犬皮肤过敏反应综述:过敏诊断专家指南（兽医病理学杂志2023） ...

王帆

A review of cutaneous hypersensitivity reactions in dogs: A diagnostician’s guide to allergy

犬皮肤过敏反应综述:过敏诊断专家指南（兽医病理学杂志2023）

 

作者：Charles W. Bradley , Elizabeth A. Mauldin, and Daniel O. Morris

 

翻译：王帆

 

Abstract

摘要

Allergic dermatoses are common in people and domestic animals. Resultant lesions are routinely biopsied and submitted for histological examination to confirm a diagnosis or rule out diseases with overlapping or atypical clinical features. Diagnostic pathologists and clinicians are often faced with the difficult task of determining whether an allergic reaction pattern is present on both the microscopic and macroscopic levels and correlating histopathologic findings with clinical and historical data to achieve a precise clinical diagnosis. The bulk of the current veterinary literature on allergic dermatoses focuses on atopic dermatitis in dogs, distantly followed by cats, horses, and other animals. The objectives of this review are to demonstrate the key histopathologic and clinical diagnostic features of the various allergy-mediated reaction patterns, and to provide diagnosticians with a practical guide for clinicopathological correlations. Current concepts in the pathophysiology of immediate hypersensitivity reactions, with a focus on atopic dermatitis, are discussed. Points of potential histopathologic overlap between the “classic” allergic reaction pattern and less common inflammatory, predominately eosinophilic, conditions that may mimic this pattern will be discussed with the goal of highlighting the critical need for collaboration between pathologists and clinicians in furthering patient care.

过敏性皮肤病常见于人和家养动物。疾病所产生的病变进行常规活检并送检进行组织学检查，以确诊或排除具有重叠或不典型临床特征的疾病。诊断病理学家和临床医生经常面临的困难任务是确定过敏反应模式是否存在于显微镜和宏观水平，并将组织病理学结果与临床和病史相关联，以实现精确的临床诊断。目前关于过敏性皮肤病的兽医文献大部分集中在犬的特应性皮炎，其次是猫、马和其他动物。本综述的目的是展示各种过敏反应介导的反应模式的关键组织病理学和临床诊断特征，并为诊断医师提供临床病理相关性的实用指南。讨论了速发型超敏反应的当前病理生理学概念，重点是特应性皮炎。我们将讨论“经典”过敏反应模式和不太常见的炎症(主要是嗜酸性粒细胞)可能模拟这一模式之间可能存在的组织病理学重叠点，目的是强调在进一步治疗患犬时，病理学家和临床医师之间迫切需要合作。

 

 

Keywords

关键词

allergy, atopic dermatitis, canine, eosinophilic dermatitis, skin

过敏症，特应性皮炎，犬，嗜酸性皮炎，皮肤

 

The Coombs and Gell classification scheme breaks hypersensitivity reactions into 4 categories. Allergic diseases are generally considered to be type I hypersensitivity reactions (both immediate and late phase) to foreign substance involving immunoglobulin (Ig) E, and less frequently type IV (delayed, cell-mediated) reactions. Allergic skin disease includes atopic dermatitis, cutaneous adverse food reaction (CAFR; food allergy), hypersensitivities to ectoparasites, contact hypersensitivity, and some adverse drug reactions (ADRs), although ADRs may fall under any of the 4 Coombs and Gell subtypes. Allergic hypersensitivity reactions may affect other organ systems and mucosal surfaces with separate, though potentially concurrent, disease manifestations such as allergic bronchitis (asthma), allergic rhinitis, allergic conjunctivitis, inflammatory bowel syndromes, oral eosinophilic granuloma, and anaphylaxis.

Coombs和Gell分类方案将超敏反应分为4类。过敏性疾病通常被认为是涉及免疫球蛋白(Ig) E的对外来物质的I型超敏反应(速发期和迟发期)，以及较少出现IV型(迟发型，细胞介导)反应。过敏性皮肤病包括特应性皮炎、皮肤食物不良反应(CAFR;食物过敏)、外寄生虫超敏反应、接触性超敏反应和一些药物不良反应(ADR)，但ADR可能属于4种Coombs和Gell亚型中的任何一种。过敏性超敏反应可影响其他器官系统和黏膜表面，其疾病表现(如过敏性支气管炎(哮喘)、过敏性鼻炎、过敏性结膜炎、炎性肠综合征、口腔嗜酸性肉芽肿和过敏性休克)可能单独出现，但也可能同时出现。

 

Allergic dermatitis is common in companion animal veterinary practice, with pruritus being the most frequent presenting complaint. Although the problem is commonplace, the pathogenesis of allergic dermatitis is incompletely understood. Diagnosis and effective treatment of allergic dermatitis are challenging due to varied clinical presentations, varied responses to therapy, and presenting clinical signs that can mimic other cutaneous diseases.Diagnostic pathologists may be equally challenged when asked to diagnose or rule out allergic skin disease as the histopathologic findings are not always straightforward, clinical information that is critical to a diagnosis may be lacking, and other disease processes can have histopathologic overlap. The main task of the diagnostician in this scenario is not to diagnose allergic skin disease, but to rule out other conditions that have overlapping clinical phenotypes and to assess the tissue for histopathologic features that support or refute the clinical diagnosis. As such, it behooves the pathologist to understand the known pathophysiology of allergic skin disease in domestic animal species and common histopathologic and clinical correlates.

过敏性皮炎在伴侣动物兽医临床上很常见，瘙痒是最常见的主诉。尽管这一问题很常见，但其发病机制尚不完全清楚。由于过敏性皮炎的临床表现多样，对治疗的反应各异，并且表现出与其他皮肤病相似的临床症状，因此诊断和有效治疗具有挑战性。当被要求诊断或排除过敏性皮肤病时，诊断病理学家可能面临同样的挑战，因为组织病理学结果并不总是直接的，可能缺乏对诊断至关重要的临床信息，并且其他疾病过程可能有组织病理学重叠。在这种情况下，诊断医师的主要任务不是诊断过敏性皮肤病，而是排除有重叠临床表型的其他疾病，并评估组织，以确定支持或反对临床诊断的组织病理学特征。因此，病理学家有必要了解家养动物过敏性皮肤病的已知病理生理学以及常见的组织病理学和临床相关性。

 

Most of the veterinary literature on allergic dermatoses is focused on atopic dermatitis of companion animals, primarily dogs, with fewer publications available on cats, distantly followed by horses, livestock, and nontraditional pets. Canine atopic dermatitis (cAD) has been thoroughly reviewed by a prior task force of the American College of Veterinary Dermatology (2001), the International Task Force on Canine Atopic Dermatitis (2003–2011), and currently the International Committee on Allergic Disease of Animals (since 2013). Eosinophils are not resident leukocytes in the skin.

关于过敏性皮肤病的兽医文献大多集中在伴侣动物(主要是犬)的特应性皮炎，关于猫的文献较少，其次是马、家畜和非传统宠物。犬特应性皮炎(cAD)已经由美国兽医学会(2001年)、国际犬特应性皮炎工作组(2003-2011年)和目前的国际动物过敏性疾病委员会(2013年以来)进行了全面审查。嗜酸性粒细胞不是皮肤内的常驻白细胞。

 

Eosinophilic dermatitis may lead a diagnostician to consider a hypersensitivity response or parasitism. Despite the commonality of allergic skin disease, other dermatoses with eosinophilic infiltrates should be carefully ruled out. For example, varying severities of perivascular eosinophilic dermatitis can be encountered in biopsy samples of pemphigus foliaceus, canine acute eosinophilic dermatitis and edema (CAEDE), zinc-responsive dermatosis of the Siberian husky and Nordic breed dogs, sterile pustular erythroderma of miniature schnauzers, and in samples of furunculosis (where bare hair shafts and keratin may provoke eosinophil chemotaxis). Falling back on allergic skin disease as a probable diagnosis with simply the presence of an eosinophilic dermatitis is a pitfall that should be avoided if other clinical or histopathologic features are not supportive.

嗜酸性皮炎可能导致诊断医师考虑超敏反应或寄生。尽管过敏性皮肤病具有共性，但有嗜酸性粒细胞浸润的其他皮肤病应仔细排除。例如，在落叶型天疱疮的活检样本、犬急性嗜酸性皮炎和水肿(CAEDE)、西伯利亚哈士奇和北欧犬的锌反应性皮肤病、迷你雪纳瑞的无菌脓疱性红皮病和疖病(毛干和角蛋白暴露可能引起嗜酸性粒细胞趋化)样本中，可能会出现不同程度的血管周围嗜酸性皮炎。如果其他临床或组织病理学特征不支持，则应避免将过敏性皮肤病作为仅存在嗜酸性皮炎的可能诊断。

 

Before diving in, practical considerations to optimize the diagnostic utility of a cutaneous biopsy sample need to be addressed. An open line of communication between the clinician and diagnostician is essential. A concise, pertinent, and accurate clinical history are needed, including signalment, responses to prior therapy, current ectoparasite control measures, lesion descriptions and distribution, and clinical differential diagnoses. If glucocorticoid therapy has been utilized, this should be known and a “wash-out” period avoiding glucocorticoids for 3 weeks is recommended, when possible, due to the effects of glucocorticoids on leukocytes, particularly eosinophils, which may alter the histopathologic interpretation. A longer wash-out period may be needed if reposital steroids are used. Surgical scrub and clipping should be avoided so as not to impart artifacts to the epidermis and to preserve the diagnostic value of pustules and crusts. Multiple punch biopsy samples (preferably two to four, 6 to 8 mm diameter samples) are recommended for most cases as diagnostic information may vary between sites due to the natural evolution of lesions, secondary surface trauma and microbial infections.

在深入研究之前，我们需要解决优化皮肤活检样本诊断效用的实际考虑。临床医师和诊断医师之间的开放沟通至关重要。需要一份简明、有针对性和准确的临床病史，包括特征、既往治疗效果、目前的体外寄生虫控制措施、病变描述和分布以及临床鉴别诊断。如果使用了糖皮质激素治疗，应了解这一点，并且建议在可能的情况下采用3周的“停药期”，避免使用糖皮质激素，因为糖皮质激素对白细胞(尤其是嗜酸性粒细胞)产生影响，这可能会改变组织病理学解读。如果使用恢复期类固醇，则可能需要较长的停药期。应避免手术洗刷和剃毛，以免给表皮带来伪影，并保留脓疱和结痂的诊断价值。由于病变的自然演变、继发性表面创伤和微生物感染可能会导致不同部位的诊断信息不同，因此建议对大多数病例进行多个采样活检(最好是2-4个，6-8 mm直径的样本)。

 

Classic Cutaneous Hypersensitivity Reactions

典型皮肤过敏反应

Canine Atopic Dermatitis

犬特应性皮炎

Atopic dermatitis is a genetically predisposed inflammatory and pruritic skin disease with characteristic clinical features associated with elevated allergen-specific IgE antibodies, most commonly directed against environmental allergens. Though clinical signs of cAD are characteristic, they can vary with pruritus (the unpleasant sensation of itch) being the most consistent finding. Canine atopic dermatitis is common, chronic, and progressive, generally with a juvenile to early adult age of onset of 6 months to 3 years. Strong breed predilections for the development of cAD support a genetic basis, with golden retrievers, West Highland white terriers, German shepherd dogs, cocker spaniels, and French bulldogs commonly reported, though predilections also appear to have geographic variations. Based on genomic studies, the predisposing genotypes may be breed-specific.

