高压氧治疗猫皮肤诺卡菌病的疗效观察

王帆

Positive effects of hyperbaric oxygen therapy in a cat with cutaneous nocardiosis

高压氧治疗猫皮肤诺卡菌病的疗效观察

作者：Andrew C. Simpson and Dominique J. Wiener

翻译：徐晋

Hyperbaric oxygen therapy (HBOT) has been beneficial in treating people with nocardiosis. This report describes Nocardia spp. affecting a cat, with lesions confined to the skin. To the best of the authors’ knowledge, this is the first report of HBOT, combined with amikacin, used to successfully treat feline cutaneous nocardiosis.

摘要 – 高压氧治疗(HBOT)对治疗诺卡菌病的病人有益。本报告描述了诺卡菌感染的猫病例，病变局限于皮肤。据作者所知，这是HBOT联合阿米卡星成功治疗猫皮肤诺卡菌病的首次报道。

Introduction

简介

Nocardia spp. are common soil saprophytes that can cause cutaneous lesions, with or without systemic signs, through wound contamination or inhalation. The prognosis for nocardiosis is guarded, with treatments often requiring prolonged courses of systemic antimicrobials.

诺卡菌属是常见的土壤腐生菌，可通过伤口污染或吸入引起皮肤病变，伴或不伴全身症状。诺卡菌病预后谨慎，治疗通常需要长期使用全身性抗菌药物。

Hyperbaric oxygen (HBO) therapy (HBOT) has bactericidal effects, works synergistically with antimicrobials and is reportedly safe in cats.This report describes the beneficial use of HBOT with systemic amikacin therapy for the successful treatment of cutaneous nocardiosis.

高压氧(HBO)治疗(HBOT)具有杀菌作用，与抗菌药物协同，据报道对猫安全。本报告描述了HBOT联合全身用阿米卡星成功治疗皮肤诺卡菌病的有益用途。

Case report

病例报告

A 9-year-old spayed female domestic short hair cat was presented with a 16 month history of erythematous nodules affecting the left pinna and base of the left ear. Complete blood count, serum biochemistry and urinalysis were all within normal limits; feline leukaemia virus and feline immunodeficiency virus testing were both negative.

一只9岁雌性绝育家养短毛猫，因16个月以来红斑结节波及左侧耳廓及左耳基部就诊。全血细胞计数、血清生化和尿液分析均在正常范围内；猫白血病病毒和猫免疫缺陷病毒检测均为阴性。

Physical examination showed multiple erythematous nodules with moderate serous exudate along the medial/lateral aspects of the left pinna, with complete alopecia caudally and curling distally (Figure 1). A 2.0×2.1 cm subcutaneous nodule was palpated on the left submandibular region. The remainder of the physical examination was normal. The cat was deemed otherwise healthy.

体格检查可见沿左侧耳廓内/外侧多个红斑结节伴中度浆液性渗出，尾侧完全脱毛，远端卷曲（图1）。左下颌下方可触及2.0×2.1 cm皮下结节。其余体格检查正常。该猫其他方面是健康的。

Fine needle aspiration of the submandibular nodule and impression smear cytological evaluation of the pinna revealed pyogranulomatous inflammation, without infectious organisms. Skin biopsies were acquired for histopathological examination, deep tissue culture (aerobic and anaerobic) and 16S-23S rRNA PCR. Histopathological examination revealed a pyogranulomatous dermatitis. There were multifocal-coalescing pyogranulomas characterized by epithelioid macrophages, neutrophils and multinucleated giant cells, surrounding filamentous bacteria intermixed with eosinophilic, clubshaped radiating structures (Splendore-Hoeppli reaction; Figure 2). Culture grew acid-fast, Gram-positive, rod-shaped organisms consistent with Nocardia spp. Failure to subculture precluded antimicrobial susceptibility testing. PCR (16S-23S rRNA) produced an 851 nucleotide sequence in the reverse direction with 99.88% homology to Nocardia (GenBank MH699195.1, MH091575.1). Forward sequencing could not identify the species. Nocardiosis was diagnosed based on histopathological, microbiological and molecular findings.         

