermatitis with edema (CAEDE) is an uncommon syndromic disorder in dogs with a unique clinical presentation. Most but not all dogs have a history of moderate to severe gastrointestinal (GI) upset. The skin lesions arise during or after treatment of the GI disease. The affected dogs develop bright red macules or generalized erythema that is most evident on the glabrous skin of the abdomen (Fig. 1). The diagnosis is based on both clinical features and histologic features. Although the etiology is not known, adverse drug reaction or unknown systemic hypersensitivity may play a role. Some cases can be difficult to distinguish from canine sterile neutrophilic dermatosis (also known as canine Sweet’s syndrome [CSS]) due to overlapping clinical criteria and to eosinophil degranulation in tissue section.

图1. CAEDE患犬标志性的腹部红皮病。

Fig. 1. Marked abdominal erythroderma in a dog with CAEDE.

临床特点

CLINICAL FEATURES

1999年，Holm及其同事发表了一份9只犬的病例分析，这些犬都表现为急性的拱形至波浪形红斑和斑块，伴有水肿。皮肤活检显示伴有水肿的大量嗜酸性细胞炎性浸润。该综合征被比作人的嗜酸性蜂窝织炎(威尔斯综合征)。病例系列中描述的第一只犬是拉布拉多犬，它在治疗贾第鞭毛虫病时出现了皮肤病变。Holm及其同事提出，皮肤病变是由过敏反应(如药物或节肢动物叮咬)引起的，但无法确定原因。

In 1999, Holm and colleagues published a case series of 9 dogs that presented with an acute onset of erythematous arciform to serpiginous macules and plaques with edema. Skin biopsies revealed a robust eosinophilic inflammatory infiltrate with edema. The syndrome was likened to eosinophilic cellulitis (Wells syndrome) in people. The first dog described in the case series was a Labrador retriever that developed skin lesions while being treated for giardiasis. Holm and colleagues proposed that the skin lesions were triggered by hypersensitivity reaction (eg, drugs or arthropod bites) but definitive causation could not be established.

将该综合征与犬异位性皮炎(CAD)进行鉴别是很重要的。虽然CAD患犬可能会出现急性加重表现(爆发)，可能表现为全身红斑，但突发性丘疹斑块病变以及组织学特征，使Holm和同事认为此病例表现独特。患犬没有能提示为CAD的皮肤皱褶处和四肢趾间的病变表现(如红斑、色素沉着和苔藓化)，瘙痒通常也不是一种特点。并且尽管CAD是一种IgE介导的疾病，但在组织学上，嗜酸性粒细胞只是炎性浸润的一个次要成分。Holm及其同事报道的急性皮炎具有明显的嗜酸性细胞，有些病例有火焰样胶原表现。火焰样胶原(即密集的嗜酸性蛋白沉积在真皮胶原蛋白上的病变)见于严重的嗜酸性皮肤病，如猫嗜酸性肉芽肿综合征。

It is important to differentiate this syndrome from canine atopic dermatitis (CAD). Although dogs with CAD can have acute exacerbations (flares), which may be manifest by generalized erythema, the abrupt onset of the maculopapular lesions along with the histologic features made Holm and colleagues’ cases unique. The affected dogs did not have flexural fold or distal extremity lesions (eg, erythema, hyperpigmentation, and lichenification) that define CAD, and pruritus was generally not a feature. And, although CAD is an IgE-mediated disease, histologically, eosinophils are only a minor component of the inflammatory infiltrate. The acute dermatitis reported by Holm and colleagues was markedly eosinophilic and some cases had collagen flame figures. Collagen flame figures (ie, foci of densely eosinophilic protein deposits on dermal collagen) are found in intense eosinophilic dermatosis, such as the feline eosinophilic granuloma complex.

