推测猫疱疹病毒相关的多形红斑

王帆

Presumptive herpesvirus-associated erythema multiforme in a cat

推测猫疱疹病毒相关的多形红斑

翻译：王佳妮

Erythema multiforme (EM), an uncommon immune-mediated skin disorder of cats, conceivably could be triggered by feline herpesvirus type-1 (FHV-1) infection, in a manner analogous to human herpesvirus-associated EM (HAEM). This report describes a 10-year-old Persian-mixed cat with a presumptive diagnosis of HAEM.

多形红斑(EM)是猫一种罕见的免疫介导性皮肤病，可能由猫疱疹病毒1型(FHV-1)感染引发，其方式类似于人类疱疹病毒相关的EM (HAEM)。这篇报告描述了一只10岁杂交波斯猫的HAEM的推测诊断。

Introduction

引言

Feline erythema multiforme (EM) is an immune-mediated skin disease with various potential triggering factors. An association between feline herpesvirus type-1 (FHV-1) and EM has been suggested previously, where it would be a counterpart to human herpesvirus-associated EM (HAEM).

猫多形红斑(EM)是一种具有多种潜在触发因素的免疫介导性皮肤病。猫疱疹病毒1型(FHV-1)和EM之间的联系之前已经提出，它可能与人类疱疹病毒相关EM (HAEM)的相对应。

Case presentation

病例报告

A 10-year-old male neutered Persian-mixed cat was presented with a three week history of anorexia, weight loss,respiratory distress and mildly pruritic dermatitis. Previous systemic therapies included ceftriaxone, marbofloxacin and methylprednisolone acetate. The cat lived with 20 rescued cats, was regularly vaccinated, and had a history of recurrent rhinitis and conjunctivitis. On physical examination dullness, cachexia (body condition score 1 of 9), clear nasal discharge and mild ulcerative glossitis were detected. Skin lesions were generalized including the paw pads, and consisted of alopecia, white to yellow scales, crusts and erosions. Erosions showed a striking annular or polycyclic configuration on the trunk and a bilaterally symmetrical distribution on the face (Figure 1). Cytological examination of impression smears from erosive lesions on the dorsal trunk showed numerous Malassezia yeast and bacteria (cocci and rods which were undergoing phagocytosis by granulocytes). Increased serum acute phase proteins such as serum amyloid A and haptoglobin and elevation of liver enzyme activities, possibly resulting from the prolonged anorexia and consequent lipidosis, were recorded. Feline immunodeficiency virus and feline leukaemia virus tests were negative.

一只10岁雄性已去势杂交波斯猫出现3周的厌食、体重减轻、呼吸窘迫和轻度瘙痒性皮炎病史。全身治疗用药史包括头孢曲松、马波沙星和醋酸甲泼尼龙。这只猫与20只被救助猫一起生活，定期接种疫苗，有复发性鼻炎和结膜炎病史。体格检查发现有精神沉郁、恶病质（体况评分1/9分）、清亮鼻分泌物和轻度溃疡性舌炎。皮肤病变为全身性包含爪垫，包括脱毛、白色至黄色皮屑、结痂和糜烂。位于躯干和面部双侧对称分布的糜烂病变呈明显的环状或多环状形状（图 1）。背侧躯干糜烂病变的压片细胞学检查显示大量马拉色菌和细菌（被粒细胞吞噬的球菌和杆菌）。记录了血清淀粉样蛋白 A 和触珠蛋白等血清急性期蛋白的增加以及肝酶活性的升高，这可能是由于长期厌食和随后的脂质沉积所致。猫免疫缺陷病毒和猫白血病病毒检测均为阴性。

Differential diagnoses included FHV-1 dermatitis, EM (not drug-induced, according to the history), non- thymoma/thymoma-associated exfoliative dermatitis,cutaneous lymphocytosis and dermatophytosis. A total body CT scan confirmed a severe bilateral rhinopathy and ruled out a thymoma. Skin biopsies from the neck and the trunk revealed lymphocytic interface dermatitis and folliculitis, with basal and suprabasal apoptotic cells, scant lymphocytic satellitosis, and diffuse parakeratotic and orthokeratotic hyperkeratosis. Sebaceous glands were not observed (Figure 2). Fungal elements were not highlighted using periodic acid Schiff stain.Immunohistochemical investigation showed a prevalence of CD3-positive T cells in the inflammatory infiltrate (Figure 3). FHV-1 DNA was detected, using realtime (RT)-PCR, in oral and nasal samples taken using brushes and in the lesional skin of the dorsal neck,and not in the peripheral whole blood. RNA in situ hybridization (RNA-ISH, Leica Biosystems Nussloch GmbH; Nussloch, Germany) on formalin-fixed paraffin-embedded skin samples (FFPE) using a FHV1-ICP0 probe (ACD; Newark, CA, USA), 4 yielded negative results. The oral brush sample also was PCR-positive for feline calicivirus. Famciclovir (Teva, Teva Italia S.r.l.;Milan, Italy) at 85 mg/kg per os twice daily and lysine (Herpless, Candioli pharmaceutical; Turin, Italy) at 500 mg p.o. twice daily were administered through an oesophagostomy feeding tube. The cat was bathed daily for three days, sparing the neck and the head, with a shampoo containing 0.5% climbazole and 3% chlorhexidine (Douxo pyo shampoo, Ceva Animal Health, Agrate Brianza, Italy). Three days later the skin condition was improved (Figure 4) and a cough appeared; doxycycline (Ronaxan 20, Boehringer Ingelheim Animal Health; Milan, Italy) at 10 mg/kg p.o. once daily was initiated. After 11 days of treatment, the upper respiratory tract signs, ulcerative glossitis and erosive dermatitis were no longer present. Unfortunately, three weeks later the cat died as a consequence of pneumonia as suggested by clinical signs and chest radiographs.

