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Sterile pyogranuloma syndrome in a dog successfully treated with immunosuppressive therapy and reconstructive seed grafting
免疫抑制疗法联合颗粒状皮肤移植重建成功治疗犬无菌性脓性肉芽肿综合征
作者：Hilary H. Chan | Amanda K. Burrows | Giselle Hosgood | Rudayna Ghubash| Amanda O'Hara
翻译：王帆
Abstract
This report describes a case of sterile pyogranuloma syndrome managed with immunomodulatory therapy and seed skin grafting. Seed skin grafting can be considered as part of a multimodal treatment approach for cutaneous defects caused by ulcerative immune-mediated diseases where secondary intention healing is delayed or contraindicated, and other forms of wound reconstruction may be prohibitive.
摘要
本报告描述了1例通过免疫调节治疗和颗粒状皮肤移植治疗的无菌性脓肉芽肿综合征病例。对于由溃疡性免疫介导的疾病引起的皮肤缺损，如果二期愈合延迟或禁忌，可以考虑将颗粒状皮肤移植作为多模式治疗方法的一部分，而其他形式的伤口重建可能无法实施。
INTRODUCTION
介绍
Sterile pyogranuloma syndrome (SPS) is an uncommon immune-mediated skin disease of dogs characterised by plaques, ulcers and draining nodules. Lesions may be solitary or generalised and located on the pinnae, muzzle, periocular regions and distal limbs. Affected dogs may demonstrate systemic signs of lethargy and inappetence. Diagnosis is confirmed by histopathological examination and the exclusion of infectious aetiologies including fungal, bacterial and oomycotic agents. Medical management with prednisolone, azathioprine, ciclosporin and low-level laser therapy are effective. This report describes the use of seed grafting to enhance epithelialisation of full-thickness skin defects on the distal limbs of a dog that was receiving immunomodulatory medical therapy for SPS.
无菌性脓性肉芽肿综合征(SPS)是一种犬的不常见的免疫介导皮肤病，以斑块、溃疡和有瘘道的结节为特征。病变可能是孤立的或全身的，位于耳廓、口周、眼周区域和肢体远端。患犬可能表现出嗜睡和食欲不振的全身性症状。诊断是通过组织病理学检查和排除感染病因，包括真菌、细菌和卵菌病原。药物治疗包括泼尼松龙、硫唑嘌呤、环孢素，以及低剂量激光治疗是有效的。这篇报道描述了使用颗粒状皮肤移植来增强远端肢体上全层皮肤缺损的上皮再生，这只犬正在接受SPS的免疫调节药物治疗。
CASE REPORT
病例报告
A 3.5-year-old male, castrated shih tzu weighing 4.6kg presented to a veterinary dermatology referral clinic with a one month history of severe, progressive, nodular to ulcerative dermatitis. The dog was inappetent, lethargic and dysphagic.
一只3.5岁的雄性已去势西施犬，体重4.6公斤，因一个月的严重、渐进性结节性至溃疡性皮肤病就诊于兽医皮肤科转诊诊所。这只犬食欲下降、嗜睡、吞咽困难。
Physical examination revealed a deep, welldemarcated ulcer located on the caudolateral carpal region of the right forelimb (Figure 1a) measuring 40mm×32mm encircling two-thirds of the circumference of the carpus; an erosive lesion with a central tract draining serous discharge affecting the caudomedial tarsal region of the left hind limb measuring 20mm in diameter, and a focal crusted, ulcerated nodule draining a serous discharge on the dorsal aspect of the head measuring 10mm×3mm. Bilateral submandibular lymphadenomegaly, unilateral enlargement of the left mandibular salivary gland, marked bilateral episcleral injection, ocular discharge and corneal neovascularisation were present. Multiple skin biopsy samples were collected from the right forelimb and left hind limb lesions. Aerobic and anaerobic bacterial and fungal cultures and PCR testing for mycobacterial organisms were negative. Histopathological examination demonstrated a multifocal to coalescing population of neutrophils, histiocytes, eosinophils, lymphocytes, plasma cells and mast cells in the dermis, associated with tissue cavitation, draining sinus formation, consistent with a pyogranulomatous dermatitis, furunculosis and cellulitis (Figures 2a, b). A diagnosis of SPS was confirmed. Haematological analysis revealed a mild neutrophilia and eosinophilia. Serum biochemical analysis was within reference limits. Ultrasound-guided fine needle aspiration (FNA) of the left salivary gland and submandibular lymph nodes confirmed a pyogranulomatous sialoadenitis and lymphadenitis, respectively. Ophthalmological examination confirmed a diagnosis of bilateral superficial keratitis. Treatment with prednisolone 1mg/kg, twice daily per os, and topical 1% prednisolone acetate and 0.12% phenylephrine hydrochloride (Prednefrin Forte, Allergan Australia Pty Ltd; Sydney, Australia) eye drops, four times daily were instituted.