2006年的一项回顾性研究记录了Holm及其同事所描述的CAEDE综合征与胃肠道疾病之间的关系。在这项研究中，29只犬中有22只犬的呕吐和/或腹泻接受了治疗。其中17只犬的皮肤病变先于胃肠道症状出现，5只犬皮肤病变与胃肠道症状同时出现。典型的腹泻和呕吐常伴有吐血和/或便血，需要住院治疗。大多数犬有低蛋白血症。同Holm及其同事的病例一样，临床病变表现一致:鲜红色、有时呈靶样斑(即皮肤中央正常)和丘疹或斑块伴有或不伴有全身性红斑和水肿。腹侧皮肤病变一致且大多更严重。采用皮肤药物评分法确定发病机制为副反应的可能性。虽然大多数犬为了治疗胃肠道治疗时接受了多种药物治疗(如止吐药、抗组胺药、H2受体拮抗剂和抗生素)，但只有6只有胃肠道疾病的患犬的药物评分呈阳性。大多数犬接受了甲硝唑治疗，但其因果关系尚未证实。事实上，一只被认为由甲硝唑引起皮肤病变的巴吉度犬，在6周后无意中又用了甲硝唑(给予重复剂量)，皮肤病变没有复发。在7只没有胃肠道疾病的犬中，有1只犬(巴辛吉)的药物评分为阳性。在接受帕罗西汀治疗行为问题时出现了典型的CAEDE病变表现。

A 2006 retrospective study documented an association of the CAEDE syndrome, as described by Holm and colleagues, with GI illness. In that study, 22 of 29 dogs were treated for vomiting and/or diarrhea. Of those, 17 developed skin lesions prior to the GI upset and 5 dogs developed skin lesions concomitantly. Marked diarrhea and vomiting were often accompanied by hematemesis and/or hematochezia and necessitated hospitalization. A majority of dogs were hypoalbuminemic. Like Holm and colleagues’ cases, the clinical lesions were consistent: bright red, sometimes targetoid (ie, central clearing) macules, and papules or plaques with or without generalized erythema and edema. The ventral abdominal skin was consistently and most severely affected. A cutaneous drug scoring method was applied to determine the likelihood of an adverse reaction as the etiologic mechanism. Although most dogs received multiple medications (eg, antiemetics, antihistamines, H2 receptor antagonists, and antibiotics) for the treatment of the GI illness, only 6 dogs with GI disease had a positive drug score. Metronidazole was given to most dogs, but a cause and effect were not proved. In fact, 1 Basset hound whose lesions were believed triggered by metronidazole was unintentionally challenged (given repeated doses) 6 weeks later with no recurrence of skin lesions. Of the 7 dogs without GI illness, 1 dog (a basenji) had a positive drug score. Lesions typical of CAEDE-developed lesions arose while receiving paroxetine for a behavioral problem.

凯恩和同事在2017年进行的一项后续研究调查了患有胃肠道疾病的CAEDE病例。与之前的研究一样，大多数犬在治疗胃肠道症状后或治疗期间出现皮肤病变，但也有几只犬在出现胃肠道症状前1至2天出现皮肤病变。在18只犬中，3只犬的胃肠道疾病病因是胰腺炎，3只犬为食物副反应，5只犬被诊断为炎性肠病。在剩下的8只犬中引起胃肠道疾病的病因尚不明确。8只犬的药物评分与药物副反应可能一致。

A follow-up study in 2017 by Cain and colleagues investigated those cases of CAEDE with GI illness. As in the prior study, most dogs developed skin lesions after or during treatment of GI distress, but a couple dogs developed the skin lesions 1 day to 2 days prior to the GI upset. Of the 18 dogs, the cause of the GI disorder was identified as pancreatitis in 3 dogs and adverse food reactions in 3 dogs, and 5 dogs were diagnosed with inflammatory bowel disease. A cause for the GI disease was not found in the remaining 8 dogs. Eight dogs had a drug score that was consistent with the possible adverse drug reaction.

组织学上，Cain及其同事的研究表明，皮肤炎症表现的严重程度从非常轻度到重度(图2)。组织学病变可分为3种模式:模式1：在伴有血管扩张的真皮浅部有非常轻微的嗜酸性粒细胞炎症，伴有或不伴有中性粒细胞炎症。模式2：炎症范围较广，向真皮纵深扩展，伴有少量火焰样胶原蛋白。模式3：炎症最为严重且呈扩散性。重要的是，病理学家应该认识到CAEDE可引起广泛的炎症反应。组织学病变可能代表皮肤病变的进展，但不能预测患者的预后或诱因。

Histologically, Cain and colleagues’ study showed that the cutaneous inflammation ranged in severity from very mild to severe (Fig. 2). The histologic lesion fells into 3 patterns: pattern 1 had very mild eosinophilic with or without neutrophilic inflammation in the superficial dermis with vascular ectasia; pattern 2 had more extensive inflammation that extended into the deeper dermis with few collagen flame figures; and pattern 3 had the most severe and diffuse inflammation. It is important for pathologists to recognize the wide range of inflammation that can occur with CAEDE. The histologic lesions likely represent progression of skin lesions, they but do not predict patient outcome or trigger.