特应性皮炎是一种遗传易感的炎症性和瘙痒性皮肤病，其特征性临床特征与过敏原特异性IgE抗体升高相关，最常针对环境过敏原。虽然cAD的临床症状是特征性的，但它们可以变化，其中最一致的表现是瘙痒(令人不快的瘙痒感觉)。犬特应性皮炎是一种常见的慢性进行性疾病，一般在青少年至成年早期发病，发病年龄为6个月至3岁。对cAD发展的强烈的品种偏好支持了遗传基础，金毛猎犬、西高地白梗、德国牧羊犬、可卡犬和法国斗牛犬经常被报道， 但品种倾向性似乎也有地理差异。基于基因组学研究，易感基因型可能具有繁殖特异性。

 

To date, there is no test available to establish a diagnosis of cAD and histopathologic findings are highly variable. Canine atopic dermatitis is generally a diagnosis of exclusion that requires first ruling out other common and treatable causes of pruritus in young dogs (eg, ectoparasites and superficial bacterial and fungal infections) and then ruling out other causes of allergic skin disease (eg, ectoparasite hypersensitivity and adverse food reaction). The diagnosis of “atopic-like disease” has been made previously if elevated IgE levels are not detected following exposure to an allergen and the dog has signs otherwise consistent with cAD, although it is not entirely clear whether this represents a separate disease or a failure of allergen specific IgE detection.

迄今为止，还没有可用的检测方法来确定cAD的诊断，并且组织病理学检查结果有很大的差异。犬特应性皮炎通常是一种排除性诊断，首先需要排除青年犬瘙痒的其他常见和可治疗原因(如体外寄生虫和浅表细菌和真菌感染)，然后排除过敏性皮肤病的其他原因(如体外寄生虫超敏反应和食物不良反应)。如果暴露于过敏原后未检测到IgE水平升高，并且犬出现与cAD相一致的其他症状，则被诊断为“异位样疾病”，但尚不完全清楚这是一种单独的疾病还是过敏原特异性IgE检测的失败。

 

Canine atopic dermatitis offers a spontaneous large animal model for study of AD in people. There is significant overlap in the lesion distribution, immunologic profile, prevalence, and therapeutic considerations. The progression differs as people develop AD at an early age and often have a reduction in the severity of disease in adulthood. In people, the atopic state may progress to involve other allergic conditions such as allergic bronchitis and allergic rhino-conjunctivitis/sinusitis (“hay fever”). This progression, which is termed the “atopic march,” is not recognized with cAD.

犬特应性皮炎为人类特应性皮炎的研究提供了一种自发性的大动物模型。两者在病变分布、免疫学特征、患病率和治疗方面有显著重叠。随着人们在早期发病和成年期疾病严重程度的降低，疾病的进展也有所不同。在人类中，特应性状态可能发展为其他过敏性疾病，如过敏性支气管炎和过敏性鼻炎-结膜炎/鼻窦炎(“花粉热”)。这种被称为“特应性病程”的进展在cAD中不被识别。

 

Clinical diagnosis. The clinical diagnosis of cAD follows exclusion of other causes of pruritus and a response to anti-inflammatory therapy, and may be supported by a demonstrated reaction to a particular allergen via intradermal testing or serum-based allergen testing. Most of the clinical lesions recognized with cAD are secondary to self-trauma and may be complicated by microbial infection (predominately Staphylococcus pseudintermedius or Malassezia spp.). Biopsy is not commonly recommended by dermatologists to support a diagnosis of cAD, but a biopsy may be procured to rule out other dermatoses if lesions are atypical or refractory to standard therapies. A detailed set of clinical diagnostic criteria for cAD have been developed and modified over the years as an aid to practitioners and for standardizing clinical trial participants. Presently, the use of the criteria of Favrot is employed in an attempt to differentiate cAD (including non-food-induced and food-induced cases) from other non-cAD conditions.

临床诊断。cAD的临床诊断需要排除其他病因引起的瘙痒和对抗炎治疗的反应，并可能通过皮内试验或血清过敏原试验证实对特定过敏原有反应来支持。cAD的大多数临床病变是继发于自我损伤，并可能并发微生物感染(主要是假中间葡萄球菌或马拉色菌属)。皮肤科医师通常不建议通过活检来支持cAD的诊断，但如果皮肤病变不典型或标准疗法难治性，可通过活检来排除其他皮肤病。多年来，已经制定并修改了一套详细的cAD临床诊断标准，以帮助执业医师和规范临床试验参与者。目前，Favrot标准被用于区分cAD(包括非食物诱发和食物诱发的病例)和其他非cAD疾病。

 

The common lesions of cAD include erythema, alopecia, and lichenification of haired skin in the perioral, periocular, ventral and pedal regions (Fig. 1a–h), and flexural surfaces (Fig. 1a–c, g). Pedal lesions may also include nodular interdigital cysts/furunculosis (Fig. 1e). Dogs may have a history of chronic or repeated episodes of otitis externa, which has been reported as the initial presenting complaint in 43% of dogs with cAD. There are common variations to the distribution of lesions that are somewhat breed-dependent. These phenotypes have been reviewed by Wilhelm et al. A prospective study by Picco et al showed that cAD and CAFRs/food allergy (see below) are indistinguishable based on clinical presentation. Therefore, practitioners may use the term cAD to cover both food-induced and non-food-induced cAD cases. It is not clear whether food-induced cAD shares the same pathogenesis as other environmental allergens or if it is a manifestation of CAFR without concurrent gastrointestinal signs. Based on current studies, the engrained dogma that lesion distributions vary between cAD and CAFRs (ie, that food allergic dogs frequently present with otitis and perianal dermatitis or “ears and rears”) is no longer supported.

cAD的常见病变包括口周、眼周、腹侧和足部区域记忆屈曲面(图1a-c, g)的有毛皮肤的发红、脱毛和苔藓化(图1a-h)。足部病变也可能包括结节性指间囊肿/疖病(图1e)。犬可能有慢性或反复发作的外耳炎病史，据报道，43%患cAD的犬的初始主诉为外耳炎。病变的分布有一些常见的多样性，在一定程度上依赖于品种。Wilhelm等对这些表型进行了综述。Picco等人的一项前瞻性研究表明，根据临床表现，cAD和cCAFR/食物过敏(见下文)无法区分。因此，医师可以使用术语cAD来涵盖食物诱发和非食物诱发的cAD病例。目前尚不清楚食物诱导的cAD是否与其他环境过敏原具有相同的发病机制，或者是否只是CAFR的一种表现，但不伴有胃肠道症状。基于目前的研究，cAD和CAFR之间病变分布不同的根深蒂固的教条(即食物过敏的犬经常出现耳炎和肛周皮炎或“耳朵和背部”)不再得到支持。

 

Clinical differential diagnoses for cAD may include other allergic skin diseases such as CAFR, ectoparasitism, Malassezia dermatitis (MD; Fig. 1g), ADR, and pemphigus foliaceus. In senior dogs, epitheliotropic cutaneous lymphoma may mimic the inflammatory lesions and pruritus that are typical of cAD, and a biopsy may be indicated.

cAD的临床鉴别诊断可能包括其他过敏性皮肤病，如CAFR、外寄生虫病、马拉色菌皮炎(MD;图1g)、ADR和落叶型天疱疮。在老年犬中，嗜上皮性皮肤淋巴瘤可能与典型cAD的炎症病变和瘙痒相似，可能需要进行活检。

 

Histopathologic findings. The primary, consistent histopathologic lesion in cAD is superficial perivascular dermatitis (Fig. 1j, k). In terms of achieving a final diagnosis, this is the least helpful of the dermatopathologic patterns. The degree of inflammation in cAD can be minimal. As the clinical lesions of cAD are secondary to surface trauma and microbial infection, the histopathologic changes encountered in a biopsy, especially in chronic refractory cases, are no different. Epidermal hyperplasia, surface-oriented inflammation, edema, superficial fibroplasia, and pustules or folliculitis associated with secondary microbial infection are often the predominant findings. The histopathologic changes only allow for exclusion of other differentials and to support the clinician’s observations. The pathologist must correlate their findings with the clinical distribution of lesions. Clinical photos or body maps, in addition to lesion descriptions, may be useful.

组织病理学结果。cAD的主要一致的组织病理学病变是浅表血管周皮炎(图1j, k)。在最终诊断方面，这是皮肤病理学模式中帮助最小的。cAD的炎症程度可以很轻。由于cAD的临床病变是继发于表面创伤和微生物感染，在活检中遇到的组织病理学改变，特别是慢性难治性病例，没有什么不同。主要表现为表皮增生、表面向下的炎症、水肿、浅表纤维增生以及与继发微生物感染相关的脓疱或毛囊炎。组织病理学改变仅允许排除其他鉴别，并支持临床医师的观察结果。病理学家必须把他们的发现与病变的临床分布联系起来。除了病变描述外，临床照片或机体分布图可能也有用。

 

Canine atopic dermatitis is associated with perivascular mononuclear dermatitis with varying degrees of eosinophilic and neutrophilic infiltrates. Early in the course of disease or in nonlesional atopic skin, the degree of inflammation can be minimal. As lesional skin is generally biopsied, the degree of inflammation may range from mild to severe, and other chronic histologic changes are often prominent, including epidermal hyperplasia and acanthosis, spongiosis, sebaceous gland hyperplasia, and variable apocrine gland ectasia (Fig. 1j, k). Of note, sebaceous gland hyperplasia in wire-haired fox terriers has been associated with proliferation of Demodex injai and may not represent allergy (Supplementary Fig. S1). This lesion has also been seen by the authors in other terrier dogs. As an extension of the epidermis, follicular walls may be acanthotic and spongiotic (Fig. 1j, k). In the face of chronic inflammation, atrophy of the inferior follicle is common and telogen phase may predominate. Close attention should be paid to the stratum corneum to look for evidence of surface trauma. These changes include compact orthokeratotic hyperkeratosis and foci of parakeratotic hyperkeratosis, presumably from rapid keratinocyte turnover and failure of complete maturation (Fig. 1j, m). Small eosinophilic intraepidermal pustules may be identified. Eosinophilic intracorneal and subcorneal pustules may also be encountered with ectoparasitism, and ectoparasitism (e.g., sarcoptic mange) can easily be misdiagnosed as allergic dermatitis in the absence of surface mites (Fig. 2a). If larger eosinophilic pustules are present, scrutiny for evidence of acantholysis, including step sectioning, is recommended to rule out pemphigus foliaceus (Fig. 2c).

