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Discriminatory features of acute eosinophilic dermatitis with oedema (Wells-like syndrome) and sterile neutrophilic dermatosis (Sweet’s-like syndrome) in dogs 犬伴水肿性急性嗜酸性皮肤病（Wells样综合征）和无菌性中性粒细胞性皮肤病（Sweet样综合征）的鉴别特征 翻译：侯宁 Background – Canine acute eosinophilic dermatitis with oedema (CAEDE) and sterile neutrophilic dermatosis have overlapping clinical and histopathological features. Hypothesis/Objectives – The objective of this study was to identify features that differentiate these entities. Animals – Forty dogs. Methods and materials – Retrospective case series. Forty cases with diagnoses of either CAEDE and/or sterile neutrophilic dermatosis were included based on histopathological review. Medical records (29 of 40 dogs) were reviewed for clinical findings and historical data. Commercially available immunohistochemical stains for granulocytes and a Luna stain were performed (40 of 40 dogs) to assess the granulocytic infiltrate. Results – Nineteen cases had been previously diagnosed as CAEDE, seven cases had been designated as sterile neutrophilic dermatosis and 14 cases had overlapping features. Based on review and receiver operating characteristic (ROC) curve analysis, 30 cases with >12% eosinophils, enumerated by Luna staining, were diagnosed as eosinophilic dermatitis and oedema. Ten cases were diagnosed as sterile neutrophilic dermatosis. Dogs with CAEDE frequently had gastrointestinal signs (24 of 30;80%) and pruritus (11 of 30;33%). In dogs with sterile neutrophilic dermatosis, five of 10 (50%) had diagnoses of or histories compatible with immune-mediated polyarthropathy. Conclusions and clinical importance – In this case series, CAEDE was encountered more frequently than neutrophilic dermatosis and could be distinguished by the eosinophilic infiltrate, aided by a Luna stain. Concurrent arthralgia was more frequently identified with neutrophilic dermatosis. It remains unclear whether CAEDE and sterile neutrophilic dermatosis are separate disease entities or varied manifestations of the same disease. 背景– 犬伴水肿性急性嗜酸性皮肤病(CAEDE)和无菌性中性粒细胞性皮肤病具有相似的临床和组织病理学特征。 假设/目标– 本研究目的是这两种疾病的鉴别特征。 动物– 四十只犬。 方法和材料– 对一系列病例进行回顾性分析。根据组织病理学检查结果，收纳了40例诊断为CAEDE和/或无菌性中性粒细胞性皮肤病的病例。对(40只犬中的29只)病例的临床表现和病史数据进行回顾分析。通过商品化的粒细胞免疫组化染色和Luna染色(对40只犬中的40只)评估粒细胞的浸润情况。 结果–有19例之前已被诊断为CAEDE，7例被诊断为无菌性中性粒细胞性皮肤病，14例同时具有这两种疾病的特征。根据回顾性分析和受试者特征(ROC)曲线，经Luna染色计数，30例嗜酸性粒细胞> 12%的患犬诊断为伴水肿性嗜酸性皮肤病。10例诊断为无菌性中性粒细胞性皮肤病。CAEDE患犬常出现胃肠道症状(24/30；80%)和瘙痒(11/30；33%)。在无菌性中性粒细胞性皮肤病患犬中，10只中的5只(50%)被诊断患有免疫介导性多关节病或病史与其相符。 结论和临床意义– 在这一系列病例中，CAEDE比中性粒细胞性皮肤病更常见，并且可通过Luna染色根据嗜酸性浸润进行鉴别。并发关节痛更多见于中性粒细胞性皮肤病。目前尚不清楚CAEDE和无菌性中性粒细胞性皮肤病是两种独立疾病，或是同一疾病的不同表现。
Introduction 介绍 Acute granulocytic dermatoses that lack evidence of an infectious cause are diagnostic challenges for dermatopathologists. In these conditions, a single cell type may predominate; but occasionally, there is a mixed inflammatory infiltrate. Canine acute eosinophilic dermatitis with oedema (CAEDE, Wells-like syndrome/WLS) and sterile neutrophilic dermatosis (Sweet’s-like syndrome/ SLS) are uncommon hypersensitivity reactions that cause erythematous and oedematous macules and plaques in dogs. Some authors have likened CAEDE to the human entity of Wells’ syndrome, an eosinophilic and granulomatous cellulitis first reported in 1971, although the histological lesions differ between the canine and human conditions.Sterile neutrophilic dermatosis is a rare disease in dogs, reported in few case studies, that has been compared to acute febrile neutrophilic dermatosis (Sweet’s syndrome) of humans. 缺乏感染证据的急性粒细胞性皮肤病的诊断对皮肤病理学家而言是项挑战。这些情况中，可能出现单一类型细胞明显增多；但偶尔存在混合型炎性浸润。犬伴水肿性急性嗜酸性皮肤病（CAEDE，Wells样综合征/WLS）和无菌性中性粒细胞性皮肤病（Sweet样综合征/SLS）是两种不常见的过敏反应，可引起犬的红斑性和水肿性的斑点和斑块。有些作者会把CAEDE比作人类的Wells样综合征，一种最早报道于1971年的嗜酸性肉芽肿性蜂窝织炎，但犬和人疾病的组织病理学病变不同。无菌性嗜中性粒细胞性皮肤病在犬中罕见，仅有几例病例报道，人们会将其与人的急性发热性嗜中性皮肤病（Sweet样综合征）相对比。