图2. 皮肤中度嗜酸性炎性浸润，伴有水肿和血管扩张(箭头)（HE染色，原图方大10倍）

Fig. 2. Moderate dermal eosinophilic inflammatory infiltrate with edema and ectatic blood vessels (arrows) (hematoxylin-eosin, original magnification*10).

病因学

ETIOLOGY

虽然CAEDE的发病机制尚不明确，但Mauldin和Cain的研究普遍反驳了CAEDE与人威尔斯综合征有相似之处，后者更倾向于四肢的局灶性病变。大多数犬病例的常见因素包括:明显呕吐和腹泻，可能需要住院治疗；低蛋白血症；多种药物治疗；腹侧分布的急性发作性红皮病和水肿。药物副反应等诱因可能发挥一定作用，但并非是所有病例的确定病因。该综合征可能是全身性I型过敏反应的表现。

Although the pathogenesis of CAEDE remains elusive, the studies by Mauldin and Cain generally refute a similarity of CAEDE with Wells syndrome in people, which tends to be more focal lesion on an extremity. The factors common to most canine cases include the following: significant vomiting and diarrhea, which may require hospitalization; hypoproteinemia; treatment with multiple medications; and acute-onset erythroderma and edema in a ventrally oriented distribution. A trigger such as adverse drug reaction may play a role but it is not a definitive cause for all cases. The syndrome is likely a manifestation of systemic type I hypersensitivity reaction.

临床鉴别诊断

CLINICAL DIFFERENTIAL DIAGNOSES

临床上，CAEDE患者出现散在的靶样病变（牛眼样），类似于多形红斑和血管炎。有些犬可能会出现类似荨麻疹的指压性水肿或面部水肿。虽然在许多情况下，组织学上明显表现血管损伤(如红细胞胞吐和血管周围纤维蛋白积聚)，但典型血管炎(如纤维蛋白样坏死或白细胞破裂)通常不是一种特征表现。此外，皮肤没有血管损伤症状(皮肤坏死或局部缺血)。一般来说，高质量的皮肤活检可以鉴别这些疾病。

Clinically, CAEDE patients develop discrete targetoid (bull’s eye) lesions that mimic erythema multiforme and vasculitis. Some dogs may develop pitting edema or facial edema that resembles urticaria. Although vascular damage is histologically evident in many cases (eg, erythrocyte diapediesis and perivascular fibrin accumulation), overt vasculitis (eg, fibrinoid necrosis or leukocytoclasia) is generally not a feature. Furthermore, the skin does not show signs of vascular compromise (cutaneous necrosis or ischemia). Generally, good-quality skin biopsies can distinguish these conditions.

犬伴水肿的急性嗜酸性皮炎的治疗方法

TREATMENT OF CANINE ACUTE EOSINOPHILIC DERMATITIS WITH EDEMA

在三项关于CAEDE的研究中，都停止使用在皮肤病变出现前的所有药物。常用的药物包括止吐药、H1和H2受体拮抗剂、胃黏膜保护剂、驱虫药和各种抗生素，包括甲硝唑。对于皮肤而言，药物治疗包括皮质类固醇(例如：主要是泼尼松)和抗组胺药(例如：苯海拉明、西替利嗪和羟嗪)。胃肠道疾病一般在皮肤病变前就已恢复。在Cain和同事的研究中，胃肠道症状在一周内恢复，而皮肤病变大约需要3周的时间才能恢复。皮肤病变通常不会复发。Cain及其同事报告了1例复发皮肤病变，但没有出现胃肠道症状的病例。

In each of the 3 studies on CAEDE, drugs administered prior to the onset of skin lesions were withdrawn. Commonly administered medications included antiemetics, H1 and H2 receptor antagonists, gastroprotectants, anthelmintics, and various antibiotics, including metronidazole. For the skin, medications included corticosteroids (eg, mainly prednisone) and antihistamines (eg, diphenhydramine, cetirizine, and hydroxyzine). The GI disease generally resolved before the skin lesions. In Cain and colleagues’ study, GI signs resolved within a week’s time whereas the skin lesions took approximately 3 weeks to resolve. The skin lesions typically do not recur. Cain and colleagues reported 1 case of recurrent skin lesions but these occurred without GI signs.