犬特应性皮炎伴有不同程度的嗜酸性粒细胞和中性粒细胞浸润的血管周单核细胞皮炎。在病程早期或非皮肤病变性特应性皮肤中，炎症程度可能很小。由于病变皮肤通常进行活检，因此炎症程度可能从轻度到重度不等，而且其他慢性组织学变化通常很明显，包括表皮增生和棘皮症、海绵样水肿、皮脂腺增生和不同程度的顶浆汗腺扩张(图1j, k)。值得注意的是，丝毛猎狐梗的皮脂腺增生与隐在蠕形螨增生相关，可能不代表过敏(补充图S1)。作者在其他梗犬身上也发现了这种病变。作为表皮的延伸，毛囊壁可能呈棘皮症和海绵样水肿(图1j, k)。面对慢性炎症，毛囊下段萎缩常见，且可能以静止期为主。应密切注意角质层，寻找表面创伤的证据。这些变化包括正角化型角化过度和角化不全型角化过度，推测是由于角质形成细胞快速更新和未能完全成熟导致(图1j, m)。可以发现小的表皮内嗜酸性粒细胞脓疱。角质层内和角质层下的嗜酸性粒细胞脓疱也可能伴有外寄生虫，而外寄生虫(如：疥螨)在没有表面螨虫的情况下很容易被误诊为过敏性皮炎(图2a)。如果有较大的嗜酸性粒细胞脓疱，建议仔细检查棘层松解的证据，包括分段切片，以排除落叶型天疱疮(图2c)。

 

Early in cAD, or during flare states, an eosinophilic inflammatory infiltrate may be present, although this is frequently a minor component of the inflammation described in published studies. As the cytokine profile shifts from a Th2- to a Th1- weighted immune response, the inflammation is more commonly lymphocytic and plasmacytic. Perivascular mast cells may be more numerous and reactive with nuclear prominence. Superficial vascular ectasia may be slight or prominent, occasionally with marginated granulocytes, imparting the erythema seen grossly. A biopsy of nonlesional skin in dogs with cAD may reveal minimal lymphocytic and eosinophilic inflammation without epidermal or adnexal hyperplasia or histopathologic changes may be absent.

在cAD早期或发作期，可能存在嗜酸性粒细胞炎症浸润，但这通常是已发表研究中描述的炎症的次要组成部分。随着细胞因子从Th2免疫应答转变为Th1免疫应答，炎症通常是淋巴细胞性和浆细胞性。血管周围肥大细胞可能更多，并具有核突出的反应性。浅表血管扩张可能轻微或明显，偶尔伴有边缘的粒细胞，形成肉眼可见的发红。cAD犬的非病变皮肤活检可能显示轻微的淋巴细胞和嗜酸性粒细胞炎症，没有表皮或附件增生，或者可能没有组织病理学改变。

 

Pathogenesis of cAD. Categorization as a type 1 (late phase) hypersensitivity reaction oversimplifies the complexity of cAD, whose pathogenesis involves intertwining alterations in the epidermal barrier and dysregulation of immune responses to allergens and commensal microorganisms. An inciting cause has not been pinpointed in cAD as the barrier, immune system, cutaneous microenvironment, and microbes continuously alter one another with multilayered interactions, although genetic predispositions are proposed.

cAD发病机制。将其归类为1型(晚期)超敏反应过度简化了cAD的复杂性，因为cAD的发病机制涉及表皮屏障的改变和对过敏原和共生微生物的免疫应答失调交织在一起。虽然有人提出遗传易感性，但由于屏障、免疫系统、皮肤微环境和微生物通过多层次相互作用不断改变彼此，因此尚未确定cAD的诱因。

 

The epidermal barrier. Primary epidermal barrier dysfunction is likely an early contributor to development cAD. Prior studies have focused on the epidermis as a mechanical barrier, and defects in the epidermis allow for allergen penetration and interaction with an altered immune system. In the process of cornification, filaggrin (FLG, filament aggregating protein) binds keratin tonofilaments to facilitate cell compaction, and its breakdown products (hygroscopic amino acids) are moisturizing and acidifying. In humans, homozygous FLG deletions or loss of function defects causes ichthyosis vulgaris, which is associated with AD in up to 50% of cases. People with heterozygous FLG mutations are also predisposed to AD. It should be noted that many atopic individuals do not have an FLG mutation. In cAD, altered expression of FLG has been proposed based on reduced immunolabeling of FLG in keratinocytes in atopic compared with normal beagles. Chervet et al also demonstrated reduced immunofluorescent labeling of the C-terminus of FLG in corneocytes compared with the N-terminus, supporting a loss of function mutation in cAD. Aside from a group of Labrador retrievers from the United Kingdom, a significant association with specific FLG mutations and cAD has not been made. Altered lipid composition and organization of the stratum corneum are documented in cAD, including reduction in ceramides (a major constituent of extracellular lipids). Keratinocytes also contribute to and respond to the inflammatory environment of cAD via lymphocyte stimulation and act as facultative antigen-presenting cells with varied antimicrobial peptide production (see Supplemental Material).

表皮屏障。原发性表皮屏障功能障碍可能是cAD发生的早期因素。之前的研究将表皮作为一个机械屏障，而表皮的缺陷使过敏原能够穿透并与改变的免疫系统相互作用。角化过程中，丝聚合蛋白(FLG)与角蛋白张力丝结合促进细胞致密化，其分解产物(吸湿性氨基酸)具有保湿酸化作用。在人类中，FLG纯合缺失或功能缺陷的缺失会导致寻常型鱼鳞病，多达50%的病例与AD相关。具有杂合性FLG突变的人也易患AD。值得注意的是，许多特应性体质的个体并没有FLG突变。在cAD中，与正常比格犬相比，特应性皮炎犬角质形成细胞中FLG的免疫标记减少，因此有人提出FLG的表达发生改变。Chervet等人也证明了角化细胞中FLG的c端与n端相比免疫荧光标记减少，支持cAD的功能缺失突变。除了一组来自英国的拉布拉多寻回犬外，尚未发现与特定FLG突变和cAD有显著关联。cAD患犬的角质层脂质成分和组织发生改变，包括神经酰胺(细胞外脂质的主要成分)减少。角质形成细胞也通过淋巴细胞刺激促进cAD的炎症环境并对其做出反应，并作为具有不同抗菌肽产生的兼性抗原提呈细胞(见补充材料)。

 

The immune response. Investigations into the immune response of cAD have recently revolutionized treatment strategies in veterinary dermatology with the small molecule inhibitor oclacitinib (Apoquel; Zoetis, Parsippany, NJ, USA) and the advent of the monoclonal antibody lokivetimab (Cytopoint, Zoetis), which targets interleukin (IL)-31. Oclacitinib is a member of the Janus kinase/signal transducers and activators of transcription (JAK/ STAT) family. Oclacitinib is a nonselective JAK inhibitor, but it predominately inhibits JAK1 and the function of JAK1-dependent cytokines (IL-2, IL-4, IL-6, IL-13, and IL-31). Lokivetimab is a caninized anti-canine IL-31 monoclonal antibody which neutralizes IL-31 and prevents it from binding to dorsal root ganglia of pruritogenic peripheral nerve endings. Calcineurin inhibitors (eg, cyclosporin) are also used commonly in an attempt to avoid adverse effects of chronic glucocorticoid therapy and inhibit T-cell proliferation via inhibition of IL-2 production. Atopica (Elanco, Greenfield, IN, USA) is a modified cyclosporine labeled for refractory AD in dogs and cats. Understanding the complex cutaneous immune environment gives context to these therapies and may provide avenues for future therapeutic success.

免疫反应。对cAD免疫反应的研究最近彻底改变了兽医皮肤科的治疗策略，小分子抑制剂奥拉替尼以及靶向白细胞介素(IL)-31的单克隆抗体洛基维特单抗的问世。奥拉替尼是Janus激酶/信号转导和转录激活因子(JAK/ STAT)家族成员。奥拉替尼是一种非选择性JAK抑制剂，但它主要抑制JAK1和JAK1依赖性细胞因子(IL-2、IL-4、IL-6、IL-13和IL-31)的功能。洛基维特单抗是一种犬源化抗犬IL-31单克隆抗体，可中和IL-31并防止其与致痒性周围神经末梢的背根神经节结合。钙调磷酸酶抑制剂(如环孢素)也常用于避免慢性糖皮质激素治疗的不良反应，并通过抑制IL-2生成来抑制T细胞增殖。阿托皮卡是一种改良的环孢素，用于治疗犬和猫的难治性AD。了解复杂的皮肤免疫环境可以为这些疗法提供背景，并可能为未来的治疗成功提供途径。

 

Inflammation in AD is predominately lymphocytic, and in cAD increased numbers of T cells are present in lesional and nonlesional skin. Evidence supports that Th-2 weighted immune responses are involved in the development/sensitization and perpetuation of cAD, but with disease progression the immune response appears to shift to a mixed Th-1/Th-2 or Th-1 predominance.This may coincide with overlapping microbial infection. Cutaneous mRNA profiling in cAD has demonstrated increased IL-4 (which stimulates IgE production) and IL-5 in lesional skin. Others have failed to detect differences in the levels of IL-4 in cAD and healthy skin, although this may speak to disease chronicity and shifting away from a Th-2 predominant cytokine profile. IL-31 is produced by activated Th2 cells, mast cells, dendritic cells, eosinophils, and basophils and is a potent inducer of pruritus in dogs; hence, the target of lokivetimab and oclacitinib in breaking the itch-scratch cycle. Other Th subsets are more recently highlighted as contributory to the cytokine profile in cAD, including Th9 (IL-9 promotes mast cell growth, cytokine production, and regulatory T-cell stimulation) and Th22 (IL-22 plays a role in epithelial proliferation and differentiation, and antimicrobial peptide production), and upregulation of both IL-9 and IL-22 has been demonstrated in dogs.