There is both clinical and histological overlap between CAEDE/WLS and SLS (Figures 1 and 2), and their pathogeneses and clinical outcomes are poorly characterized. Histopathological changes may be suggestive of one entity over the other, based on a predominantly eosinophilic or neutrophilic infiltrate; however, when there is a mixture of the two cell types these conditions may be listed as differentials with potentially different prognoses. The objective of this study was to determine if there were clinical or histopathological features of these two conditions that could be used to better differentiate these entities, providing more clarity for prognostic outcomes. CAEDE/WLS和SLS存在临床和组织学上的相同点（图1和图2），其发病机理和临床结果尚不清楚。根据明显的嗜酸性或嗜中性细胞浸润，这种组织病理学的变化可能提示其中一种疾病。但当存在两种细胞类型混合时，应将其列为不同的鉴别类型，预后不同。本研究目的是确认这两种疾病是否能通过临床或组织病理学特征来进行鉴别诊断，从而提供更明确的预后结果。 Figure 1. Clinical lesions from two dogs, one with acute eosinophilic dermatitis with oedema and the other with sterile neutrophilic dermatitis. Canine acute eosinophilic dermatitis with oedema and sterile neutrophilic dermatitis can have overlapping clinical presentations with (a) marked diffuse erythroderma of the ventrum of a dog with acute eosinophilic dermatitis and oedema and (b) erythematous macules and plaques on the ventrum of a dog with sterile neutrophilic dermatitis. 图1. 两只犬的临床病变，一只出现伴水肿性急性嗜酸性皮肤病，另一只出现无菌性嗜中性粒细胞性皮肤病。犬伴水肿性急性嗜酸性皮肤病和无菌性嗜中性粒细胞性皮肤病存在相同的临床表现，（a）一只伴水肿性急性嗜酸性皮肤病患犬腹部典型的弥散性红斑，（b）一只无菌性嗜中性粒细胞性皮肤病患犬腹部可见合并的红斑样斑点和斑块。
Methods and materials 方法和材料 The surgical biopsy database of the School of Veterinary Medicine, University of Pennsylvania, was searched from 1 January 2004 to 31 December 2015 for cases in which skin punch biopsies were evaluated and eosinophilic dermatitis with oedema (CAEDE/WLS) and/or sterile neutrophilic dermatitis (SLS) were considered most likely amongst the pathologists’ differential diagnoses. Cases were excluded if there was evidence to support an infectious disease (folliculitis or furunculosis affecting more than one hair follicle in a submitted biopsy). No infectious agents were identified on haematoxylin and eosin (H&E), Gram and periodic acid Schiff stains applied in all cases for this study. No cases were included if there was evidence of vasculitis (including leucocytoclasia, fibrinoid vascular necrosis or ischaemic dermatopathy). 在宾夕法尼亚大学兽医学院2004年1月1日到2015年12月21日的手术活检病例数据库中，选取病例学家高度怀疑伴水肿性嗜酸性皮肤病（CAEDE/WLS）和/或无菌性嗜中性粒细胞性皮肤病（SLS）并已通过皮肤打孔活检进行鉴别诊断的病例。排除有证据显示为感染疾病的病例（活检可见超过一个毛囊感染的毛囊炎或疖病）。本研究中所有病例经苏木精-伊红染色（H&E）、革兰氏染色和过碘酸席夫染色均未发现感染性病原体。存在血管炎证据（包括白细胞碎裂，纤维素样血管坏死或缺血性皮肤病）的病例需要排除。
Medical records were requested from the submitting veterinarian. Cases were excluded if there was a positive bacterial skin culture or if there was suspicion for an infectious cause based on clinical course. Modified Naranjo drug scoring was performed as described previously. A drug score of 0 was assigned if clinical information was insufficient to document drug exposure or association. Serial sections of the formalin-fixed, paraffin-embedded tissue were processed for H&E staining (to ensure consistency with recut slides), Luna stain as reported previously,and immunohistochemical staining. 从提交病例的兽医师处获得病例。如果皮肤细菌培养阳性或根据临床表现怀疑存在感染，则需排除该病例。按照之前的描述进行改良的Naranjo药物评分。如果药物暴露或相关的临床信息不足则药物评分为0。组织经过福尔马林固定，石蜡包埋后进行连续切片，如前所述进行H&E染色（保证切片的连续性），Luna染色和免疫组化染色。
All cases were reviewed by two of the authors blinded to the initial interpretation and clinical information. Cases were characterized as compatible with CAEDE, SLS or CAEDE/SLS if there was overlap such that the two entities could not be distinguished. On review of H&E stained slides, all of the cases were categorized as patterns 1–3 as reported previously. Briefly, Pattern 1 is characterized by a mild superficial perivascular to interstitial granulocytic infiltrate with dermal oedema, vascular prominence and minimal epidermal hyperplasia. Pattern 2 is characterized by a moderate interstitial infiltrate that extends to the mid-to-deep dermis with oedema, and with or without collagen flame figures (Figure 2a). Pattern 3 is characterized by a more severe interstitial to diffuse inflammatory infiltrate throughout the dermis with epidermal oedema, vesicles or ulcers and frequently has collagen flame figures. 所有病例均由两名不了解初始情况和临床信息的作者进行审核。病例特征符合CAEDE，SLS或CAEDE/SLS表现，如果存在这两种疾病的共同特征就无法进行区别。经H&E染色的切片，按之前报告将所有病例分为1-3型。简而言之，1型的特点为轻度表皮血管周至间质的粒细胞浸润并伴有真皮水肿，血管明显和极少的表皮增生。2型特点为中度的间质浸润并延伸至真皮浅层至深层，伴有水肿，伴有或未伴有胶原火焰图形（图2a）。3型特点为整个真皮层严重的间质性至弥散性炎性浸润，伴有水肿、水疱或溃疡，且常出现胶原火焰图形。