体格检查显示在右前肢腕骨尾侧有一个深的、界限分明的溃疡(图1a)，溃疡大小为40mm×32mm，环绕腕骨周长的三分之二。糜烂性病变伴有中央有窦道和血清分泌物，影响左后肢尾侧跗骨区，直径为20mm，头部背侧局部结痂溃疡性结节伴窦道和血清分泌物，大小为10mm×3mm。双侧下颌淋巴结肿大，单侧左侧颌下腺肿大，明显双侧巩膜浅层充血，眼分泌物及角膜新生血管形成。从右侧前肢和左侧后肢病变处采集多个皮肤活检样本。需氧和厌氧细菌培养和真菌培养及分枝杆菌PCR检测均为阴性。组织病理学检查显示真皮内中性粒细胞、组织细胞、嗜酸性粒细胞、淋巴细胞、浆细胞和肥大细胞多灶或聚集，与组织空腔、窦道形成相关，与脓性肉芽肿性皮炎、疖病和蜂窝组织炎一致(图2a, b)。确诊为SPS。血液学分析显示轻度中性粒细胞增多和嗜酸性粒细胞增多。血清生化分析在参考范围内。超声引导下左唾液腺和下颌淋巴结细针穿刺抽吸(FNA)分别证实为脓性肉芽肿性唾液腺炎和淋巴结炎。眼科检查确诊为双侧浅表性角膜炎。口服泼尼松龙1mg/kg，每日两次，外用1%醋酸泼尼松龙和0.12%盐酸苯肾上腺素滴眼液，每天四次。
Cutaneous ulcers were flushed with sterile saline and a propylene glycol hydrogel (INTRASITE Gel, Smith & Nephew; London, UK) applied directly to the surface, which was covered by a hydrophilic nonadhesive foam dressing (KRUUSE; Langeskolv, Denmark), rayon fleece (Soffban, Essity; Stockholm, Sweden) and a light conforming bandage (Fun-Flex Pet Bandage; KRUUSE). Dressings were changed twice each week (Figure 1b). After three weeks of prednisolone therapy, there was noticeable contraction of the right forelimb lesion with new epithelium emanating centrally from the margins (Figure 1c). The rate of epithelialisation had plateaued by the fourth week of prednisolone treatment. The open wound remained a substantial size, encircling half of the circumference of the carpus and measured 25×20mm. Granulation tissue had become exuberant and was elevated 3mm above the wound surface (Figure 1d). The left hind limb lesion measured 5mm in diameter (Figure 3). Full-thickness skin seed grafting was recommended to enhance epithelialisation of the open wound and obviate any further contracture.
皮肤溃疡用无菌生理盐水冲洗和丙二醇水凝胶直接表面涂抹，表面覆盖亲水性非粘性泡沫敷料，人造羊毛和一种轻型绷带。每周更换两次敷料(图1b)。经过三周的泼尼松龙治疗后，右侧前肢病变明显收缩，新上皮细胞从边缘中央形成(图1c)。在泼尼松龙治疗的第四周，上皮再生率已趋于不变。开放性伤口的大小仍然很大，环绕腕骨的一半周长，测量为25×20mm。肉芽组织旺盛，凸起创面3mm高(图1d)。左后肢病变直径5mm(图3)。建议采用皮肤全层颗粒状移植，以增强开放伤口的上皮化，并消除任何进一步的挛缩。
Seed grafting was performed as described recently.Full-thickness donor skin of approximately 4cm2 in area was harvested from the right lateral thorax, including the panniculus muscle. The graft was stretched and sutured across a piece of sterile cardboard with the subcutaneous tissue facing uppermost. The panniculus muscle and subcutaneous fat were meticulously excised until the corrugated surface of the dermis was visualised. A 4mm diameter skin biopsy punch (Biopunch, Ted Pella, Inc.; Redding, CA, USA) was used to harvest the seed grafts from the donor skin. Fifteen seed grafts were implanted into pockets in the granulation tissue of the right forelimb wound (Figures 1d, 4a) and a single seed graft was implanted into the left hind limb wound. The graft sites were covered with petrolatum-impregnated gauze (Jelonet; Smith & Nephew) followed by antimicrobial polyhexamethylene biguanide-impregnated gauze bandage (Kerlix AMD, Cardinal Health; Dublin, OH, USA), absorbent rayon fleece (Soffban; Essity) and a cohesive layer (Fun-Flex Pet Bandage; KRUUSE) for protection. Bandage dressings were changed at 5, 10, 16, 21 and 36d post-surgery. The grafts became incorporated into the wound bed and progressive epithelialisation emanating from the grafts was noted at sequential bandage changes. Complete epithelialisation of both lesions without contracture was achieved at 46d post-surgery (Figures 3d, 4b). The graft site was smooth and alopecic with an even surface. The owner was satisfied with the cosmetic outcome and reported excellent limb function without reduced range of motion of the carpal or tarsal joints.