特应性皮炎的炎症主要是淋巴细胞性的，而cAD患犬的皮肤病变和非皮肤病变皮肤中T细胞数量增加。有证据表明，Th-2免疫反应参与了cAD的发生、致敏和持久，但随着疾病的进展，免疫反应似乎向Th-1/Th-2或Th-1混合优势转变。这可能与重叠的微生物感染相吻合。cAD患犬的皮肤mRNA表达谱显示，皮肤病变皮肤中IL-4(刺激IgE产生)和IL-5升高。其他研究未能检测到cAD和健康皮肤中IL-4水平的差异，但这可能与疾病的慢性和脱离Th2主导的细胞因子谱有关。IL-31由活化的Th2细胞、肥大细胞、树突状细胞、嗜酸性粒细胞和嗜碱性粒细胞产生，是犬瘙痒的强效诱导剂。因此，洛基维特单抗和奥拉替尼在打破瘙痒-抓挠循环方面的靶点。其他Th亚群最近被强调对cAD的细胞因子谱有贡献，包括Th9 (IL-9促进肥大细胞生长，细胞因子产生和调节性T细胞刺激)和Th22 (IL-22在上皮细胞增殖和分化和抗菌肽产生中起作用)，并且在犬中也证明了IL-9和IL-22的上调。

 

Dermal mast cells can degranulate following IgE cross linking as well as with IgE-independent pathways. Studies have reported varied results on whether or not mast cell numbers in the skin of cAD are increased, decreased, or similar compared with normal dogs.It is the authors’ impression that they are more numerous or prominent in lesional skin of cAD. Mast cell degranulation allows for the release of histamine, leukotrienes, prostaglandins, proteases, and cytokines that promote vasodilation, eotaxis, and the Th2 immune response.

皮肤肥大细胞可在IgE交联后脱颗粒，也可通过非IgE依赖性途径脱颗粒。与正常犬相比，cAD犬皮肤中的肥大细胞数量是增加、减少还是相似，已有研究报道了不同的结果。作者的印象是，在cAD的皮肤病变中，其数量较多或突出。肥大细胞脱颗粒可释放组胺、白三烯、前列腺素、蛋白酶和促进血管舒张、趋化和Th2免疫应答的细胞因子。

 

The presence of an eosinophilic infiltrate in canine skin, even if mild, should prompt an evaluation for or a suspicion of a hypersensitivity response (not solely type I). The degree of eosinophilic infiltration in studies evaluating the skin of dogs with cAD is highly variable. Circulating eosinophilia and neutrophilia have been reported to be significantly higher in dogs with cAD compared with normal dogs. Neutrophilic infiltrates are also variable, and less contributory toward a diagnosis as they may be a reflection of a superimposed infection. Basophils are rarely reported in association with cAD, though are more frequently implicated in the cutaneous allergic immune response in human and mouse studies. This may be due to lack of detection in routine histology and a lack of a validated immunohistochemical assay for canine basophils.

犬皮肤中出现嗜酸性粒细胞浸润，即使是轻度，也应提示评估或怀疑超敏反应(而不仅仅是I型)。在评估cAD犬皮肤的研究中，嗜酸性粒细胞浸润的程度有很大差异。据报道，与正常犬相比，cAD犬的循环嗜酸性粒细胞和中性粒细胞显著增多。中性粒细胞浸润也有差异，但对诊断的帮助较小，因为它们可能反映了叠加感染。嗜碱性粒细胞与cAD相关的报道很少，但在人类和小鼠的研究中，嗜碱性粒细胞更多地与皮肤过敏免疫反应有关。这可能是由于在常规组织学中缺乏检测，以及缺乏犬嗜碱性粒细胞经过验证的免疫组化检测。

 

Microbial interactions. The cutaneous microenvironment contains a complex ecosystem of commensal bacteria and fungi, including potential pathogens. Abnormal shifts in the cutaneous microflora (dysbiosis) are documented in both AD and cAD. In dogs with cAD, reduced bacterial diversity in lesional and nonlesional atopic skin and increased proportions of Staphylococcus spp. have been shown with both culture-dependent and culture-independent methods. S. pseudintermedius, followed by Staphylococcus schleiferi, both of which may be identified as commensals, are the most frequently detected pathogens in canine bacterial dermatitis and folliculitis (Fig. 1f), whereas Staphylococcus aureus is most associated with AD in people. Lesional skin in cAD may harbor more bacteria, particularly Staphylococcus, compared with normal skin. Whether this is due to an altered keratinocyte barrier, changes in the chemical microenvironment, or decreased antimicrobial peptide production is unclear. Increased colonization may lead to pruritus and contribute to clinical signs of cAD. Lesions of bacterial dermatitis and folliculitis may manifest clinically as “moth-eaten” alopecia, papules, pustules, crusts, and collarettes (Fig. 1f). The bacterial infection and the subsequent inflammatory response may mask or exacerbate the histopathologic changes, including the superficial perivascular dermatitis and epidermal hyperplasia seen in cAD.

微生物相互作用。皮肤微环境包含一个复杂的共生细菌和真菌生态系统，包括潜在的病原体。皮肤微生物群的异常变化(生态失调)在AD和cAD中均有记录。在患cAD的犬中，培养依赖和非培养方法均显示出皮肤病变和非皮肤病变性特应性皮肤的细菌多样性减少，葡萄球菌属的比例增加。假中间葡萄球菌，其次是施氏葡萄球菌，这两种细菌可能是共生的，是犬细菌性皮炎和毛囊炎中最常检出的病原体(图1f)，而金黄色葡萄球菌与人类特应性皮炎的相关性最高。与正常皮肤相比，cAD患犬皮肤病变处可能携带更多细菌，以葡萄球菌为主。这是由于角质形成细胞屏障的改变、化学微环境的变化还是抗菌肽生成减少，目前尚不清楚。增加的定植可能导致瘙痒，并有助于cAD的临床症状。细菌性皮炎和毛囊炎的皮肤病变在临床上可表现为“虫蛀样”脱毛、丘疹、脓疱、结痂和表皮环(图1f)。细菌感染和随后的炎症反应可能掩盖或加剧组织病理学改变，包括在cAD中看到的浅表血管周皮炎和表皮增生。

 

Dermatitis associated with Malassezia overgrowth (Malassezia dermatitis, MD) is typically pruritic, erythematous, and may exacerbate lesions and discomfort in cAD. Secondary lesions of MD include excoriation, lichenification, hyperpigmentation, and intertrigo (Fig. 1g). Paronychia (inflammation of the claw bed), often with red-brown discoloration of the claw and hair, and ceruminous otitis are commonly identified with MD. To further complicate the matter, type I hypersensitivity reactions to Malassezia pachydermatis extracts have been reported in atopic dogs. Malassezia may not only act as an opportunistic pathogen but also as an allergen. Hyperplastic dermatosis of West Highland white terriers is a rare disease, formerly referred to as epidermal dysplasia of West Highland white terriers or colloquially as “armadillo Westie syndrome” (Fig. 1g). Based on the prevalence of MD in this condition, and prior case reports of concurrent cAD, it is likely that this represents either a severe allergic response with secondary MD or an allergic response to Malassezia itself. Histopathologic findings of MD in dogs overlap those with cAD and may include patchy parakeratotic hyperkeratosis, irregular epidermal hyperplasia, edema, and lymphocyte exocytosis (Fig. 1k, l) T-cell-predominant superficial perivascular dermatitis is generally present. Yeast is inconsistently present histologically.

与马拉色菌过度增殖(马拉色菌皮炎，MD)相关的皮肤病典型表现为瘙痒、发红，并可能加剧cAD的皮肤病变和不适。MD的继发性病变包括抓痕、苔藓样化、色素沉着和间擦疹(图1g)。甲沟炎(爪床炎症)(通常伴有爪和毛发的红棕色变色)和耵聍性耳炎通常被认为是MD。使问题进一步复杂化的是，在特应性疾病犬中有对厚皮马拉色菌提取物的I型超敏反应。马拉色菌不仅可能是一种条件致病菌，也可能是一种过敏原。西高地白梗的增生性皮肤病是一种罕见疾病，以前称为西高地白梗的表皮发育不良，俗称为“西部犰狳综合征”（“armadillo Westie syndrome”）(图1g)。根据MD在这种情况下的患病率，以及之前并发cAD的病例报告，这可能代表继发性MD的严重过敏反应或马拉色菌本身的过敏反应。犬MD的组织病理学表现与cAD重叠，可能包括斑片状角化不全性角化过度、不规则表皮增生、水肿和淋巴细胞外排(图1k, l)，普遍存在以T细胞为主的浅表血管周皮炎。酵母菌在组织学上呈现不一致。

 

CAFRs and Food Allergy/Sensitivity

CAFR和食物过敏/食物敏感

CAFRs in dogs encompass cutaneous lesions secondary to food allergy and food intolerance. Food intolerance is due to an alternate pathogenesis with maldigestive/malabsorptive enteropathies, toxicities, or idiosyncratic causes of cutaneous, enteric, or other signs. Food allergies (also known as food sensitivities) are caused by an amplified immune response to a dietary antigen. Clinical manifestations of CAFR with an allergic phenotype (food allergy) include pruritus or urticaria with or without gastrointestinal signs. Strictly speaking, to date most cases of food allergy reported in the veterinary literature fall under the broader umbrella of CAFR as immunologic profiling of reported cases has not been routinely performed. Cutaneous lesions of food allergy are clinically indistinguishable from cAD and dermatologists/clinicians may refer to this as food induced cAD when there is a lack of gastrointestinal signs, as discussed above. The gold standard for diagnosis of a CAFR (including food allergy) is an elimination diet trial (including novel or hydrolyzed protein diets) followed by food-item provocation. Serum food-specific IgE and IgG elevations in dogs demonstrate low repeatability and poor accuracy in documentation of food allergy and intradermal testing is also unreliable for a diagnosis. Histopathology of the gastrointestinal tract is nondiscriminatory for differentiating CAFR or food allergy from other causes of chronic enteritis/inflammatory bowel disease. The recommendations for the duration of an elimination diet trial vary, but an elimination trial of 8 weeks may provide upward of 90% sensitivity for a diagnosis.

犬CAFR包括继发于食物过敏和食物不耐受的皮肤病变。食物不耐受是由消化不良/吸收不良的肠病、毒性反应或食物特异性反应，导致的皮肤、肠道或其他症状。食物过敏(也称为食物敏感)是由对食物抗原的放大免疫反应引起的。伴过敏表型(食物过敏)的CAFR临床表现包括瘙痒或荨麻疹，伴或不伴胃肠道症状。严格地说，到目前为止，兽医文献中报告的大多数食物过敏病例都属于更广泛的CAFR范畴，因为对报告病例的免疫学分析尚未常规进行。食物过敏的皮肤病变在临床上与cAD难以区分，如上文所讨论，当缺乏胃肠道症状时，皮肤科医师/临床医师可将其称为食物诱发的cAD。诊断CAFR(包括食物过敏)的金标准是在食物激发后进行食物排查试验(包括新奇蛋白或水解蛋白饮食)。犬的血清食物特异性IgE和IgG升高表明食物过敏的重复性和准确性较低，皮内试验也不可靠。胃肠道组织病理学在鉴别CAFR或食物过敏与其他原因的慢性肠炎/炎性肠病方面无鉴别意义。关于食物排查试验的持续时间，建议各不相同，但8周的食物排查试验可能使诊断的灵敏度达到90%以上。

 

Other diagnostic assays have been investigated for CAFRs. Lymphocyte proliferation assays have been reported to have good accuracy (80%), with 100% positive and 50% negative predictability in the diagnosis of CAFR, but these tests are currently only offered in research facilities due to rapid processing requirements. Patch testing (with controlled surface application of a potential allergen and evaluation of a reaction) was found to be accurate and negative predictability was excellent, though positive predictability is low. There was unsatisfactory accuracy of diagnosis with endoscopic evaluation, fecal food-specific IgE, and hair and saliva testing.