For indirect immunohistochemical evaluation, 5 um serial sections on negatively charged glass slides were used. Immunohistochemical stains included eosinophil myeloperoxidase (EPX), neutrophil myeloperoxidase (NPX) and neutrophil elastase (NE). A BIOCARE intelliPATH Flx ( Biocare Medical; Pacheco, CA, USA) automatic universal staining system was used. Slides were heated in a 60°C oven for 1 h. Deparaffinization and rehydration of slides were obtained in several changes of PRO PAR clearant (Anatech Ltd; BattleCreek, MI, USA) and progressively decreasing grades (from 100% to 95% and to water) of ethanol. Hydrogen peroxide was applied for 10 min to inactivate endogenous peroxidases. Primary antibodies were applied for 30 min at room temperature. All antibodies were commercially available: rabbit polyclonal against EPX (1:50) (PA5-62200, Thermo Fischer Scientific; Waltham, MA, USA), NPX (1:25) (ab9535, Abcam; Cambridge, UK) and NE (1:1,000) (ab68672, Abcam).Target retrieval was performed by immersion in a citrate buffer, pH ~9.0, for ~60 min in a BioCare decloaking chamber. The immunodetection used an EnVisionTM+ kit (DAKO; Carpinteria, CA, USA) containing an ENV mono or poly-HRP enzyme labelled polymer followed by conjugated mouse or rabbit secondary antibody, applied for 30 min and followed by a 5 min buffer wash. Visualization of antibody binding was obtained via DAB+ chromogen (3 min), 3,30-diaminobenzidine solution. Counterstaining was obtained using haematoxylin for 1 min followed by progressive alcoholic dehydration and coverslipping. Positive controls included a canine mast cell tumour for eosinophils, and suppurative (post-grooming) furunculosis for neutrophils. 间接免疫组化评估选取5μm的连续石蜡切片，载玻片带负电。免疫组化染色包括嗜酸性粒细胞过氧化物酶染色（EPX），嗜中性粒细胞过氧化物酶染色（NPX）和中性粒细胞弹性蛋白染色（NE）。使用BIOCARE intelliPATH Flx自动通用染色系统。切片经过60℃烤箱烤片1h。使用不同浓度的PRO PAR clearant，和浓度逐步降低的酒精（从100%到95%再到水）将玻片脱蜡至水。目标抗原修复在BiaCare暴露盒中进行，ph9.0柠檬酸盐缓冲液中浸泡6o分钟。过氧化氢酶消化10分钟以消除内源性过氧化物酶。一抗室温下孵化30分钟。所有抗体为商品化购得：兔抗EPX多克隆抗体（1:50），抗NPX多克隆抗体(1:25) 和抗NE多克隆抗体 (1:1,000) 。免疫检测使用EnVisionTM+试剂盒，试剂盒组成包括单聚或多聚HRP酶标鼠源或兔源二抗，孵育3分钟后用缓冲液冲洗。通过DAB+染液3,3’-二氨基联苯胺盐酸盐（3分钟）使抗体复合物显色。苏木素衬染1分钟后经梯度酒精脱水并封片。阳性对照组包括犬肥大细胞瘤中的嗜酸性粒细胞染色，化脓性（冲洗后）疖病中中性粒细胞染色。通过显微镜观察，每个样本用DP27相机选取五个400倍下的典型视野（0.55mm直径）拍照，并进行嗜酸性粒细胞计数。
Slides were evaluated via microscopy and five representative x 400 fields (0.55 mm field diameter) were photographed with a DP27 camera (Olympus; Tokyo, Japan) in each sample to enumerate the eosinophil population. Images were evaluated in a .tiff format using Adobe Photoshop ELEMENTS 12 (Adobe Inc.; San Jose, CA, USA) with a grid (0.1 mm) overlay. Polymorphonuclear cells closely associated with positive granules were counted as eosinophils and the total number of polymorphonuclear cells in the same fields were counted. The number identified as eosinophils was then divided by the total number of polymorphonuclear cells to establish a percentage of eosinophilia of the dermal infiltrate. Receiver operating characteristic (ROC) curve analysis was performed using the R v3.3.2 software platform and the ROCR package. A one sample proportion test was conducted for each breed within the 40 cases to determine if the proportion differs from the target proportion calculated for the same breeds included in the histopathology database (125,206 total cases). 通过Adobe Photoshop ELEMENTS 12软件给tiff格式的图片覆盖网格（0.1mm）进行评估。含有阳性颗粒的核分叶细胞计为嗜酸性粒细胞，统计同一视野中分叶细胞的总数。将嗜酸性粒细胞的数量除以分叶细胞的总数得到嗜酸性粒细胞真皮浸润的百分数。使用R v3.3.2软件平台和ROCR软件包建立受试者特征（ROC）曲线分析。在40个病例中针对每个犬只品种进行了单个样本比例统计，以确定该比例与组织病理学数据（共计125,206例）中相同品种计算的目标比例是否不同。
Results 结果 Signalment 特点 Forty cases met the inclusion criteria. The median age was 64.5 months (range 12–159 months). Twenty-seven of the dogs were female and 13 of the dogs were male with a 2.07:1 sex ratio. Various breeds were included in this case series. Labrador retriever (6), miniature schnauzer (4), English bulldog (3), pug (3), basset hound (2) and Yorkshire terrier (2) were represented in more than one instance. Three dogs were mixed-breed (Table 1). 四十例病例符合入选标准。患犬平均年龄为64.5个月（从12-159个月）。27只犬为雌性，13只雄性，性别比例为2.07：1。病例系列中包含多品种犬。其中拉布拉多巡回犬（6）、迷你雪纳瑞（4）、英国斗牛犬（3）、巴哥犬（3）、巴吉度猎犬（2）及约克夏梗（2）病例均超过一例。有三只犬为杂交品种（表1）。