如最近所述，进行了颗粒状移植。从右侧胸外侧采集约4平方厘米的全层供皮，包括胸腹肌。将移植皮拉伸并缝合在一块无菌纸板上，皮下组织朝上。仔细切除腹肌和皮下脂肪，直到看到真皮层的波纹面。使用直径4毫米的皮肤活检打孔器，从移植皮中获取颗粒状皮肤。将15个颗粒状皮植入右前肢创面肉芽组织袋中(图1d, 4a)，将1个颗粒状皮植入左后肢创面。移植部位用浸渍凡士林的纱布覆盖，其次是浸渍抗菌聚亚己基双胍纱布绷带，吸水的人造羊毛和粘合层用于保护。分别于术后5、10、16、21、36d更换绷带敷料。移植皮被纳入创面床，从移植皮中产生的上皮细胞在连续的绷带变化中被注意到。术后46d，两个病灶均实现完全上皮化，无挛缩(图3d, 4b)。移植皮部位光滑、脱毛、表面平整。宠主对美观效果感到满意，并报告了良好的肢体功能，腕部或跗骨关节的活动范围没有减少。
Prednisolone was tapered to 0.5mg/kg p.o., once daily yet dysphagia and self-trauma of the right carpal region relapsed. Ciclosporin (Atopica, Elanco; Greenfield, IN, USA) 5mg/kg p.o., once daily was commenced and prednisolone dosage was tapered and withdrawn after four weeks. At the 17month follow-up, ciclosporin (Atopica; Elanco) was reduced to 5mg/kg p.o., every second day as the dog remained in remission with no development of new cutaneous lesions (Figures 3e, 4c) nor evidence of lymphadenitis, sialoadenitis and keratitis.
泼尼松龙逐渐减少到0.5mg/kg，每日1次，但吞咽困难和右腕区自我创伤复发。环孢素开始每天一次，每次5mg/kg，泼尼松龙的剂量逐渐减少，四周后停用。在17个月的随访中，环孢素减少到口服隔日一次5mg/kg，因为犬处于缓解状态，没有新的皮肤病变的发展(图3e, 4c)，也没有淋巴结炎、唾液腺炎和角膜炎的证据。
DISCUSSION
讨论
This case report describes the resolution of fullthickness cutaneous ulcerations in a dog caused by SPS, achieved using a combination of immunosuppressive medical therapy and surgical skin seed grafting. We demonstrate the use of prednisolone and ciclosporin to control the immune-mediated SPS and highlight the utility of seed grafting to resolve the challenges in re-epithelialisation of full-thickness wounds affecting the distal limbs. Such technique provided rapid epithelialisation and coverage of the wound compared to the expected results with the alternative of secondary intention healing. This resulted in minimal contracture, good long-term limb function and an acceptable cosmetic outcome.
这个病例报告描述了解决由SPS引起的犬全层皮肤溃疡，实现了免疫抑制药物治疗和外科颗粒状皮肤移植的结合。我们展示了使用泼尼松龙和环孢素来控制免疫介导的SPS，并强调了颗粒状移植的用途，以解决影响远端肢体的全层伤口的再上皮化的难题。这种技术提供了快速的伤口上皮化和覆盖，与替代二期愈合的预期结果相比。这导致了轻微的挛缩，良好的长期肢体功能和可接受的美观结果。
A diagnosis of SPS was made based on clinical presentation, histopathological examination, failure to demonstrate an infectious cause and response to therapy. Sterile pyogranulomatous dermatitis and lymphadenitis was considered less likely owing to the presence of dermal nodules and plaques. Leishmaniasis is not endemic in Australia and therefore was not included as a differential diagnosis.