已经对CAFR的其他诊断检测法进行了研究。据报道，淋巴细胞增殖检测在诊断CAFR方面具有良好的准确性(80%)，100%的阳性和50%的阴性预测性，但由于快速处理要求，这些检测目前仅在研究机构中提供。斑贴试验(对潜在过敏原进行有控制的表面应用并评估反应)是准确的，阴性可预测性非常好，但阳性可预测性较低。内镜评估、粪便食物特异性IgE、毛发和唾液检测的诊断准确性不理想。

 

No sex predispositions for CAFR are recognized. Breed predilections are infrequently reported for CAFR. Picco et al reported that German shepherd dogs, West Highland white terriers, Boxers, Rhodesian ridgebacks, and Pugs were overrepresented, though many of these breeds are also predisposed to cAD. As the clinical history and the outcomes of treatment are not always discerning between CAFR and non-food-induced cAD, the cutaneous histopathologic findings reported to date for either disease state (as described above) should be viewed in the same light and both should be maintained as differential diagnoses by the pathologist along with ectoparasitism.

目前尚未发现CAFR的性别易感性。CAFR的品种易感性很少被报道。Picco等人报道，德国牧羊犬、西高地白梗、拳击犬、罗得西亚脊背犬和巴哥犬的比例过高，但这些品种中的许多也容易患cAD。由于临床病史和治疗结果并不一定能区分CAFR和非食物诱发的cAD，因此迄今报告的两种疾病情况(如上所述)的皮肤组织病理学检查结果应以相同的角度看待，病理学家应将两者以及外寄生虫作为鉴别诊断加以保持。

 

Flea Allergic Dermatitis

跳蚤过敏性皮炎

Flea allergic dermatitis (FAD; aka flea bite dermatitis, flea bite hypersensitivity) is common and most frequently associated with the bite of Ctenocephalides felis. It is encountered in geographical climes that are favorable to the flea and may be nonseasonal. Dogs may be infested by fleas with little to no clinical signs and flea infestation is not synonymous with FAD. The onset of FAD is generally between 1 and 6 years of age. Clinical lesions are typically distributed along the caudal dorsum, hind legs, and tail base, and chewing may be seen more commonly compared with scratching, licking, and rubbing (Fig. 1i). Alopecia and papular dermatitis may develop. In German shepherd dogs and bulldog-type breeds, fibropruritic nodules may be encountered. Historically, FAD has been associated with pyotraumatic dermatitis or “hot spots” (Fig. 2i), but the relationship is not exactly clear and concurrent cAD is possible. FAD is thought to involve both immediate and late phase type I hypersensitivities. Low-molecular-weight haptens in flea saliva and numerous allergens have been identified by studying IgE reactivity of sera.

跳蚤过敏性皮炎(FAD;又称跳蚤叮咬性皮炎，跳蚤叮咬超敏反应)是最常见的，最常与猫栉首蚤叮咬相关。它发生在对跳蚤有利的地理气候中，可能是非季节性的。犬可能被跳蚤感染，但几乎没有临床症状，跳蚤感染不是FAD的同义词。FAD一般在1 ~ 6岁发病。临床病变通常沿尾背、后腿和尾部底部分布，啃咬可能比抓挠、舔和摩擦更常见(图1i)。可能出现脱毛和丘疹性皮炎。在德国牧羊犬和斗牛犬类型的品种中，可能会遇到纤维性瘙痒结节。从历史上看，FAD与脓性创伤性皮炎或“热斑”相关(图2i)，但两者之间的关系并不完全明确，并发cAD是可能的。FAD被认为包括速发和迟发I型超敏反应。通过对血清IgE反应性的研究，发现了跳蚤唾液中的低分子量半抗原和许多过敏原。

 

Histopathologic changes in known flea bite sites include edema and perivascular dermatitis composed of mast cells, eosinophils, and mononuclear cells with intraepidermal eosinophilic pustules. These findings are variable and histologic lesions in the skin are nonspecific. With flea bites or intradermal testing of flea antigen, erythematous wheals develop within 1 minute and resolve in 2 to 4 hours. At 4 hours, eosinophils predominate (the late phase reaction) with smaller numbers of neutrophils. Chronic lesions are not fully documented in the literature, but superimposed lesions of self-trauma are seen. Further complicating the clinical picture, dogs with cAD may be predisposed to development of FAD, and FAD may be a complicating factor in cAD. Ectoparasitism by mites (e.g., Sarcoptes scabiei, Cheyletiella spp.) may have similar histopathologic findings (Fig. 2a). Again, the diagnostician is left with a reaction pattern supportive of underlying allergic skin disease and/or ectoparasitism, and a final diagnosis is left to the clinician after documentation of disease progression, clinical examination, and response to treatment.

已知跳蚤叮咬部位的组织病理学改变包括水肿和由肥大细胞、嗜酸性粒细胞和伴有表皮内嗜酸性粒细胞脓疱的单核细胞组成的血管周皮炎。这些发现是多变的，皮肤的组织学病变是非特异性的。跳蚤叮咬或跳蚤抗原皮内试验可在1分钟内形成发红风疹，并在2 ~ 4小时内消退。4小时时，嗜酸性粒细胞占主导(迟发期反应)，中性粒细胞数量较少。慢性病变在文献中没有完整的记载，但可以看到自我损伤的叠加病变。进一步复杂化的临床情况是，cAD犬可能易发生FAD, FAD可能是cAD的一个复杂因素。螨虫(例如疥螨、姬螯螨)的外寄生虫可能有类似的组织病理学结果(图2a)。同样，诊断医师会得到一种支持潜在过敏性皮肤病和/或外寄生虫的反应模式，在记录疾病进展、临床检查和对治疗的反应后，最终诊断留给临床医师。

 

Allergic Contact Dermatitis

过敏性接触性皮炎

Allergic contact dermatitis (ACD) is generally considered uncommon to rare, but the incidence may be geographically dependent as it is more frequently reported in tropical and subtropical regions. A definitive diagnosis of ACD is difficult, as it requires restriction and provocation testing and patch testing with the allergen. ACD is more frequently reported in people, with some hypothesizing that the canine haircoat may offer some degree of protection. In addition, ACD in people is most commonly caused by haptens (eg, heavy metals, industrial chemicals, cosmetics) that dogs do not contact. Lesion distribution of ACD is generally along sparsely haired regions of the ventrum, face, ears, scrotum, perineum, and ventral paws or at sites of application of the sensitizing or irritating agent. Differential diagnoses include cAD, ectoparasitism, CAFR, ADRs, infection, and irritant contact dermatitis. ACD and cAD may occur concurrently, which can confound the diagnosis, and historical reports of ACD in dogs should be scrutinized.

过敏性接触性皮炎(ACD)通常被认为不常见或罕见，但发病率可能与地理位置有关，因为它在热带和亚热带地区更常报告。ACD确诊较困难，需进行排查和激发试验和斑贴试验。ACD在人类中更常见，一些假设是犬的被毛可能提供某种程度的保护。此外，人类的ACD最常见的原因是犬不接触的半抗原(如重金属、工业化学品、化妆品)。ACD的病变分布通常沿腹部、面部、耳朵、阴囊、会阴和腹爪的毛发稀疏区域，或在应用致敏或刺激剂的部位。鉴别诊断包括cAD、外寄生虫、CAFR、ADR、感染和刺激性接触性皮炎。ACD和cAD可能同时发生，可混淆诊断，应仔细检查犬ACD的病史报告。

 

ACD is an exaggerated antigen-specific immune response (historically considered a type IV hypersensitivity, but potentially with a component of a type I hypersensitivity) to percutaneous penetration of allergen (haptens), requiring prior exposure/sensitization. This is delineated from irritant contact dermatitis (ICD), which represents a nonspecific inflammatory reaction to an irritating or caustic surface agent, for which prior exposure is not required (though irritants may act as allergens in allergic individuals) for which prior exposure is not required. To date, the pathogenesis of ACD in dogs has not been established, but parallels can be drawn from investigations in people and rodent models. Reported allergens include metals, topical medications and their vehicles (eg, neomycin and propylene glycol), shampoos and topical dermatological products, plastics, cement, wood, and plants (potentially contributing to the geographically variable incidence) including the families Commenlacae (eg, “wandering jew” or “wandering dude,” Tradescantia fluminensis and spiderwort, Tradescantia virginiana) and Amarlidaceae (Hippeastrum), and Trachelospermum asiaticum (Asian jasmine).

ACD是对过敏原(半抗原)经皮渗透产生的过度抗原特异性免疫应答(历史上被认为是IV型超敏反应，但可能包含I型超敏反应的一部分)，需要之前的暴露/致敏。刺激性接触性皮炎(ICD)是一种对刺激性或腐蚀性表面活性剂的非特异性炎症反应，无需事先暴露(尽管在过敏个体中，刺激物可能作为过敏原)。迄今为止，犬的ACD发病机制尚未确定，但可以从人类和啮齿动物模型的研究中得出相似之处。已报道的过敏原包括金属、外用药物及其载体(如新霉素和丙二醇)、香波和外用皮肤病产品、塑料、水泥、木材和植物(可能导致地理发病率不同)，包括Commenlacae科(如“白花紫露草”或“wandering dude”，紫叶水竹草和紫露草属, 紫露草)和Amarlidaceae科(朱顶红属)和亚洲络石(亚洲茉莉)。

 

Histopathologic findings in ACD are nonspecific and inconsistent, and a biopsy sample may be nondiagnostic with a pattern of superficial perivascular to lichenoid dermatitis, potentially with a predominance of neutrophils or eosinophils, and variable spongiosis and vesicle formation. Robust studies on histopathologic findings of ACD in domestic animals are lacking. There may be histopathologic overlap with ICD and ACD, although ICD may impart a more direct cytotoxic effect on keratinocytes with subsequent inflammation. Therefore, careful attention should be paid to epidermal changes, including confluent parakeratosis with variable hyperplasia and spongiosis, compact orthokeratotic hyperkeratosis (ichthyosiform irritant reaction), or necrosis (as a chemical/caustic insult). If there is time for the epidermis to begin to repair following exposure, a band of diffuse parakeratosis in the stratum corneum subtended by a layer of basketweave orthokeratin may be suggestive of a surface irritant.