Histopathology 组织病理学 All cases had a dermal interstitial granulocytic infiltrate with oedema that varied in degree of severity (Figure 2a, b). Cases were categorized as patterns 1–3 as reported previously. For cases diagnosed as CAEDE, there were six with Pattern 1, seven with Pattern 2 and six with Pattern 3. Cases that had overlapping features included one with Pattern 1, seven with Pattern 2 and three with Pattern 3. SLS cases included four with Pattern 1, two with Pattern 2 and one with Pattern 3. SLS cases generally had a comparable pattern, but the distribution of the infiltrate in Pattern 1 was deeper within the dermis compared to that typically encountered with CAEDE. 所有病例均存在不同程度的真皮间质粒细胞浸润，并伴有水肿（图2a,b）。如前所述病例分为1-3型。诊断为CAEDE的病例中，6例为1型，7例为2型，6例为3型。具有相同特征的病例中包括1例1型，7例2型和3例3型。诊断为SLS的病例包括4例1型，2例2型和1例3型。SLS病例通常具有相似的发病类型，但与典型的CAEDE比例相比1型对于真皮层的浸润程度更深。
The immunohistochemical staining with EPX, NPX and NE demonstrated considerable overlap. NPX and NE stained the cytoplasm of both eosinophils and neutrophils in both case and control samples. At lower dilutions of antibody (1:50), the EPX staining was nonspecific between eosinophils and neutrophils, but at a dilution specific for eosinophils (1:250), the cytoplasmic staining was only slightly more intense than nonspecific background staining (Figure 2c). This staining was not quantifiable. 经免疫组化EPX、NPX和NE染色出现明显的相同表现。病例样本和对照组样本中，NPX和NE均可以着染嗜酸性粒细胞和嗜中性粒细胞的细胞质。但当抗体稀释浓度较低时（1:50），EPX染色在嗜酸性粒细胞和嗜中性粒细胞间是非特异性的，嗜酸性粒细胞在特定稀释浓度（1:250）下细胞质染出的颜色仅稍浓于非特异性的背景染色（图2c）。该染色无法定量。
The EPX was less specific than the Luna stain. The Luna stain demonstrated specific staining of eosinophilic granules (Figure 2d) as reported previously; this was used for final assessment of the degree of dermal eosinophilia. The percentage of eosinophils in the dermal infiltrate of all cases ranged from 0 to 88.06%. Cases diagnosed as CAEDE based on the reviewed histopathological interpretation ranged from 10.08 to 88.06% eosinophilia. Cases diagnosed as SLS ranged from 0 to 9.15% eosinophilia. Cases with overlapping features ranged from 2.15 to 49.5% (Figure 3). EPX的特异性不如Luna染色。如前所述Luna染色可以特异性着染嗜酸性颗粒（图2d）；被用于真皮嗜酸性粒细胞增多程度的最终评估。在所有病例中真皮中嗜酸性粒细胞浸润率的范围为0至88.06%。根据回顾性组织病理学表现诊断为CAEDE的病例中，嗜酸性粒细胞增多的范围为10.08%至88.06%。诊断为SLS的病例中嗜酸性粒细胞增多的范围为0至9.15%。具有相同特征的病例中增多范围为2.15%至49.5%（图3）。
Figure 2. Histopathological findings and immunohistochemical and histochemical stains to highlight eosinophils in dogs with eosinophilic acute dermatitis with oedema and sterile neutrophilic dermatitis. (a)Perivascular to diffuse interstitial granulocytic dermatitis with proteinaceous oedema and dermal haemorrhage, Pattern 2 (Haematoxylin & Eosin, H&E). (b) Distinction between eosinophils and neutrophils is lost with mixed infiltrates and following eosinophil degranulation (H&E). (c) Eosinophil myeloperoxidase (EPX), though specific for eosinophils (darker cytoplasmic staining; arrowhead), produces frequent nonspecific staining of neutrophils (block arrow) and histiocytes. (d) Examples of eosinophilic granules adjacent to intact nuclei (arrow heads) demonstrate specificity for eosinophils with a Luna stain. 图2. 伴水肿性嗜酸性急性皮肤病和无菌性嗜中性粒细胞性皮肤病患犬的组织病理学发现，及免疫组化和组织化学对嗜酸性粒细胞的突出染色。 （a）血管周至弥散性间质性粒细胞性皮肤病，伴有蛋白样水肿和真皮层出血，2型（苏木素和伊红染色，H&E）。（b）嗜酸性粒细胞和嗜中性性粒细胞间的区别在于缺少混合浸润和嗜酸性颗粒脱颗粒（H&E）。（c）嗜酸性粒细胞过氧化物酶（EPX），虽然是嗜酸性粒细胞特异性（细胞质较深染；箭头），但经常会非特异性着染嗜中性粒细胞（粗箭头）和组织细胞。（d） 完整的细胞核旁相邻的嗜酸性颗粒（箭头）例子，表明Luna染色对嗜酸性粒细胞具有特异性。
Classification 分类 Nineteen cases were classified as eosinophilic dermatitis and oedema (CAEDE), seven were classified as neutrophilic dermatitis (SLS) and 14 cases had overlapping features of both conditions (CAEDE/SLS). Follow-up data were available for 15 cases of CAEDE, six cases of SLS and eight cases of CAEDE/SLS. The median times at follow- up were 13.5, 13 and 36 months, respectively. 19例归类为伴水肿性嗜酸性皮肤病（CAEDE），7例被分类为嗜中性粒细胞性皮肤病（SLS），14例具有两种疾病的共同特征（CAEDE/SLS）。回访数据记录了15例CAEDE，6例SLS和8例CAEDE/SLS病例。回访的平均时间分别为13.5个月，13个月和36个月。
In the ROC curve analysis, a cut-off point of 12% (pink line, Figure 3) provided 97.5% of cases classified as CAEDE or SLS with a 95% confidence interval (CI). Cases designated CAEDE/SLS were reclassified as SLS or CAEDE, and clinical data were tabulated with 30 cases as CAEDE and ten cases as SLS (Table 1). Medical records and follow-up information were available for 16 CAEDE cases and seven SLS cases. ROC曲线分析，临界点为12%（粉色线，图3），97.5%的病例分类为CAEDE或SLS，置信区间为95%（CI）。将CAEDE/SLS病例重新分类为SLS或CAEDE病例，将30例CAEDE病例和10例SLS病例的临床数据做成表格（表1）。包含16例CAEDE和7例SLS的病历记录和回访信息。
