兽研引言
暗色丝孢霉病是指由在宿主组织内增殖的深色色素（黑化）丝状真菌引起的一组多样化的感染。涉及众多菌属，最常见的是链格孢属、枝孢瓶霉属、小球壳孢属、Lomentospora属和瓶霉属。这类腐生生物在环境中普遍存在，呈全球性分布。尽管疾病仍不常见，但人类和动物的感染发病率持续增加。感染通常为机会性，因环境（土壤、木材和腐烂植物）中的创伤性接种而发生。好发部位包括面部区域（鼻部）和远端肢体（趾部），因为这些部位最常接触周围环境。分布通常为皮肤或皮下组织内的局灶性或多灶性局部侵袭，但也有播散性疾病的报道。免疫功能正常和免疫功能受损的猫均可发病，免疫抑制被认为是疾病发展和血行播散的危险因素。
暗色丝孢霉病通常可通过病变色素沉着与其他皮肤病相鉴别。其黑色素色素是关键的毒力因子，人类的全身性感染常与不良预后相关。诊断通过细胞学或组织病理学上观察到黑化真菌成分来实现。特殊染色如Fontana-Masson染色、Grocott-Gomori六胺银染色或过碘酸-雪夫染色可突出显示真菌细胞壁和黑色素，从而优化诊断敏感性。沙氏葡萄糖琼脂（SDA）、麦芽浸膏琼脂、抑制性霉菌琼脂和马铃薯葡萄糖琼脂支持暗色丝孢霉病病原生长，最适温度为25-37°C。暗色丝孢霉病属和种的鉴定需要通过泛真菌聚合酶链反应（PCR）进行分子检测，优先使用从病变组织真菌培养物中提取的DNA，但也可使用直接从福尔马林固定石蜡包埋或新鲜或冷冻组织样本中获得的DNA。随后可利用DNA测序进行物种确认。
Cladophialophora boppii在人类中罕有报道，据我们所知尚未在动物中报道。既往病例报告详述了皮肤、甲、眼部和肺部移植组织感染。迄今为止，仅Cladophialophora bantiana和一例Cladophialophora carrionii被记录为猫的致病菌。C. bantiana主要具有嗜神经性，经典地引起猫、犬和人类的中枢神经系统疾病。然而，C. bantiana感染的猫也可发生鼻部皮肤、全身性、肺部和肾脏疾病。同样，犬中也有皮下和全身性疾病的报道。唯一一例猫C. carrionii病例记录了真菌性腹膜积液。
在动物中鉴定出一种新的暗色丝孢霉病病原（C. boppii），增加了日益增多的侵袭性真菌病报道病例，这可能受到环境变化的影响。
病例描述
一只7岁、5.6 kg、雄性去势家养短毛猫就诊，有4个月慢性干性打喷嚏、喘鸣性呼吸音、鼻背侧色素沉着和间歇性溃疡的病史。该猫生活在单猫家庭，无旅行史，可进出室内外。临床症状的严重程度随时间波动，对症治疗效果不佳。伴随的健康问题包括先天性会聚性斜视。该猫表现出中度至明显的喘鸣呼吸，胸部听诊可闻及上呼吸道传导音。鼻部检查发现鼻背侧轻度隆起和深色色素沉着，无溃疡、坏死、渗出或结节（图1A）。注意到轻度双侧下颌淋巴结肿大，其余体格检查无异常。
[图：鼻部暗色丝孢霉病病变的进展。(A) 初诊时的色素性鼻部病变。(B, C) 鼻部病变]
血液学和生化检查未发现临床相关异常。猫免疫缺陷病毒抗体和猫白血病病毒抗原血清学检测（IDEXX-SNAP FIV/FeLV Combo Test）为阴性。
在增强CT上，左侧鼻孔和右侧鼻孔的一部分被轻度对比增强的软组织衰减物质完全闭塞，该物质从吻侧向尾侧延伸进入双侧鼻腔（图2A-C）。病变导致鼻背侧畸形，伴双侧鼻骨侵蚀和轻度下颌淋巴结增大。未发现颈部或胸部异常。未进行腹部影像学检查。