犬无菌性中性粒细胞性皮肤病（斯威特综合征）

CANINE STERILE NEUTROPHILIC DERMATOSIS (SWEET’S SYNDROME)

无菌性中性粒细胞性皮肤病(CSS)是一种罕见的疾病，其特征与CAEDE重叠。此病等同于急性发热性中性粒细胞性皮肤病(也称为斯威特综合征)。患有斯威特综合症的犬和人可能表现出全身疾病症状(如发烧、中性粒细胞增多、关节炎或肺炎)。在犬上，皮肤病变表现相似，但可能比CAEDE脓疱更多，并且也可能在无毛皮肤上最明显。组织学上，真皮有明显的嗜中性粒细胞浸润，伴有或不伴有嗜酸性粒细胞浸润。推测有些病例与药物副反应有关。

Sterile neutrophilic dermatosis (CSS) is a rare disorder with features that overlap CAEDE. This condition has been equated to acute febrile neutrophilic dermatosis (also known as Sweet’s syndrome) in people. Dogs and humans with Sweet’s syndrome may show signs of systemic illness (eg, fever, neutrophilia, arthritis, or pneumonia). In dogs, skin lesions are similar but perhaps more pustular than CAEDE and also may be most apparent on glabrous skin. Histologically, the dermis contains a marked neutrophilic infiltrate with or without eosinophils. Some cases have been putatively associated with adverse drug reactions.

犬伴水肿的急性嗜酸性皮炎和犬斯威特综合征的相似处

CASES OF OVERLAPPING CANINE ACUTE EOSINOPHILIC DERMATITIS WITH EDEMA AND CANINE SWEET’S SYNDROME

CAEDE和CSS的临床病变和组织学特征可能相似。难以确诊的主要原因有三点:(1)组织切片中的嗜酸性粒细胞可能发生脱颗粒，因此很难与中性粒细胞相区分;(2)有报道称嗜酸性粒细胞是CSS炎症浸润的组成部分;(3)在早期确诊为CSS的文献中，有些病例现在可能被归类为CAEDE。事实上，小型雪纳瑞无菌性脓疱性红皮病，是一种组织学特征既能被诊断为CAEDE又能诊断为CSS的病，这取决于在皮肤炎症浸润中是否由中性粒细胞或嗜酸性粒细胞占主导地位。小型雪纳瑞也出现在Mauldin和Cain及其同事的CAEDE 研究中。这些疾病有可能有相互关联，并表现为广义上有皮肤临床表现的全身性过敏反应。对于病理学家而言，在组织切片上很难鉴别粒细胞，可以使用Luna组织化学染色法对嗜酸性粒细胞中的颗粒进行评估。

Clinical lesions and histologic features may overlap in cases of CAEDE and CSS. There are 3 main reasons why the diagnosis can be challenging: (1) eosinophils in tissue section may undergo degranulation, thus making it difficult to distinguish them from neutrophils; (2) eosinophils have been reported as a component of the inflammatory infiltrate in CSS; and (3) some cases in the older literature of diagnosis as CSS might now be classified as CAEDE. Indeed, sterile pustular erythroderma of miniature schnauzers is a condition whose histologic features can be identical to either CAEDE or CSS depending on whether neutrophils or eosinophils predominate in the dermal inflammatory infiltrate. Miniature schnauzers were represented in the CAEDE Mauldin and Cain and colleagues’ studies. It is possible that these disorders are interrelated and represent of broad spectrum of systemic hypersensitivity with skin manifestations. For pathologists who have difficulty in distinguishing the granulocytes in tissue section, a Luna histochemical stain can be applied to assess for the granules in eosinophils.

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