Cases of CAEDE/SLS were reclassified as described above. One case was recategorized from CAEDE to SLS. No cases initially diagnosed as SLS were reclassified as CAEDE. Following recategorization of the WLS/SLS cases after slide evaluation (below) the features of each condition, including clinical lesions, historical information and drug score, are reported below and in Table 1. Proportion hypothesis testing was performed to determine associations with breed following reclassification. Using the patient population of the biopsy service as a reference, the following breeds were significantly over-represented in those classified as CAEDE: miniature schnauzers four of 30 (P <0.0001), English bulldog three of 30 (P < 0.0001), Bassett hound (P < 0.0001), pug (P < 0.0001) and Yorkshire terrier (P = 0.01). Although Labrador retrievers were represented by more than one case in the dataset (three of 30 for CAEDE and three of 10 for SLS) they were not significantly over-represented compared to the general biopsy database (P = 0.85, 0.057, respectively). Mixed breed dogs (three of 30 CAEDE cases) were not significantly over-represented( P = 0.144). 如前所述对CAEDE/SLS进行重新分类。其中一例CAEDE病例重新分类为SLS。最初诊断为SLS的病例没有需要更改为CAEDE的。经过显微镜观察（下文）对每个疾病的特征进行评定，包括临床病变，组织学信息和药物评分，据此对WLS/SLS重新分类，记录如下见表1。 通过比例假设检验确定重新分类后的品种相关性。以活检中的患犬作为参考，在分类为CAEDE的病例中以下品种的比例明显较多：迷你雪纳瑞4/30（P <0.0001），英国斗牛犬3/30 (P < 0.0001)，巴吉度猎犬(P < 0.0001)，巴哥犬 (P < 0.0001)，约克夏梗 (P = 0.01)。虽然在数据库中拉布拉多巡回犬的病例数量超过一例（30例CAEDE中占3例，10例SLS中占3例），但并没有明显高于大体活检数据(分别P = 0.85, 0.057)。杂交品种犬（30例CAEDE中占3例）比例无明显增高( P = 0.144)。
Table 1. Signalment and clinical data of dogs with eosinophilic acute dermatitis with oedema/Wells’-like syndrome (CAEDE/WLS) and sterile neutrophilic dermatitis (Sweet’s-like syndrome, SLS) 表1 伴水肿性犬嗜酸性急性皮肤病/Wells样综合征（CAEDE/WLS）和无菌性嗜中性粒细胞性皮肤病（Sweet样综合征，SLS）的特征和临床数据
CBC complete blood cell count; Chem serum chemistry, EPI exocrine pancreatic insufficiency, F female, FS female spayed, IMHA immune-mediate haemolytic anaemia, IMPA immune-mediated polyarthropathy, ITP immune-mediated thrombocytopenia, M male, MC male castrated, NSF no significant findings, SLS Sweet’s-like syndrome. *All were euthanized as a result of CAEDE/WLS or SLS. CBC全血细胞计数；Chem血清生化，EPI以胰腺外分泌功能不全，F雌性，FS雌性绝育，IMHA免疫介导性溶血性贫血，IMPA免疫介导性多关节病，ITP免疫介导性血小板减少症，M雄性，MC雄性去势，NSF无明显发现，SLS Sweet样综合征 *所有CAEDE/WLS 或SLS病例均被安乐死 | CAEDE/WLS | SLS | 总计 | | | | | | | | | | | | | | 迷你雪纳瑞（4） 斗牛犬（3） 杂交品种（3） 拉布拉多巡回犬（3） 巴吉度猎犬（2） 巴哥犬（2） 约克夏梗（2） | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 6例特应性皮炎 1例以前患有ITP 1例十五个月前患有IMHA | | | | +3(N=2);+2(N=1);+1 (N = 10) 0 (N = 12) -1(N = 4);-2 (N = 1) | +2 (N = 2); +1 (N = 4) 0 (N = 2) -1 (N = 2) | | | 甲硝唑（6） 硫糖铝（3） 法莫替丁（3） 卡洛芬（2） 免疫 阿莫西林 芬苯达唑 昂丹司琼 丁丙诺啡 乙酰丙嗪 氟喹诺酮 羟乙基淀粉 糖皮质激素 | 卡洛芬（3） 免疫（2） 阿莫西林±克拉维酸（2） 甲硝唑（2） 恩诺沙星 多西环素 噻苯达唑 | | | | | | | | | | | | | |
Figure 3. Violin plots showing distribution of the percentage of eosinophils by disease category, for dogs with eosinophilic acute dermatitis with oedema/Well’s-like syndrome (CAEDE/WLS) and sterile neutrophilic dermatitis (Sweet’s-like syndrome, SLS). The median percentage is demarcated by a white dot. ROC analysis offers a 12% cut point (pink line) for distinguishing CAEDE/WLS from SLS. 图3. 小提琴样图示显示出不同分类的疾病中嗜酸性粒细胞的分布比例，分别为犬伴水肿性嗜酸性急性皮肤病/Wells样综合征(CAEDE/WLS)和无菌性嗜中性粒细胞性皮肤病（Sweet样综合征，SLS）。 平均百分比用白点标注。ROC分析区别CAEDE/WLS和SLS的临界点为12%（粉色线）。
Clinical lesions and historical information 临床病变和病史资料 Clinical lesions consisted of erythroderma, oedema, erythematous maculopapular rashes and coalescing wheals or plaques. The reported lesions were similar between CAEDE and SLS cases with a similar proportion reported with oedema, generalized erythema and papules. Most dogs presented with acute onset ventral (neck, thoracoabdominal or inguinal) to generalized/diffuse erythema and oedema (Table 1). When lesions were described on the face, the pinna was frequently involved. Wheals and plaques were grouped together due to potential overlap in clinical assessment and were present in 30% of CAEDE cases and 50% of SLS cases, and were often reported as coalescing. Two cases reported localized lesions, one of CAEDE at the dorsolateral trunk and one case of SLS with lesions restricted to the thigh and lateral stifle. Thirty-seven percent (11 of 30) of CAEDE cases reported pruritus compared to one of 10 cases with SLS. 临床病变包括红斑，水肿，红斑性斑丘疹和合并性风团或斑块。研究发现CAEDE和SLS病例具有相似的病变，水肿、全身红斑和斑块出现比例相似。大多数犬表现为急性的腹部（颈部、胸腹部或腹股沟）至全身性/弥散性红斑和水肿（表1）。当病变出现在面部时，常累及耳廓。由于在临床评估中风团和斑块可能会出现相同表现，所以将他们分为一类，出现在30%的CAEDE病例中和50%的SLS病例中，并常合并出现。两例病例出现局灶性病变，1例CAEDE病例中病变位于躯干背外侧，1例SLS病例中病变位于大腿和膝外侧。37%（11/30）的CAEDE病例出现瘙痒，而在10例SLS病例中出现1例。