SPS的诊断基于临床表现、组织病理学检查、未能证明感染原因和对治疗的反应。无菌性脓性肉芽肿性皮炎和淋巴结炎被认为不太可能由于真皮结节和斑块的存在。利什曼病在澳大利亚不是地方病，因此没有被列入鉴别诊断。
Immunosuppressive drug therapy is indicated for treatment of SPS. In this case, prednisolone was selected for rapid onset of anti-inflammatory and immunosuppressive effects. Following four weeks of medical therapy and wound management, further re-epithelialisation was precluded by excessive granulation tissue and the location of the wound, thereby warranting surgical intervention.
免疫抑制药物治疗是治疗SPS的适应症。在这种情况下，选择泼尼松龙快速开始抗炎和免疫抑制效果。经过四周的药物治疗和伤口处理，过多的肉芽组织和伤口位置阻止了进一步的上皮再生，因此需要进行手术干预。
Seed skin graft reconstruction to repair distal limb cutaneous defects caused by trauma or excision of neoplasia has been reported previously in 15 dogs. A successful outcome was reported for all dogs. Given the location and the relative size of the cutaneous defects in this case, the technique of seed grafting was considered a suitable option to achieve wound epithelialisation and resolution. The time to complete re-epithelialisation in our case was consistent with the average time reported of approximately six weeks.While new epithelium is, of course, devoid of adnexal structures, skin seed graft sites are reported to undergo partial hair regrowth. Hair growth can be sporadic and arises from hair follicles in the seeds that survive the transplant process.
此前已报道15只犬，通过颗粒状皮肤移植重建修复损伤或肿瘤切除引起的远端肢体皮肤缺损。所有犬均报告了成功的结果。鉴于该病例中皮肤缺损的位置和相对大小，颗粒状移植技术被认为是实现伤口上皮化和愈合的合适选择。在我们的病例中，完成再上皮化的时间与报道的平均时间一致，约为6周。虽然新的上皮细胞当然没有附件结构，但据报道，颗粒状皮肤移植部位会发生部分毛发再生。毛发生长可以是零星的，生长于移植过程中存活下来的皮肤毛囊中。
Ciclosporin treatment was initiated as a result of excessive polyphagia secondary to prednisolone administration and relapse of dysphagia consistent with sialoadenitis when the prednisolone dosage was tapered. At the time of writing, the dog remains in remission receiving ciclosporin 5mg/kg p.o., every second day.
环孢素治疗是由于服用泼尼松龙继发的过度吞食和吞咽困难的复发，当泼尼松龙剂量逐渐减少时，吞咽困难与唾液腺炎一致。在撰写本文时，该犬仍处于缓解期，接受隔日一次口服环孢素5mg/kg。
Extracutaneous signs of lymphadenitis, sialoadenitis and keratitis developed simultaneously with the cutaneous signs. Regional lymphadenopathy has been reported previously in cases of cutaneous SPS.Idiopathic pyogranulomatous lymphadenitis is a sterile immune-mediated disease, predominantly affecting the English springer spaniel breed that responds to corticosteroid administration. Sialoadenitis causing dysphagia and association with cutaneous canine SPS has not been reported previously. Cytological analysis of the FNA from the salivary gland confirmed pyogranulomatous inflammation. The sterile pyogranulomatous submandibular lymphadenitis and sialoadenitis in our case were not confirmed by histopathological or microbiological testing, yet the response to corticosteroid treatment, onset of dysphagia coincident with the skin lesions and relapse with prednisolone withdrawal suggest that there was an immune-mediated aetiology.
淋巴结炎、唾液腺炎和角膜炎的皮肤外症状与皮肤症状同时出现。局部淋巴结病已在皮肤SPS病例中报道过。特发性脓性肉芽肿性淋巴结炎是一种无菌免疫介导的疾病，主要影响英国史宾格猎犬品种，皮质类固醇治疗有效。唾液腺炎引起吞咽困难，此前未报到与犬皮肤SPS有关。唾液腺FNA细胞学分析证实为脓性肉芽肿性炎症。本病例中的无菌性脓性肉芽肿性下颌淋巴结炎和唾液腺炎未进行组织病理学或微生物学检测，但使用皮质类固醇治疗有效、吞咽困难与皮肤病变同时发生，以及泼尼松龙停药后症状再复发，提示存在免疫介导的病因。
Immune-mediated keratitis is rare as the cornea is an immune privilege site, yet it has been reported in a single case of SPS. In the current case, clinical resolution was achieved with topical immunosuppressive therapy suggesting that an immune-mediated process was likely.