鉴别诊断包括FHV-1皮肤病、EM(根据病史，非药物诱导)、非胸腺瘤/胸腺瘤相关表皮剥脱性皮炎、皮肤淋巴细胞增生和皮肤癣菌病。全身CT扫描证实为严重的双侧鼻病，排除胸腺瘤。颈部和躯干皮肤活检显示淋巴细胞界面性皮炎和毛囊炎，伴有基底层和基底上层细胞凋亡，少量淋巴细胞卫星现象，弥漫性角化不全性角化过度和正角化性角化过度。皮脂腺未被观察到(图2)。使用高碘酸席夫染色未见真菌元素。免疫组化研究显示炎症浸润中CD3阳性T细胞发病(图3)。在使用刷子采集的口腔和鼻腔样本，以及颈背部的病变皮肤样本中，使用实时(RT)-PCR检测到FHV-1 DNA，但在外周血中没有。使用 FHV1-ICP0 探针对福尔马林固定石蜡包埋的皮肤样本 (FFPE)进行RNA原位杂交，检查4个视野结果为阴性。口腔刷样品进行猫杯状病毒PCR检测为阳性。通过食管造口术饲管，给予泛昔洛韦口服剂量85 mg/kg ，每日两次，和赖氨酸口服剂量500 mg，每日两次给药。患猫连续三天除颈部和头部外每日洗澡，使用含0.5%氯咪巴唑和3%氯己定香波。3天后皮肤状况改善(图4)，出现咳嗽症状。开始给予多西环素口服剂量10mg/kg，每日一次。治疗11天后，溃疡性舌炎、糜烂性皮肤病等上呼吸道症状消失。不幸的是，三周后，通过临床症状和胸部x光片表明患猫死于肺炎。

Discussion

讨论

This report describes a cat with presumptive HAEM. Truncal annular and polycyclic erosive dermatitis and symmetrical facial erosive-ulcerative dermatitis were remarkable features. It remains unclear how secondary bacterial and yeast overgrowth contributed to the dermatological picture. To avoid additional distress to this anorexic cat, biopsies of facial and tongue lesions were not taken and therefore it cannot be known if these lesions were related to the EM or directly caused by FHV-1 or calicivirus infection. Histologically, lack of sebaceous glands has not been reported previously in feline EM although it has been described in cats with exfoliative dermatitis without thymoma, a condition considered a possible form of feline EM. In an attempt to clarify the role of FHV-1 in causing EM, we performed RNA-ISH on FFPE samples. This technique has shown 100% concordance with quantitative (q)RT-PCR to distinguish between herpetic dermatitis and other skin diseases in cats infected with FHV-1. However, RNA-ISH yielded negative results, suggesting a lack of viral replication in the EM lesions. In people, HAEM is thought to be triggered by viral DNA fragments reaching distant skin sites through the peripheral blood, yet we were unable to demonstrate viral DNA in the peripheral blood with the available probes.

该报告描述了一只疑似HAEM患猫。显著特征为躯干环形和多环形糜烂性皮肤病和对称性面部糜烂性溃疡性皮肤病。目前尚不清楚继发性细菌和酵母菌过度增殖是如何导致皮肤病的。为了避免给这只厌食患猫带来额外的痛苦，没有对患猫面部和舌部病变进行活检，因此无法知道这些病变是否与EM相关或直接由FHV-1或杯状病毒感染引起。组织学上，以前没有报道过猫EM中缺乏皮脂腺，但这已经在没有胸腺瘤的表皮剥脱性皮炎患猫中进行了描述，这种情况被认为是猫EM的一种可能形式。为了阐明FHV-1在引起EM中的作用，我们对FFPE样本进行了RNA-ISH。该技术与定量(q)RT-PCR100%一致，可区分感染FHV-1的猫的疱疹性皮肤病和其他皮肤病。然而，RNA-ISH 产生了阴性结果，表明EM病变中缺乏病毒复制。在人类中，HAEM被认为是由病毒DNA片段通过外周血到达远处皮肤部位触发的，然而我们无法用可用的探测点证明外周血中的病毒DNA。

The case for virus-triggered EM in this cat was supported by the rapid improvement of skin and oral lesions after starting antiviral therapy, including areas not treated with the antiseptic shampoo. However, a causative role for FHV-1 could not be definitively inferred because calicivirus also was detected by PCR and famciclovir also may be effective against feline calicivirus. Nevertheless, and notably, calicivirus has not been reported as a cause of EM in either cats or people.