ACD的组织病理学表现无特异性且不一致，如果活检样本表现为浅表血管周至苔藓样变皮炎，可能以中性粒细胞或嗜酸性粒细胞为主，以及不同程度的海绵样水肿和水疱形成，则可能无法诊断。关于家养动物ACD的组织病理学发现，目前缺乏可靠的研究。ICD和ACD在组织病理学上可能有重叠，但ICD可能对角质形成细胞产生更直接的细胞毒性作用，进而引发炎症。因此，应注意表皮的变化，包括融合了角化不全伴不同程度的增生和海绵样水肿，致密型正角化性角化过度(鱼鳞病样刺激反应)，或坏死(作为化学/腐蚀性损伤)。如果暴露后表皮有时间开始修复，在由一层编织角蛋白覆盖的角质层中出现的弥漫性角化不全可能提示表面刺激物。

 

Urticaria and Angioedema

荨麻疹和血管性水肿

Urticaria (multifocal and coalescing erythematous wheals) and angioedema (Fig. 1h) occur secondary to mast cell degranulation and histamine release, and unlike other erythematous dermatoses lesions blanch under applied pressure (diascopy). These lesions may be encountered with allergic flares, but nonimmunologic mechanisms can also cause mast cell degranulation. Causes include adverse food or drug reactions, arthropod envenomation, excessive heat or cold, and dermatographism. The diagnostician is tasked with ruling out other causes for vasodilatation and edema such as vasculitis, lymphangitis, infectious disease processes, and neoplasia. Urticaria/angioedema may manifest histopathologically as edema with separation of collagen bundles and vascular dilation with minimal inflammation. With chronicity, there may be interstitial fibrosis and interstitial histiocytes engulfing edema fluid. If there is a basophilic tint to the edema (ie, myxedema or mucin), cutaneous mucinosis of shar-pei dogs or hypothyroidism may be considered as histopathologic differentials, but the clinical progression and signalment should be telling.

荨麻疹(多灶性和融合性发红风疹)和血管性水肿(图1h)继发于肥大细胞脱颗粒和组胺释放，与其他发红性皮肤病不同，皮肤病变在压力作用下变白。这些病变可伴发过敏性发作，但非免疫机制也可引起肥大细胞脱颗粒。原因包括食物或药物不良反应、节肢动物中毒、过热或过冷以及皮肤划痕症。诊断医师的任务是排除导致血管扩张和水肿的其他原因，如血管炎、淋巴管炎、感染性疾病过程和肿瘤。荨麻疹/血管性水肿的组织病理学表现为水肿伴胶原束分离和血管扩张，炎症轻微。慢性时，可能出现间质纤维化和间质组织细胞吞噬水肿液。如果水肿处有嗜碱性染色(即黏液性水肿或黏蛋白)，沙皮犬皮肤黏蛋白沉积症或甲状腺功能减退症可能被认为是组织病理学的鉴别，但应注意临床进展和特征。

 

Adverse Reactions to Treatment of Allergy

过敏治疗的不良反应

ADRs to medicaments used to treat chronic hypersensitivities occur and the resultant skin lesions may be biopsied. In these cases, the history and clinical courses may otherwise be supportive of chronic allergic skin disease. The histologic pattern may differ from chronic hyperplastic superficial perivascular dermatitis, as above. Examples of ADRs secondary to the treatment of chronic hypersensitivities include calcinosis cutis, cutaneous and adnexal atrophy with chronic glucocorticoid therapy, and adverse reaction to topical sprays containing betamethasone. Chronic use of cyclosporine or other calcineurin inhibitors has been associated with the development of gingival hyperplasia and lymphoplasmacytic lichenoid psoriasiform dermatosis (Fig. 2b). More recently, opportunistic infections by Burkholderia cepacia complex have been reported in dogs treated with cyclosporine and were associated with severe neutrophilic and pyogranulomatous furunculosis, with potential for progression to sepsis. Other systemic and cutaneous signs associated with cyclosporine therapy are rarely reported. An increased incidence of cutaneous histiocytomas has been reported with oclacitinib therapy versus cyclosporine therapy, but a larger retrospective cohort study showed no increased prevalence of skin masses with oclacitinib therapy versus age-/breed-matched control dogs that were oclacitinib-naïve.

用于治疗慢性超敏反应的药物会发生不良反应，由此产生的皮肤病变可能需要活检。在这些病例中，病史和临床过程可能支持慢性过敏性皮肤病。组织学模式可能不同于上述慢性增生性浅表血管周皮炎。继发于慢性超敏反应治疗的不良反应包括皮肤钙质沉着症、慢性糖皮质激素治疗导致的皮肤和附件萎缩，以及外用含倍他米松喷雾剂的不良反应。长期使用环孢素或其他钙调磷酸酶抑制剂与牙龈增生和淋巴细胞浆细胞苔藓样银屑病样皮肤病的发生相关(图2b)。最近，在接受环孢素治疗的犬中报告了博克霍尔德氏菌复合体的条件致病性感染，并与重度中性粒细胞性和化脓性肉芽肿性疖病相关，有可能进展为脓毒症。与环孢素治疗相关的其他全身和皮肤症状报道很少。据报道，奥拉替尼治疗组的皮肤组织细胞瘤发病率高于环孢素治疗组，但一项更大规模的回顾性队列研究表明，与年龄/品种匹配的对照犬(奥拉替尼-naïve)相比，奥拉替尼治疗组的皮肤肿块患病率并未增加。

 

Other Canine Dermatoses to Consider

其他需要考虑的犬皮肤病

With the commonality of allergic skin disease, the nonspecific histopathologic findings in many cases, and the potential for a disconnect between the clinician and the diagnostician in terms of history, sample acquisition, or communication, there are other entities that the diagnostician should keep in mind to avoid a misdiagnosis or misinterpretation. If the dermal inflammatory infiltrate contains a significant eosinophilic component, other features in the biopsy samples or history may aid in arriving at a correct or more specific diagnosis. In some instances, there may be a history and clinical lesions supportive of chronic allergic skin disease, but the biopsy submitted to the diagnostician may indicate another disease. A few examples are included below.

由于过敏性皮肤病的共性，许多病例的非特异性组织病理学发现，以及临床医师和诊断医师在病史、样本采集或沟通方面可能存在脱节，因此诊断医师应记住其他问题，以避免误诊或误解。如果真皮炎性浸润含有明显的嗜酸性粒细胞成分，活检样本或病史中的其他特征可能有助于作出正确或更特异的诊断。在某些情况下，可能有支持慢性过敏性皮肤病的病史和临床病变，但提交给诊断医师的活检可能提示另一种疾病。下面包括几个例子。

 

Pemphigus Foliaceus

落叶型天疱疮

Pemphigus foliaceus is the most common cutaneous autoimmune disease in dogs with autoantibodies targeting desmocollin 1 of the desmosome and subsequent acantholysis. Pemphigus foliaceus is characterized histopathologically by broad pustules with nondegenerate granulocytes and acantholytic keratinocytes that span multiple adnexal units. Both neutrophils and eosinophils may be present in the dermis and pustules, and the significance of the eosinophilic versus neutrophilic infiltrate is not known.If pustules and crusts are not captured, the resultant histopathologic picture is that of a chronic hyperplastic dermatitis, which is also seen in allergy and pyoderma (Fig. 2c, d). Anecdotally, cases of pemphigus may have a higher incidence of chronic allergic dermatitis, but whether this is a comorbidity, trigger, or a true association is not yet determined. ADRs may have histologic lesions similar to those observed in pemphigus foliaceus.

落叶型天疱疮是犬中最常见的皮肤自体免疫性疾病，其自身抗体靶向攻击桥粒中的桥粒胶蛋白1和随后的棘层松解。落叶型天疱疮的组织病理学特征为跨越多个附件单位的宽脓疱，其中有非退行性中性粒细胞和棘层松解性角质形成细胞。真皮和脓疱中可能同时存在中性粒细胞和嗜酸性粒细胞，嗜酸性粒细胞和中性粒细胞浸润的意义尚不清楚。如果未获得脓疱和结痂，则组织病理学结果为慢性增生性皮炎，这也见于过敏和脓皮病(图2c, d)。据轶事，天疱疮病例的慢性过敏性皮炎发生率可能较高，但这是一种共病、触发因素还是真正的关联尚不确定。ADR可能有与落叶型天疱疮相似的组织学病变。

 

Canine Acute Eosinophilic Dermatitis and Edema

犬急性嗜酸性粒细胞皮炎及水肿

CAEDE (formerly Wells-like syndrome) is an uncommon syndrome in dogs with an acute presentation of erythroderma and edema, and in most cases is associated with gastrointestinal signs preceding or concurrent with skin lesions.Skin lesions may manifest as generalized violaceous erythroderma (Fig. 2d, e), plaques, red targetoid macules, or patches. While most dogs fully recover, systemic signs may be severe and potentially fatal leading to euthanasia or death (multiorgan failure). Peripheral eosinophilia may be encountered along with hypoproteinemia and hypocholesterolemia, which are attributed to vascular leakage with marked peripheral edema. Holm et al first reported on this condition in a case series of dogs, drawing clinical comparisons with Wells syndrome in people. The gastrointestinal signs are not attributed to a specific gastrointestinal disease and are not universally present. ADR has also been investigated as a putative cause retrospectively, and many cases have a recent history of treatment with drugs directed at enteric disturbances. However, not all cases have positive drug associations when subjected to a scoring rubric. Histopathologic patterns associated with CAEDE, which were reported by Cain et al, encompass a spectrum of severity. Inflammatory patterns range from mild superficial inflammation with vascular ectasia (pattern 1), moderate mid-dermal to superficial dermal inflammation and edema (pattern 2), to severe and diffuse eosinophilic infiltrates in the dermis with edema, variable epidermal vesiculation, and the formation of collagen flame figures (pattern 3). The histopathologic pattern can overlap with AD, especially in patterns 1 and 2, but key discriminating features include abrupt onset, often with gastrointestinal signs, lack of histologic features of chronicity (epidermal, adnexal hyperplasia), and dramatic erythema with relatively sparse inflammation in pattern 1 (Fig. 2f). Distinguishing eosinophils from neutrophils in CAEDE can be difficult due to eosinophil degranulation, but may be aided by a Luna stain. An attempt to distinguish CAEDE from sterile neutrophilic dermatosis should be made. Sterile pustular erythroderma of miniature schnauzers may also contain an eosinophilic infiltrate and can have overlapping histopathologic features of CAEDE (pattern 3) and sterile neutrophilic dermatosis.