下颌下方结节细针抽吸和耳廓压片细胞学显示脓性肉芽肿性炎症，无微生物感染。采集皮肤活检样本进行组织病理学检查、深部组织培养（需氧和厌氧）和16S-23S rRNA PCR。组织病理学检查提示脓性肉芽肿性皮炎。可见多灶性融合性脓性肉芽肿，其特征为上皮样巨噬细胞、中性粒细胞和多核巨细胞，周围为丝状细菌，混合有嗜酸性、棒状放射结构（Splendore-Hoeppli反应；图2）。培养出抗酸、革兰阳性、杆状微生物，与诺卡菌属一致。传代培养失败导致无法进行药敏试验。PCR(16S-23s rRNA)产生851个反向核苷酸序列，与诺卡菌(GenBank MH699195.1，MH091575.1)的同源性为99.88%。正向测序无法鉴定菌种。根据组织病理学、微生物学和分子结果诊断为诺卡菌病。

Treatment was initiated with HBOT alone due to the cat’s fractious nature with oral medications. A series of 12 HBO treatments, each at 2 atmospheres absolute (ATA) with 45 min duration at pressure, were performed in a HVM Model 3200 Veterinary Hyperbaric Chamber (Hyperbaric Veterinary Medicine; Boca Raton, FL, USA). The initial HBOT involved once daily treatment for six days, then single treatments every three to four days for six additional treatments. Subsequently, there was reduction of erythema and size of nodules, including the submandibular swelling, and resolution of serous exudate (Figure 3). Four weeks after discontinuing HBOT, the submandibular swelling enlarged, with more nodules, ulceration, and exudate of the base of the left ear and pinna. HBOT then was restarted concurrently with amikacin (amikacin sulfate, Sagent Pharmaceuticals; Schaumburg, IL, USA), 9.6 mg/kg subcutaneously once daily. Twice-weekly urinalyses and serum chemistries were evaluated throughout the entire course. HBO treatments were performed once every two to seven days (total of six additional treatments) with no adverse events. After five of these HBO treatments, and three weeks of amikacin, all lesions resolved. The alopecia and curling of the pinna persisted, and pruritus resolved. Twelve days after starting amikacin, urine sediment revealed 0-3 granular casts per high power field with no azotemia. As a consequence of concern for early-onset renal damage, amikacin frequency was decreased to thrice-weekly dosing (Monday, Wednesday, Friday) and then continued for five additional weeks. Amikacin injections were continued thrice weekly for three weeks after the final HBO treatment; the cylindruria resolved. There had been no recurrence of cutaneous lesions 10 months after discontinuation of amikacin and HBOT.

由于猫脾气不好不易喂药，开始单使用HBOT治疗。在HVM 3200型兽医高压氧舱(Hyperbaric Veterinary Medicine；Boca Raton，FL，USA)中进行一系列12次HBO治疗，每次在2个绝对大气压(ATA)下进行，持续45 min。初始HBOT包括每日一次治疗6天，然后每3-4天一次、再治疗6次。随后，红斑和结节尺寸减小，包括下颌下肿胀，浆液性渗出物消退（图3）。停止HBOT后4周，颌下肿胀增大，伴结节增多、溃疡，左耳基部及耳廓渗出。然后重新开始HBOT，同时皮下注射阿米卡星9.6 mg/kg，每日一次。在整个过程中每周做两次尿液分析和血清生化检查。HBO治疗每2-7天进行1次（共额外治疗6次），未见不良反应。在5次HBO治疗和3周阿米卡星治疗后，所有病变均消退。脱毛和耳廓卷曲持续存在，瘙痒消退。开始阿米卡星治疗后12天，尿沉渣显示每个高倍视野有0-3个颗粒管型，无氮质血症。由于担心早期肾损伤，将阿米卡星给药频率降至每周3次（周一、周三、周五），然后再持续5周。末次HBO治疗后继续注射阿米卡星，每周3次，共3周；管型尿消退。停用阿米卡星和HBOT后10个月病变未复发。

Discussion

讨论

Hyperbaric oxygen therapy has been reported to be beneficial when combined with antimicrobials in humans affected by Nocardia. To the best of the authors’ knowledge, this is the first report of HBOT used to successfully treat feline cutaneous nocardiosis. The partial response to HBOT used alone, followed by worsening of lesions once stopping therapy, along with the ability to use less frequent amikacin dosing, suggest at least a synergistic effect against Nocardia. Catalase and superoxide dismutase have been reported as mechanisms through which Nocardia evades oxygen-dependent killing by neutrophils. It has been proposed that high concentrations of oxygen delivered via HBOT saturate these enzymes, which subsequently allow more effective leucocyte-killing capacity. Hyperoxic states also can potentiate the activity of aminoglycosides, prolong the postantibiotic effect, form free radicals with bactericidal effects and stimulate phagocytosis.