开始抗病毒治疗后皮肤和口腔病变的快速改善支持了这只猫病毒触发的EM的病例，包括未用抗菌香波治疗的区域。然而，无法明确推断FHV-1的致病作用，因为通过 PCR 也检测到杯状病毒，泛昔洛韦也可能对猫杯状病毒有效。然而，值得注意的是，无论是猫还是人，都没有报道杯状病毒是导致EM的病因。

Figure 1. Clinical presentation of a cat with presumptive feline herpesvirus-1 (FHV1)-associated erythema multiforme (EM).(a) Tufts of hairs trapped in thick scales are easily epilated leaving large areas of complete alopecia and erosive dermatitis. (b) A closer view reveals the unique annular or polycyclic configuration of the erosions. (c) Note the nasal planum and periocular skin involvement. (d) Scaling dermatitis also is present on the paw pads.

图 1. 疑似猫疱疹病毒 1 (FHV1) 相关多形红斑 (EM) 的猫的临床表现。 (a) 困在厚皮屑中的毛簇很容易脱毛，留下大面积的完全脱毛和糜烂性皮肤病。 (b) 近距离观察揭示了糜烂的独特环状或多环结构。 (c) 注意鼻平面和眼周皮肤发病。 (d) 爪垫上也存在皮屑性皮肤病。

Figure 2. Histological evaluation of skin biopsies from the neck and the trunk of a cat with presumptive feline herpesvirus-1 (FHV1)-associated erythema multiforme (EM). (a) Diffuse and severe hyperkeratosis with alternate layers of parakeratotic and basket wave or laminar orthokeratosis with loss of sebaceous glands. A mild superficial and perifollicular inflammatory infiltrate is present. Haematoxylin & eosin, x4. (b) Note lymphocytic interface dermatitis with hyperkeratosis and serocellular crust. H&E, x20. (c) Note basal cell vacuolization (black arrow) and basal and supra-basilar apoptotic keratinocytes (black arrowheads). H&E, x40.

图2.对疑似猫疱疹病毒1型(FHV1)相关多形红斑(EM)的猫颈部和躯干皮肤活检的组织学评估(a)弥漫性、严重的角化过度，交替出现角化不全层和篮状波纹或片状正角化层，皮脂腺消失。轻度浅表及毛囊周围炎性浸润。苏木素和伊红，4倍。(b)伴有角化过度和血清细胞性结痂的淋巴细胞性界面性皮炎。HE染色，20倍。(c)注意基底细胞空泡化(黑色箭头)，基底层和基底上层细胞凋亡(黑色箭头)。HE染色，40倍。

Figure 3. Immunostaining of histopathological sections of skin biopsies for CD3 positive cells, from the neck and the trunk of a cat with presumptive feline herpesvirus-1 (FHV1)-associated erythema multiforme (EM).

(a) and (c) CD3-positive cells are numerous in the epidermis, the follicular walls and the superficial dermis. x40. (b) and (d) Fewer CD20-positive cells in the superficial dermis and in the outer root sheath of hair follicles. x40.

图 3. 疑似猫疱疹病毒 1 (FHV1) 相关多形红斑 (EM) 猫颈部和躯干皮肤活检组织病理学切片的 CD3 阳性细胞免疫染色。

(a) 和 (c) CD3 阳性细胞在表皮、毛囊壁和真皮浅层中数量众多。40倍。 (b) 和 (d) 真皮浅层和毛囊外根鞘中的 CD20 阳性细胞减少。40倍。

Figure 4. Three days after the beginning of systemic antiviral therapy and antiseptic shampoo, the skin condition of a cat with presumptive feline herpesvirus-1 (FHV1)-associated erythema multiforme (EM) improved markedly.

a) Note reduction of erosions and moist dermatitis replaced by crusts and scale. (b) Milder erosions are still visible around the nares and periocular region.

图 4. 全身抗病毒治疗和抗菌香波开始三天后，疑似猫疱疹病毒 1 (FHV1) 相关多形红斑 (EM) 的猫的皮肤状况显着改善。

a) 注意由结痂和皮屑所替代的糜烂和湿性皮炎的减少。 (b) 在鼻孔和眼周区域周围仍然可以看到较轻微的糜烂。