CAEDE(以前称为Wells样综合征)是一种罕见的综合征，在犬中以红皮病和水肿为急性表现，在大多数病例中与胃肠道症状相关，在皮肤病变之前或同时发生。皮肤病变可表现为泛发紫红色红皮病(图2d、e)、斑块、红色靶样斑点或斑片。虽然大多数犬完全康复，但全身症状可能很严重，可能致命，导致安乐死或死亡(多器官衰竭)。外周血嗜酸性粒细胞增多可伴有低蛋白血症和低胆固醇血症，这可归因于血管渗漏伴明显的外周水肿。Holm等人首先在犬的病例系列中报告了这种情况，并将其与人类的Wells综合征进行了临床比较。胃肠道症状不能归因于特定的胃肠道疾病，也不是普遍存在的。ADR也被作为推定的原因进行了回顾性调查，许多病例近期有针对肠道紊乱的药物治疗史。然而，根据评分标准，并非所有病例都与药物呈正相关。Cain等报道了CAEDE相关的组织病理学模式，包括一系列严重程度。炎症模式包括轻度浅表炎症伴血管扩张(模式1)，中度真皮中至浅表炎症和水肿(模式2)，以及真皮内重度和弥漫性嗜酸性粒细胞浸润伴水肿、不同程度的表皮水疱形成和胶原火焰图形成(模式3)。组织病理学模式可与AD重叠，尤其是模式1和2，但关键的鉴别特征包括突然发病。通常有胃肠道症状，缺乏慢性组织学特征(表皮、附件增生)，模式1中有明显的发红和相对稀疏的炎症(图2f)。由于嗜酸性粒细胞脱颗粒，CAEDE中的嗜酸性粒细胞和中性粒细胞可能难以鉴别，但Luna染色可能有助于鉴别。应尝试区分CAEDE与无菌性中性粒细胞性皮肤病。小型雪纳瑞的无菌性脓疱性红皮病也可能含有嗜酸性粒细胞浸润，并可能有CAEDE(模式3)和无菌性中性粒细胞性皮肤病的重叠组织病理学特征。

 

Eosinophilic Furunculosis of the Face

面部嗜酸性粒细胞疖病

Eosinophilic furunculosis of the face is an uncommon skin disease in dogs that is clinically distinctive and is characterized by an eruption of papules, pustules, and ulcerative plaques on the dorsal muzzle/nasal bridge (Fig. 2g). The periocular region, pinna, and rarely other foci of haired skin are involved. No breed predispositions are reported, though anecdotally younger to middle-age large breed dogs may be overrepresented. There have been suggestions that bites or stings be an inciting cause with a subsequent hypersensitivity reaction.The signalment, rostral muzzle location, and marked eosinophilic inflammation are the compelling factors that support the hypothesis that this is due to an insect bite hypersensitivity reaction (eg, Hymenoptera bites/stings).

面部嗜酸性粒细胞疖病在犬中是一种罕见的皮肤病，其临床特征是在鼻背/鼻梁上出现丘疹、脓疱和溃疡性斑块(图2g)。眼周区域、耳廓和罕见的其他毛发皮肤病灶均患病。没有品种易感性的报告，虽然轶事的年轻中年大型品种犬可能代表过多。有证据表明，叮咬或蜇伤是引发过敏反应的诱因。特征、口鼻部位置和明显的嗜酸性粒细胞炎症是支持昆虫叮咬过敏反应(如膜翅目叮咬/蜇伤)这一假设的令人信服的因素。

 

Typical histopathologic findings are severe eosinophilic folliculitis and furunculosis with necrosis and disruption of the follicular outer root sheath and a massive dermal infiltrate consisting of eosinophils and fewer neutrophils (Fig. 2h). The attendant inflammation may become granulomatous over time. Lesions typically respond rapidly to systemic glucocorticoid therapy.

典型的组织病理学表现为严重的嗜酸性粒细胞毛囊炎和疖病，伴有坏死和毛囊外根鞘断裂，以及由嗜酸性粒细胞和少量中性粒细胞组成的大量真皮浸润(图2h)。随着时间的推移，伴随的炎症可能变成肉芽肿性。皮肤病变通常对全身性糖皮质激素治疗反应迅速。

 

Zinc-Responsive Dermatosis

锌反应性皮肤病

Eosinophils can be identified as a superficial perivascular infiltrate in some cases of zinc-responsive dermatosis, which are seen most frequently in the Siberian husky and other Nordic breed dogs. The lesions are variably pruritic. It is not clear whether these are dogs with concurrent allergic skin disease or whether this infiltrate resolves with zinc supplementation. Although parakeratosis may be encountered from surface trauma and increased keratinocyte turnover, in zinc-responsive dermatosis the parakeratosis is generally more diffuse with involvement of the follicular ostium. In the authors’ experience, clinical histories are not typically supportive of concurrent allergic skin disease.

在某些锌反应性皮肤病病例中，嗜酸性粒细胞可被识别为血管周围浅表浸润，这种情况最常见于西伯利亚哈士奇和其他北欧犬。皮肤病变有不同程度的瘙痒。目前尚不清楚这些犬是否同时患有过敏性皮肤病，或者这种浸润是否在补充锌后消退。虽然表面创伤和角质形成细胞更新增加可导致角化不全，但在锌反应性皮肤病中，角化不全通常更为弥漫性，并累及毛囊开口。根据作者的经验，临床病史通常不支持并发过敏性皮肤病。

 

Lesions of Surface Trauma

表面损伤病变

Localized lesions secondary to chronic or intense pruritus with or without superficial or deep bacterial infection may be biopsied, including fibropruritic nodules, acral lick dermatitis/granuloma, and pyotraumatic/acute moist dermatitis. Fibropruritic nodules in dogs are exophytic, restricted to the superficial dermis, and are composed of dense collagen, reactive fibroblasts, and a perivascular inflammatory infiltrate. These nodules are grossly distinctive, but may be biopsied to rule out infectious or neoplastic disease processes. The epidermis is markedly hyperplastic with exaggerated rete and may be compact from repetitive surface trauma. The inflammatory infiltrate is often mixed with a combination of lymphocytes, plasma cells, and neutrophils with few eosinophils. Fibropruritic nodules are most frequently encountered on the dorsal lumbosacral region and caudal thighs in association with chronic FAD. German shepherd and bulldog-like breeds may be predisposed. There may be histopathologic overlap with other forms of chronic trauma and dermatitis (eg, acral lick dermatitis/granuloma). Acral lick dermatitis/granulomas tend to occur on the distal limb and are resultant of chronic repetitive surface trauma. Pruritus, secondary to allergic skin disease, may be an inciting factor in some cases. The histopathological lesions may be like that described above, though frequent foci of furunculosis and subsequent granulomatous dermatitis are encountered.

继发于慢性或强烈瘙痒(伴或不伴浅表或深部细菌感染)的局限性皮肤病变可进行活检，包括纤维性瘙痒性结节、肢端舔部皮炎/肉芽肿和化脓性创伤/急性湿性皮炎。犬的纤维性瘙痒性结节是外生的，局限于真皮浅层，由致密的胶原、反应性成纤维细胞和血管周围炎性浸润组成。这些结节宏观上具有特征性，但可进行活检，以排除感染性或肿瘤性疾病过程。表皮明显增生，网状结构夸张，可因表面反复创伤而致密。炎症浸润常与淋巴细胞、浆细胞、中性粒细胞和少量嗜酸性粒细胞混合。与慢性FAD相关的纤维瘙痒性结节最常见于背侧腰骶部和大腿尾端。德国牧羊犬和斗牛犬类型的品种可能有这种倾向。可能与其他形式的慢性创伤和皮炎(如肢端舔部皮炎/肉芽肿)的组织病理学重叠。肢端舔部皮炎/肉芽肿往往发生在肢体远端，是慢性反复表面创伤的结果。在某些病例中，继发于过敏性皮肤病的瘙痒症可能是一种刺激因素。组织病理学病变可能类似上述，但经常出现疖病灶和随后出现的肉芽肿性皮炎。

 

Pyotraumatic dermatitis (colloquially known as “hot spots”) are focal ulcers or plaques that are frequently intensely pruritic (Fig. 2i). These lesions may present acutely and frequently require glucocorticoid therapy to quell the inflammation. There has historically been an association with these lesions and FAD or cAD as the inciting cause of the intense “itch-scratch cycle.” Lesions most frequently occur on the cheek, lateral thigh, neck, and lower back. Histopathological findings include ulcers with superficial neutrophilic inflammation with pustules, folliculitis, and furunculosis variably present. These lesions may or may not have a significant eosinophilic infiltrate.

脓性创伤性皮炎(俗称“热斑”)是经常剧烈瘙痒的局灶性溃疡或斑块(图2i)。这些病变可急性出现，经常需要糖皮质激素治疗来平息炎症。历史上，这些病变与FAD或cAD作为强烈的“瘙痒-搔抓循环”的诱因存在关联。病变最常发生在面颊、大腿外侧、颈部和下背部。组织病理学检查结果包括溃疡伴浅表中性粒细胞性炎症，伴脓疱、毛囊炎和不同程度的疖病。这些病变可能有，也可能没有明显的嗜酸性粒细胞浸润。

 

Other clinical lesions (reviewed by Morris et al) that may be seen in association hypersensitivity reactions include mucocutaneous pyoderma (MCP), lip fold pyoderma, and intertrigo (bacterial and/or yeast overgrowth within skin folds or due to superficial friction, which results in barrier disruption).

可能与超敏反应相关的其他临床病变(Morris等综述)包括皮肤黏膜脓皮病(MCP)、唇褶脓皮病和间擦疹(皮肤皱褶内或由于表面摩擦导致细菌和/或酵母菌过度增殖，导致屏障破坏)。

 

Conclusion

结论

Allergic dermatitis is common in dogs, though challenging to definitively diagnose and treat. Lesions are frequently complicated by self-trauma and microbial infection. Careful consideration of the clinical history of these cases allows for optimal interpretation of biopsy samples and provides a useful clinical aid. As surface-oriented eosinophilic dermatitis may have a similar histopathologic presentation across many diseases, maintaining a broad list of differential diagnoses and scrutinizing nuances in the biopsies and clinical history is essential. The diagnostic pathologist may not be able to provide a definitive diagnosis in many cases of allergy, but they still provide a critical function. The importance of working relationships and strong communication with clinical colleagues to achieve a final diagnosis cannot be overstated.