据报道，高压氧治疗与抗菌药联合治疗人类诺卡菌患者是有益的。据作者所知，这是HBOT成功用于治疗猫皮肤诺卡菌病的首例报告。单独使用HBOT后症状部分缓解，随后停止治疗后病变恶化，以及降低阿米卡星给药频率的能力，表明至少对诺卡菌有协同治疗作用。据报道，过氧化氢酶和超氧化物歧化酶是诺卡菌逃避中性粒细胞氧依赖性杀伤的机制。有人提出，通过HBOT输送的高浓度氧使这些酶饱和，从而得到更有效的白细胞杀伤力。高氧状态还可增强氨基糖苷类的活性，延长抗生素后效应，形成具有杀菌作用的自由基并刺激吞噬作用。

Amikacin was selected as empirical treatment in this case owing to easier administration and the proportionally high number of cats with nocardiosis displaying susceptibility to amikacin. Thrice-weekly dosing has been reported in treating Mycobacteria spp. in humans and could possibly reduce persistent drug levels that can contribute to renal injury. Further controlled studies are needed to support the safety and efficacy of less frequent amikacin dosing when combined with HBOT.

在本病例中，选择阿米卡星作为经验性治疗是由于更容易给药和诺卡菌病患猫对阿米卡星表现出敏感性的比例较高。据报道，在人医每周给药3次可治疗分枝杆菌属且可降低导致肾损伤的持续性药物水平。需要进一步的对照研究来支持联合HBOT时较低频率给予阿米卡星的安全性和疗效。

Figure 1. Pinnal lesions of the left ear in a cat affected by Nocardia spp. Note the erythematous nodules with moderate serous exudate and crusting along the medial, lateral and marginal aspects of the left pinna (a). There is complete alopecia on the lateral side of the pinna along with curling of the distal portion (b).

图1.诺卡菌感染猫的左侧耳廓病变。注意红斑结节伴中度浆液性渗出物和左耳廓内侧、外侧和边缘结痂(a)。耳廓外侧完全脱毛，远端部分卷曲(b)。

Figure 2. Photomicrograph of skin from a cat with cutaneous nocardiosis. (a) Severe, multifocal-coalescing, chronic, pyogranulomatous dermatitis. Haematoxylin & eosin,×20. (b) Pyogranulomas characterized by epithelioid macrophages, multinucleated giant cells and neutrophils; there are abundant bacteria in the centre. H&E, ×400. (c) Higher magnification of the bacteria in the centre of the pyogranulomas. H&E, ×600. (d) Bacteria in the centre of the pyogranulomas are filamentous and Gram-positive; there is eosinophilic, club-shaped, radiating material (Splendore–Hoeppli reaction; arrow). Gram stain, ×600.

图2. 皮肤诺卡菌病患猫的皮肤显微照片。(a)重度、多灶性融合、慢性、脓性肉芽肿性皮炎。苏木精-伊红染色，×20. (b)以上皮样巨噬细胞、多核巨细胞和中性粒细胞为特征的脓性肉芽肿；中央有丰富的细菌。H&E,×400.  (c)脓性肉芽肿中央细菌的高倍放大。H&E，×600. (d)脓肉芽肿中央的细菌为丝状、革兰阳性；存在嗜酸性、棒状、放射状物质（Splendore-Hoeppli反应；箭头所示）。革兰染色，×600。

Figure 3. Post-treatment pictures of the left ear in a cat affected by Nocardia spp. A reduction in the number of nodules and the degree of erythema and exudate affecting the left pinna is noted after 12 hyperbaric oxygen treatments (without amikacin) over the course of 15 days (a). After six additional hyperbaric oxygen treatments along with six weeks of subcutaneous amikacin injections there was complete resolution of all lesions (b).

图3. 诺卡菌感染猫左耳治疗后图片。在15天的12次高压氧治疗（无阿米卡星）后，观察到累及左侧耳廓的结节数量以及红斑和渗出程度减少(a)。在6次额外的高压氧治疗以及6周的阿米卡星皮下注射后，所有病变均完全消退(b)。

红蓝紫

洋芋那个土豆

Ryohei

马海军