[图：暗色丝孢霉病相关鼻部病变（箭头）的对比增强计算机断层扫描，以矢状位骨窗显示]
逆行鼻镜检查未见异常。顺行鼻镜检查因猫体型限制而无法进行。鼻部病变细针穿刺细胞学检查发现真菌菌丝和酵母样成分，伴有明显的混合性中性粒细胞性（非脓毒性）和巨噬细胞性炎症（补充文件；图3）。从病变处采集了三份打孔活检样本，其中一份送检进行组织病理学评估。检查显示严重的肉芽肿性皮炎，病变内可见色素性真菌酵母和菌丝形态，符合皮肤着色芽生菌病（补充材料；图4）。
[图：暗色丝孢霉病鼻部病变细针抽吸物的细胞学检查，显示真菌菌丝（黑色箭头）和]
[图：暗色丝孢霉病鼻部病变活检样本的组织病理学。带毛皮肤，真皮内浸润大量]
第二份活检样本在大学微生物实验室接种于Sabouraud葡萄糖琼脂（SDA；Oxoid，Thermo Fischer Scientific，Basingstoke，英国），在25°C培养3周后分离出一种生长缓慢、深色色素真菌（图5）。第三份活检样本在磷酸盐缓冲盐水中于–80°C冷冻，送至曼彻斯特真菌学参考中心（MRCM）进行培养和分子鉴定。测序由德国Eurofins Genomics GmbH提供。通过PCR扩增及内转录间隔区（ITS）和β-微管蛋白区域（使用ITS5/4）测序，并与参考序列比对，确认该微生物为C. boppii 21–23（补充材料）。最终菌种鉴定结果在猫初次就诊后十周获得。抗真菌药敏试验在MRCM按照EUCAST指南进行。试验表明伊曲康唑及所有其他抗真菌药的最低抑菌浓度（MIC）> 8 μg/mL。该菌种的解释折点尚未建立，这些结果的临床相关性无法确定。
[图：大学微生物实验室在沙氏葡萄糖琼脂上分离出的生长缓慢、深色色素沉着的真菌]
基于着色芽生菌病的组织病理学诊断，在等待菌种鉴定和药敏试验期间，经验性开始口服伊曲康唑（Intrafungol 10 mg/mL，Lusomedicamenta，Sociedade Técnica Farmacêutica，S.A.，Barcarena，葡萄牙；5 mg/kg PO q12h）。主人最初拒绝手术清创。第7周时临床症状保持稳定，但至第15周时病变明显进展（图1B和C）。猫出现鼻镜严重坏死、明显喘鸣、厌食和显著体重减轻（约2 kg；体况评分[BCS] 2/9）。临床检查发现黄疸、黏膜干燥、毛细血管再充盈时间延长、脉搏微弱、中度心动过速（200 bpm）和眼球内陷。血液学检查未见异常。生化检查发现轻度高胆红素血症（1.87 mg/dL；参考区间[RI]，0.1-0.3）以及碱性磷酸酶（433.8 U/L；RI，0-66）、丙氨酸氨基转移酶（381 U/L；RI，0-45）和天冬氨酸转移酶（142 U/L；RI，0-70）活性显著升高。鉴于疾病已处于晚期，进一步诊断（包括腹部超声检查和胆汁酸刺激试验）未予进行，因为结果不太可能改变治疗方案。
猫住院接受复方乳酸钠静脉输液治疗（Aqupharm 11，Infomed Fluids SRL，布加勒斯特，罗马尼亚；5 mL/kg/h）、丁丙诺啡（Buprecare Multidose .3 mg/mL，Produlab Pharma B.V.，Raamsdonksveer，荷兰；20 μg/kg IV q8h）、马罗匹坦（Vominil 10 mg/mL，VetViva Richter GmbH，Wels，奥地利；1 mg/kg IV q24h）和局部米氮平（Mirtaz 20 mg/g，Genera Inc，Rakov Potok，克罗地亚；3.8 cm涂于耳廓内侧 q24h）。