Twenty percent (six of 30) of CAEDE and 50% of SLS cases were reported to be febrile with a mean temperature of 103.5 and 104.3°F, respectively. Gastrointestinal disease was more common in CAEDE at 80% (24 of 30 cases) compared to 60% (six of 10) of SLS cases, with vomition reported most frequently. In all but four cases, the gastrointestinal (GI) signs were acute. Four cases with chronic GI disease included three cases of inflammatory bowel disease in the CAEDE category and one case with SLS of exocrine pancreatic insufficiency, diagnosed eight months before presentation. Second to GI disease, concurrent and chronic atopic dermatitis (AD; food-induced or nonfood-induced) was reported most frequently (20%; six of 30). Immune-mediated polyarthropathy (IMPA; sterile neutrophilic arthritis by arthrocentesis) was diagnosed in three cases with SLS, and two additional cases with SLS reported a steroid responsive lameness with clinical features compatible with IMPA, although arthrocentesis was not performed. One case of CAEDE reported resolved immune-mediated thrombocytopenia three years before and one case of CAEDE was diagnosed with immune-mediated haemolytic anaemia 15 months following biopsy. Two cases with CAEDE had a history of seizures (not otherwise specified). 20%（6/30）的CAEDE病例和50%的SLS病例出现发热症状，平均体温分别为103.5℉（39.6℃）和104.3℉（40.1℃）。胃肠道疾病在CAEDE中更常见有80%（24/30），而SLS病例中为60%（6/10），其中呕吐为最高发症状。除四个病例外其他胃肠道（GI）症状均为急性。4例慢病胃肠道疾病包括CAEDE分类中3例炎性肠病，SLS分类中1例胰腺外分泌功能不全，诊断于就诊前八个月。仅次于胃肠道疾病的慢性并发症中，异位性皮肤病（AD；食物诱发或非食物诱发）是最常见的（20%；6/30）。在SLS病例中诊断出3例免疫介导性发关节病（IMPA；关节穿刺导致的无菌性中性粒细胞性关节炎），另外2例为类固醇反应性跛行，虽未进行过关节穿刺，但其临床特征符合IMPA。1例CAEDE病例在活检15个月后被诊断为免疫介导性溶血性贫血。CAEDE病例中的2例具有癫痫病史（未做另外说明）。
Complete blood count and serum chemistry changes were recorded in 26 cases preceding biopsy. Of the complete blood cell counts reported, 14 of 26 had no significant findings. Mild normochromic normocytic anaemia (haematocrit of 32–39%) was reported in eight dogs, and moderate anaemia (30%) was reported in two dogs. Mild neutrophilia was reported in three dogs (two with SLS and one with CAEDE), and a mild eosinophilia was reported in two dogs with CAEDE. Mild leukopenia was reported in two dogs. Hypoalbuminemia was the most common serum chemistry abnormality identified in 11 dogs (eight CAEDE and three SLS) with a median value of 2.3 g/dL (range 1.0–2.4 g/dL; reference range 2.5–3.7 g/ dL). One case of CAEDE/WLS with hypoalbuminemia had concurrent IBD and suspected protein losing enteropathy. Neoplasia was not noted in this series. 活检前记录26个病例全血细胞计数和血清生化检查结果。在全血细胞计数中，26个病例中14例未见明显异常。8只犬出现轻度正色素正细胞性贫血（红细胞比容32-39%），2只犬出现中度贫血（30%）。3只犬出现轻度嗜中性粒细胞增多（2例SLS病例和1例CAEDE病例），2只CAEDE患犬出现轻度嗜酸性粒细胞增多。两只犬出现轻度白细胞减少。在11只犬中低白蛋白血症是最常见的血清生化异常（8例CAEDE病例和3例SLS病例），平均白蛋白浓度为2.3g/dL（范围1.0-2.4g/dL；参考范围2.5-3.7g/dL）。1例出现低白蛋白血症的CAEDE/WLS患犬同时患有IBD，疑似蛋白丢失性肠病。在这一系列病例中未发现肿瘤疾病。
Drug acore 药物评分 Twenty-seven (19 CAEDE, eight SLS) dogs had sufficient clinical information to generate a drug score. Thirteen dogs with CAEDE/WLS had a positive drug score; of these, two dogs had a 3+ score, one dog had a 2+ score and a weak association (1+) was found in ten cases. Three dogs with CAEDE had a negative drug score (two dogs with 1– and one dog with 2–). In dogs with SLS, six had a positive drug score (1+ in four dogs and 2+ in two dogs) and two had a negative drug score. Metronidazole, carprofen, famotidine, amoxicillin with clavulanate, sucralfate and vaccination [varied vaccines including those against rabies, distemper combination (canine distemper virus, canine adenovirus 2, canine parvovirus, canine parainfluenza virus, Bordetella and leptospirosis)] were the most commonly administered medications. 27只犬（19只CAEDE，8只SLS）具有充分的临床信息可以进行药物评分。13只CAEDE/WLS患犬药物评分为正分；其中2只犬为+3分，1只犬+2分，在10例病例中发现具有弱相关性（1+分）。CAEDE病例中3只犬评分为负分（2只-1分，1只-2分）。SLS的患犬中，6只正分（4只+1分，2只+2分），2只药物评分为负分。甲硝唑、卡洛芬、法莫替丁、阿莫西林克拉维酸，硫糖铝和免疫[各种疫苗包括狂犬疫苗、犬瘟联苗（犬瘟热病毒、犬腺病毒2型、犬细小病毒、犬副流感病毒、博氏杆菌和钩端螺旋体）]为最常见的用药。