过敏性皮炎在犬中很常见，但难以明确诊断和治疗。病变常并发自我损伤和微生物感染。仔细考虑这些病例的临床病史可以最佳地解读活检样本，并提供有用的临床辅助。由于许多疾病的表面导向嗜酸性粒细胞皮炎可能有相似的组织病理学表现，因此保持广泛的鉴别诊断列表，并仔细观察活检和临床病史中的细微差别至关重要。诊断病理学家可能无法对许多过敏病例做出明确诊断，但他们仍然提供了关键的功能。工作关系和与临床同事的密切沟通对于最终诊断的重要性怎么强调都不过分。

 

 

Figure 1. Cutaneous hypersensitivity reactions. (a) Canine atopic dermatitis (cAD), American pit bull terrier, dog. Severe periocular, perioral, ventral, and dorsal pedal alopecia and erythema. There is thickening from lichenification and edema of the lips, muzzle, and axillary skin. (b) cAD, ventrum, mixed breed, dog. Coalescing macular and regionally extensive ventral abdominal and inguinal erythema during a flare state. (c) cAD, flank and inguinum, shepherd-mixed breed, dog. Regional alopecia, lichenification, and hyperpigmentation predominately along a flexural surface. (d) cAD, paw, American pit bull terrier, dog. Dorsal pedal erythema, lichenification, and alopecia. (e) cAD, paw, bulldog. Interdigital erythema with nodules corresponding to chronic hyperplastic dermatitis, infundibular hyperkeratosis, and furunculosis. (f) cAD and pyoderma; ventrum, mixed breed dog. Patchy alopecia with erythema, crust, and follicular casts. Aerobic culture isolated Staphylococcus pseudintermedius with cocci identified cytologically. Recurrent bacterial infections are common with cAD (photo courtesy of Dr Peter Canning). (g) Malassezia dermatitis and cAD, West Highland white terrier, dog. Formerly termed epidermodysplasia of West Highland white terriers or “Westie Armadillo Syndrome.” There is severe ventrally oriented to generalized alopecia, lichenification, and hyperpigmentation. (h) Urticaria; ventrum; French bulldog. Multifocal and coalescing erythematous wheals may be seen in flare states of allergic skin disease. (i) Flea allergy dermatitis, Jack Russell terrier, dog. Alopecia, erythema, and multifocal hyperpigmentation. Note that head and neck are spared as lesions are largely attributed to biting/chewing in addition to scratching. (j) Histopathologic findings in cAD; The common histopathologic finding is a mixed perivascular dermatitis including lymphocytes, plasma cells, eosinophils, and occasional neutrophils. Inflammation may be of varying severity in cAD and lesions are nonspecific. The stratum corneum is compact with a surface crust and the epidermis is hyperplastic. There is generalized sebaceous gland hyperplasia. The inset shows a mild perivascular infiltrate of lymphocytes, plasma cells, and eosinophils with moderate spongiosis. Hematoxylin and eosin (HE). (k, l) Histopathologic findings in Malassezia dermatitis and cAD, West Highland white terrier, dog. There is severe epidermal hyperplasia with superficial perivascular dermatitis. There is generalized sebaceous gland hyperplasia. HE. (l) Higher magnification of the surface shows parakeratotic hyperkeratosis (arrow) and compact orthokeratosis with crust containing few cocci and surface yeast with a morphology of Malassezia spp. (arrowhead). HE.

图1。皮肤过敏反应。(a)犬特应性皮炎(cAD)，美国比特犬。严重的眼周、口周、腹侧和足背脱毛和发红。嘴唇、口鼻和腋窝皮肤的苔藓化和水肿使皮肤增厚。(b) cAD，腹，杂交犬。在发作状态下合并的斑点和区域性广泛的腹腹部和腹股沟发红。(c) cAD，体侧和腹股沟，牧羊犬杂交品种犬。沿屈曲面主要出现的区域性脱毛、苔藓化和色素沉着。cAD，爪，美国比特犬。足背发红、苔藓化和脱毛。(e) cAD，爪子，斗牛犬。指间发红伴结节，对应于慢性增生性皮炎、漏斗部角化过度和疖病。(f) cAD和脓皮病;杂交犬。伴有发红、结痂和毛囊管型的斑片状脱毛。需氧培养分离出假中间葡萄球菌，经细胞学鉴定为球菌。反复的细菌感染在cAD中很常见(图片由Peter Canning博士提供)。(g)马拉色菌皮炎和cAD，西高地白梗犬。以前称为西高地白梗的表皮发育不良或“西部犰狳综合征”。有严重的腹侧为主的全身性脱毛、苔藓化和色素沉着。(h)荨麻疹;腹底;法国斗牛犬。过敏性皮肤病发作时可出现多灶性和融合性发红风疹。(i)跳蚤过敏性皮炎，杰克罗素梗犬。脱毛、发红和多灶性色素沉着。请注意，头颈部未发生病变，因为除抓挠外，病变主要归因于啃咬/舔舐。(j) cAD的组织病理学检查结果;常见的组织病理学表现为混合性血管周皮炎，包括淋巴细胞、浆细胞、嗜酸性粒细胞，偶见中性粒细胞。cAD患犬的炎症程度可能不同，病变无特异性。角质层致密，表面结痂，表皮增生。全身皮脂腺增生。插图显示血管周围淋巴细胞、浆细胞和嗜酸性粒细胞轻度浸润，伴中度海绵样水肿。苏木精-伊红(HE)染色。(k, l)马拉色菌皮炎和cAD，西高地白梗犬的组织病理学发现。有严重的表皮增生伴浅表血管周围皮炎。全身皮脂腺增生。HE染色。(1)表面高倍镜显示角化不全性角化过度(箭头)和致密型正角化性角化过度，结痂中含有少量球菌，表面酵母菌呈马拉色菌属(箭头)形态。HE。

 

Figure 2. Adverse reactions to treatment of allergy and other canine dermatoses to consider. (a) Sarcoptic mange, haired skin, dog. There is moderate, superficial eosinophilic inflammation with epidermal hyperplasia. A fragment of a sarcoptic mite is captured burrowing in the superficial epidermis (arrowhead). The histopathologic findings in the absence of the mite overlap extensively with chronic allergic skin disease. The clinical history in this case included intense generalized pruritus. Hematoxylin and eosin (HE). (b) Lymphoplasmacytic psoriasiform lichenoid dermatosis, haired skin, dog. This lesion is often associated with chronic cyclosporine therapy (or other calcineurin inhibitors) and is characterized by discrete, irregular epidermal hyperplasia with hyperkeratosis (orthokeratotic and parakeratotic with colonies of bacterial cocci), small epidermal neutrophilic and eosinophilic pustules and crusts (arrow heads), and a lichenoid band (lacking an interface reaction) predominated by lymphocytes and plasma cells (bracket and higher magnification inset). HE. (c) Pemphigus foliaceus, haired skin, dog. Pemphigus foliaceus is a pustular acantholytic dermatitis. If surface crusts or pustules are lacking, the hyperplastic surfaceoriented inflammation may contain scattered neutrophils and eosinophils with a similar histopathologic pattern of allergic dermatitis. Acantholytic cells are demonstrated in the higher magnification inset. HE. (d, e) Canine acute eosinophilic dermatitis and edema (CAEDE), dog. Diffuse ventral erythroderma and edema with coalescing red papules and macules (photo courtesy of Dr Christine Cain). (f) CAEDE, pattern 1, dog. The dermis is expanded by edema and ectatic blood vessels with a minimal perivascular to interstitial infiltrate containing eosinophils. Note the lack of epidermal hyperplasia as the clinical progression is generally acute and marked. The degree of inflammation may be especially mild considering the degree of clinical erythroderma (d, e). HE. (g) Eosinophilic furunculosis of the face, Australian shepherd dog. Ulcerated and crusted nodules and pustules overlying the nasal bridge and dorsal periocular skin. (h) Eosinophilic furunculosis of the face, muzzle, mixed breed, dog. Severe luminal folliculitis with outer root sheath rupture and eosinophilic dermatitis. The epidermis is acanthotic and spongiotic. The lesion is putatively associated with arthropod bite hypersensitivity. The lower magnification inset demonstrates an adnexal-oriented nodular to diffuse pattern of inflammation predominated by eosinophils. HE. (i) Acute moist/ pyotraumatic dermatitis, face, 1-year-old St. Bernard dog. Severe periauricular erythema, erosions, and ulcers with purulent exudate. These lesions are intensely pruritic and historically are associated with flea allergy dermatitis and/or canine atopic dermatitis (photo courtesy of Dr Elise Enners).

图2。治疗过敏和其他犬皮肤病的不良反应需要考虑。(a)疥螨，有毛皮肤，犬。有中度浅表嗜酸性粒细胞炎症伴表皮增生。在表皮浅层挖洞时捕捉到一只疥螨的碎片(箭头)。无螨的组织病理学发现与慢性过敏性皮肤病广泛重叠。该病例的临床病史包括强烈的全身瘙痒。苏木精-伊红(HE)染色。(b)淋巴细胞浆细胞型银屑病样苔藓样皮肤病，有毛皮肤，犬。这种病变通常与慢性环孢素治疗(或其他钙调神经磷酸酶抑制剂)相关，其特征为离散的不规则表皮增生伴角化过度(正角化型和角化不全伴球菌集落)，小的表皮中性粒细胞和嗜酸性粒细胞脓疱和结痂(箭头)，以及以淋巴细胞和浆细胞为主的带状苔藓样变(缺乏界面性皮炎反应)(括号和高倍镜插图)。HE染色。(c)落叶型天疱疮，有毛皮肤，犬。落叶型天疱疮是一种脓疱性棘层松解性皮炎。如果缺乏表面结痂或脓疱，则表面增生性炎症可能含有散在的中性粒细胞和嗜酸性粒细胞，具有类似过敏性皮炎的组织病理学模式。高倍镜插图显示棘层松解的细胞。HE染色。(d, e)犬急性嗜酸性皮炎水肿(CAEDE)，犬。弥漫性腹侧红皮病和水肿，合并红色丘疹和斑点(图片由Christine Cain医生提供)。(f) CAEDE，模式1，犬。真皮因水肿和扩张的血管而扩张，血管周围至间质有极少量含嗜酸性粒细胞的浸润。由于临床进展通常是急性和显著的，因此注意没有表皮增生。考虑到临床红皮病的程度(d, e)，炎症的程度可能特别轻。(g)面部嗜酸性粒细胞疖病，澳大利亚牧羊犬。鼻梁和眼周背部皮肤上的溃疡性和结痂性结节和脓疱。(h)面部、口吻的嗜酸性疖病，杂交犬。伴有外根鞘破裂和嗜酸性皮炎的严重毛囊腔性毛囊炎。表皮呈棘皮症和海绵样水肿。据推测，这种病变与节肢动物叮咬超敏反应有关。低倍镜下可见以嗜酸性粒细胞为主的炎性反应，呈结节状至弥漫性改变。HE染色。(i)急性湿性/化脓性皮炎，面部，1岁圣伯纳犬。严重耳周发红、糜烂和溃疡伴脓性渗出。这些皮肤病变非常瘙痒，病史与跳蚤过敏性皮炎和/或犬特应性皮炎相关(图片由Elise Enners博士提供)。

 

 

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