免疫介导的角膜炎是罕见的，因为角膜是免疫赦免部位，但它已在一个单一的SPS案例被报道。在本病例中，通过外用免疫抑制治疗实现了临床缓解，这表明可能是免疫介导的过程。
This is the first case report using seed grafts for reconstruction of skin defects arising from ulcerative lesions caused by SPS. We have demonstrated that treatment of ulcerative cutaneous immune-mediated disease necessitates not only adequate control of the disease, but also effective resolution of the wounds with consideration of long-term function being of primary importance. Seed grafting is a relatively simple and robust reconstructive technique with minimal adverse effects. It is a procedure that can be performed in a general veterinary practitioner setting. In conjunction with immunosuppressive treatment, seed skin graft reconstruction should be considered as an option for the management of other ulcerative dermatoses, particularly on the distal limbs, where healing by secondary intention is delayed and wound contracture will limit the function of the limb.
这是首例使用颗粒状移植重建由SPS引起的溃疡性病变引起的皮肤缺损的病例报告。我们已经证明，溃疡性皮肤免疫介导性疾病的治疗不仅需要充分控制疾病，而且需要有效解决伤口，考虑长期功能是最重要的。颗粒状移植是一种相对简单、可靠、副作用最小的重建技术。这是一种可使用一般兽医设备进行的操作。结合免疫抑制治疗，颗粒状移植重建应被视为其他溃疡性皮肤病的一种治疗方案，特别是远端肢体，在远端肢体，继发性愈合延迟，伤口挛缩将限制肢体功能。
FIGURE 1 Photographic series of the right caudolateral carpus in a dog with sterile pyogranuloma syndrome before seed grafting. (a) Ulcerative wound at initial presentation (40mm×32mm). (b) After two weeks of prednisolone therapy and open wound management. (c) After three weeks of prednisolone therapy: granulation tissue formation with some epithelialisation (28mm×25mm). (d) After four weeks of prednisolone therapy: excessive granulation tissue at the time before seed skin grafting (25mm×20mm)
图1无菌性脓性肉芽肿综合征犬右腕骨颗粒状移植前的照片。(a)初次出现溃疡性伤口(40mm×32mm)。(b)经过两周泼尼松龙治疗和开放性伤口管理。(c)泼尼松龙治疗三周后:肉芽组织形成，部分上皮化(28mm×25mm)。(d)泼尼松龙治疗四周后:颗粒状移植前肉芽组织过多(25mm×20mm)
FIGURE 2 Skin biopsy from the right forelimb of a dog with sterile pyogranuloma syndrome. (a) Multifocal and coalescing neutrophilic to pyogranulomatous dermatitis and cellulitis with tissue cavitation and draining sinus formation (haematoxylin & eosin, ×12.5, scale bar = 500μm). (b) Higher magnification view showing pyogranulomatous dermatitis (×400, scale bar = 50μm)
图2无菌性脓性肉芽肿综合征犬右前肢皮肤活检。(a)多灶性合并中性粒细胞性至脓性肉芽肿性皮炎和蜂窝组织炎，伴组织空腔和窦道形成(苏木精和伊红，×12.5，比尺= 500μm)。(b)高倍镜显示脓性肉芽肿性皮炎(×400，比例尺= 50μm)
FIGURE 3 Photograph series of the left medial tarsus of a dog with sterile pyogranuloma syndrome. (a) Ulcerative wound exposing underlying tendons at initial presentation. (b) After two weeks of prednisolone and wound management. (c) After four weeks of prednisolone therapy (5mm diameter). (d) Six weeks post-skin graft: complete epithelialisation of the wound without contracture. (e) Seventeen months post-skin graft: alopecia at the site of seed graft
图3无菌性脓性肉芽肿综合征犬左内侧跗骨的照片。(a)初诊时溃疡性创面暴露下层肌腱。(b)泼尼松龙和伤口处理两周后。(c)泼尼松龙治疗(直径为5mm) 4周后。(d)植皮后6周:伤口上皮完全形成，无挛缩。(e)植皮后17个月:颗粒状移植部位脱毛
FIGURE 4 Photographic series of the right caudolateral carpus in a dog with sterile pyogranuloma syndrome after seed grafting. (a) Seed skin grafts implanted into wound bed (arrowheads). (b) Six weeks post-graft: complete epithelialisation of wound without contracture. (c) Seventeen months post-skin graft: alopecia at the site of seed graft, no contracture
图4颗粒状移植后无菌性脓性肉芽肿综合征犬右腕骨的照片。(a)颗粒状移植皮植入创面床(箭头)。(b)移植后6周:伤口上皮完全形成，无挛缩。(c)植皮后17个月:种移植皮处脱毛，无挛缩
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发表于 2022-11-10 08:47:26
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