Treatment and outcome 治疗和结果 Treatment protocols were similar for the two conditions, often as a consequence of overlapping clinical signs or both CAEDE and SLS maintained as differential diagnoses. Therapies included drug withdrawal, glucocorticoids, gastroprotectants, antimicrobials, intravenous fluids (including colloids in cases with severe hypoalbuminemia), antihistamines and pain medication. Most cases of CAEDE and SLS resolved [60% and 70%, respectively, with a similar duration (15.7 and 18.5 days, respectively) of clinical signs]. Two cases of SLS recurred with dermatological signs within a two month period. Three dogs with CAEDE and two dogs with SLS were euthanized as a result of their acute dermatological disease, gastrointestinal signs or syndromic involvement with an average of 2.5 days of disease duration until death. Three dogs developed respiratory distress with cardiorespiratory involvement (before euthanasia in two dogs with CAEDE and one dog with SLS). Postmortem examination was not performed in these cases. 由于两种疾病存在共同的临床症状或通常CAEDE和SLS均存在于疾病的鉴别诊断列表内，所以两种疾病的治疗方案相似。治疗包括停药、糖皮质激素、胃粘膜保护剂、抗生素、静脉补液（严重低白蛋白血症中会使用胶体液），抗组胺药和止疼药。CAEDE和SLS中的大多数病例得到恢复[分别为60%和70% ，临床症状持续时间相近（分别为15.7天和18.5天）]。有2例SLS病例在2个月内皮肤症状复发。3例CAEDE患犬和2只SLS患犬由于急性皮肤疾病，胃肠道症状或综合征被安乐死，疾病到死亡为止平均病程2.5天。3只犬发展为累及心肺的呼吸窘迫（安乐死前CAEDE患犬2只，SLS患犬1只）。这些病例在死后并未进行尸检。
Discussion 讨论 Canine acute eosinophilic dermatitis with oedema (CAEDE/WLS) and sterile neutrophilic dermatitis (SLS) have overlapping clinical and histological features (Figures 1 and 2). The degree of dermal eosinophilia is an effective means of distinguishing these entities histopathologically and a Luna stain can be useful in highlighting eosinophils when there is histological overlap with neutrophilic dermatitis. Commercially available eosinophil myeloperoxidase, neutrophil myeloperoxidase and neutrophil elastase did not allow for consistent distinction between canine eosinophils and neutrophils. Use of the Luna stain allowed for classification of the cases in this study as canine acute eosinophilic dermatitis with oedema or sterile neutrophilic dermatitis when there was histological overlap; one case was recategorized as sterile neutrophilic dermatitis instead of CAEDE. However, based on the clinical similarities, similar putative triggers/ exposures and similar outcomes with overlapping therapeutic interventions, the distinction between these entities may not be a clinical necessity at present. 犬伴水肿性急性嗜酸性皮肤病(CAEDE/WLS) 和无菌性中性粒细胞性皮肤病（SLS）存在相同高的临床和组织学特征（图1和图2）。从组织病理学角度根据真皮嗜酸性粒细胞增多的程度可以有效区分这两种疾病，当与嗜中性粒细胞性皮肤病存在相同组织学表现时，Luna染色可以突出着染嗜酸性粒细胞。商品化的嗜酸性粒细胞过氧化物酶，中性粒细胞过氧化物酶和中性粒细胞弹性蛋白酶无法稳定地区分犬嗜酸性粒细胞和嗜中性粒细胞。在本研究中当出现组织学特征相同时，通过Luna染色可以将病例分类为犬伴水肿性急性嗜酸性皮肤病或无菌性嗜中性粒细胞性皮肤病；其中1例CAEDE病例被重新分类为无菌性嗜中性粒细胞性皮肤病。然而，基于临床相似性，相似的假定诱因/暴露及在接受相同治疗后获得的相似结果，目前在临床上可能并不需要对于这些疾病进行区别。
Previous reports on CAEDE have demonstrated clinical correlates with gastrointestinal signs and pharmacotherapy. Similar findings were encountered with cases of SLS, although gastrointestinal signs were more frequently encountered with CAEDE. Some authors have likened CAEDE to the human entity of Wells’ syndrome, an eosinophilic and granulomatous cellulitis that is a rare dermatosis in people, which is often idiopathic and a diagnosis of exclusion requiring a clinicopathological diagnosis. Proposed precipitating factors include (proposed type IV) hypersensitivity reactions to medications, aeroallergens and/or food allergens, ecto- or endoparasitism, arthropod bites and myeloproliferative disorders. In dogs, the clinical differential diagnoses include erythema multiforme, vasculitis and canine sterile neutrophilic dermatosis, with histopathological evaluation being required for a definitive diagnosis. The resemblance to the human condition (clinically and histologically) is tenuous and queries whether the use of the eponym is appropriate. Though Wells’-like syndrome (WLS) seems entrenched in the veterinary vernacular, canine acute eosinophilic dermatitis with oedema (CAEDE) is the preferred and recommended term by the authors. 之前关于CAEDE的研究已经证明胃肠道症状和药物治疗的临床相关性。尽管胃肠道症状更多见于CAEDE病例中，但在SLS病例中也有相似的发现。有些作者会把CAEDE比作人类的Wells样综合征，一种人类罕见的皮肤病：嗜酸性肉芽肿性蜂窝织炎，通常为先天性，并且需要通过临床病理学诊断进行排查诊断。诱发因素包括（诱发类型IV）对药物，空气过敏原和/或食物过敏原、外/内寄生虫、节肢动物叮咬的过敏反应和骨髓增殖性疾病。犬中的临床鉴别诊断包括多形红斑、血管炎和犬无菌性嗜中性粒细胞性皮肤病，确诊需要组织病理学评估。该病与人类中的状况（临床和组织学）仅有微弱的相似点，这种命名是否合适受到了质疑。虽然似乎Wells样综合征（WLS）的名称已在兽医中根深蒂固，但犬伴水肿性急性嗜酸性皮肤病（CAEDE）是作者更喜欢也更推荐的术语。
Sterile neutrophilic dermatosis is rare and likened to acute febrile neutrophilic dermatosis (Sweet’s syndrome) of people (hence, often termed Sweet’s-like syndrome). The reported canine cases present with painful, erythematous and oedematous macules and papules, with occasional pustules and ulcers. Concurrent eosinophilic infiltrates have been documented, but not highlighted with this condition, making it unclear whether WLS or SLS was reported. The cause is unknown, but an antigen-driven T-cell-mediated immune (potentially drug-induced) reaction is speculated. Drug associations and comorbidities in people include upper respiratory disease or gastrointestinal disease and neoplasia amongst other conditions. No evidence of respiratory disease or neoplasia was reported in the present study. Some cases in dogs have been associated with nonsteroidal anti-inflammatory drug administration (NSAID) and/or lameness, which is especially noteworthy considering the proportion of cases with lameness and IMPA in the current study. Again, many of the clinical features of the human condition are not recapitulated in canine sterile neutrophilic dermatitis. 无菌性嗜中性粒细胞性皮肤病很罕见，被比作人的急性发热性嗜中性粒细胞性皮肤病（Sweet综合征）（因此，常被命名为Sweet样综合征）。已报道的犬的病例表现出疼痛、红斑和水肿性斑点和丘疹，偶尔伴有脓疱和溃疡。可见并发嗜酸性粒细胞浸润，但表现不明显，所以无法确定是WLS或SLS病例。病因未知，有假说是由于抗原引起的T细胞介导的免疫反应（怀疑药物诱导）。药物相关，人中的并发症包括上呼吸道疾病或胃肠道疾病以及肿瘤病等。目前研究报道中没有发现呼吸道疾病或肿瘤的证据。犬中一些病例与非甾体类抗炎药（NSAID）的使用和/或跛行有关，考虑到本研究中跛行和IMPA病例的比例，这点尤其值得的关注。同样，人中的许多临床特征在犬无菌性嗜中性粒细胞性皮肤病中都没有表现。
It is likely that CAEDE and SLS include a relationship between an exposure/trigger(s) and an individual immunological profile. With significant overlap aside from the type of granulocytic infiltrate and few clinical correlates, these may represent the same disease or spectrum of disease with the individual’s immune response driving minor differences and leading to arbitrary clinical division/categorization. Miniature schnauzers also appear over-represented in CAEDE (13% of cases; P < 0.0001), which is interesting, especially considering prior similarities reported with sterile pustular erythroderma and SLS in this breed, suggesting that a broader spectrum of granulocytic dermatitis is possible. Topical therapy or bathing before onset of clinical signs was not identified in these cases. English bulldogs also were over-represented based on proportion hypothesis testing (10% of cases; P < 0.0001) in this case series. Although other breeds (Bassett hound, pug and Yorkshire terrier) represented more than once is in this case series were identified to be over-represented, with a low overall number of cases caution must be exercised in overinterpreting this data. Further research, delineating CAEDE and SLS, with hopefully larger cohorts, may establish risk factors for disease onset, identify putative triggers and provide further prognostic information. CAEDE和SLS在暴露/诱发和个体免疫学特征间可能存在某种关系。除了粒细胞浸润类型及很少的临床相关性外存在明显相同点，个体免疫应答使之出现细微的区别，导致主观上临床划分/分类，但这些可能代表相同疾病或疾病谱。迷你雪纳瑞在CAEDE中较多见（13%的病例；P<0.0001），这点很有趣，特别是考虑到之前报道该品种在无菌性脓疱性红斑和SLS中的出现相似情况，可能存在更广泛性的粒细胞性皮肤病。这些病例在出现临床症状之前并未进行外部治疗或洗澡。根据比例假设检验在这一系列病例中英国斗牛犬发病率较高（病例的10%，P<0.0001）。虽然其他品种（巴吉度猎犬，巴哥犬和约克夏梗）仅有一例但也被认为高发，在病例总数较少的情况下应谨慎对数据的过度解读。希望有更壮大的团队来进一步研究，描述CAEDE和SLS，确认疾病发生的危险因素，确定潜在诱发因素，并提供更多的预后信息。
It remains unclear if these are truly separate diseases, yet differences in CAEDE and SLS were identified. For the time being, maintaining these entities as distinct is useful until more is learned about their cause and pathogenesis. Concurrent AD and pruritus or IMPA and lameness may be clues to distinguish CAEDE and SLS along with histopathological findings where a Luna stain can be a useful aid. 目前尚不清楚这些疾病是否真的是独立的疾病，但已经确认了CAEDE和SLS间的区别。目前在对他们的病因和发病机理了解更多前保持他们的独立性是有益的。并发的AD和瘙痒或IMPA和跛行可能是鉴别CAEDE和SLS的线索，此外Luna染色对于组织病理学上的发现提供了帮助。
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发表于 2022-5-7 23:05:40
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