由于肝胆酶活性升高和高胆红素血症，停用伊曲康唑。主人随后在鼻部病变处局部使用未指明制剂和剂量的特比萘芬2周。在此期间，尽管继续局部使用米氮平，猫仍保持食欲减退。在病变最坏死部分自发脱落之后停用特比萘芬。初次就诊后二十三周，猫再次接受评估。尽管全身状况明显改善，局部鼻部病变在临床上仍很重要。由于 underlying 骨结构破坏继发鼻镜吸气时塌陷，猫出现明显的吸气性呼吸困难（视频1）。此时，主人选择进行手术干预，生化检查显示先前的肝胆异常已消退。
进行了第二次头、颈和胸部CT以评估疾病范围并指导手术规划（图2D-F）。术中，感染显示深部组织侵犯，伴有鼻骨和鼻甲坏死。鉴于受累严重，实施了根治性手术清创联合鼻镜切除术，而非更保守的手术。术后恢复顺利。
术后三周，手术部位已愈合，猫恢复正常食欲和体重（4.5 kg；BCS，4/9）。该猫无病生存5个月后，暗色丝孢霉病复发，表现为鼻部重建区背外侧的孤立性小棕色坏死性斑块。病灶经手术清创，并重新以较低剂量口服伊曲康唑（5 mg/kg PO q24h；图1D）。每2个月在初级诊疗机构进行生化检查以进行治疗监测，未发现肝胆酶活性升高。
最终，真菌感染及相关呼吸系统症状消退。在重复手术清创后，提供了6个月的抗真菌治疗以防止疾病复发。尽管临床过程复杂且迁延，但结局良好，猫的生活质量显著改善。初次就诊后2年，该猫存活且无疾病复发。
讨论
据我们所知，本病例是猫或任何其他兽医物种中C. boppii感染的首例报告。它为侵袭性真菌感染发病率增加和地理传播的新兴证据提供了补充，这种模式可能受气候变化影响。2–6
显著的深色鼻部色素沉着是本病例的不寻常且决定性特征。鉴别诊断包括其他色素性真菌感染，如黑曲霉，24而鼻部黑色素瘤被认为可能性较小，因为缺乏 underlying 真皮色素沉着。25
本病例的一个挑战是就诊与暗色丝孢霉病属和种分子鉴定之间的间隔延长，可能使临床管理复杂化并延迟靶向治疗。这一延迟主要反映了地理区域因素，该地区真菌感染不常见，且真菌分子检测的兽医资源有限。本病例强调了将暗色丝孢霉病识别为色素性鼻部病变鉴别诊断的重要性，以鼓励在类似病例中更早进行诊断和治疗干预。细胞学和组织病理学是真菌感染诊断的基础，尤其是当培养和分子鉴定延迟或不可用时。在暗色丝孢霉病中，细胞学或组织学上在脓性肉芽肿性炎症内观察到色素性真菌成分通常足以支持推定诊断并启动经验性抗真菌治疗，特殊染色可进一步提高诊断敏感性。2然而，最佳实践要求快速准确的种级鉴定，以实现适当的抗真菌治疗。26鉴于存在100多种毒力各异的暗色丝孢霉病物种，抗真菌药敏试验应在治疗计划中发挥核心作用。即使药敏试验不可用，分子鉴定也有助于选择最合适的经验性治疗。26这一选择由不同真菌属和种的抗真菌敏感性概况的一般信息指导。2,26由于C. boppii物种的可用数据不足，本病例无法进行正式的抗真菌敏感性分类。随着更多病例被识别和数据收集，这种情况可能会改变。尽管存在这一局限性，报告的伊曲康唑MIC > 8 μg/mL超过了猫在5 mg/kg剂量下通常可达到的血浆浓度，这可能提示敏感性降低。27在这种情况下，手术干预可能在感染的成功管理中发挥了关键作用。
主人依从性，特别是关于治疗药物监测方面，是本病例的另一局限性。在伊曲康唑相关肝损伤病例中建议减少剂量，因为较低的总体暴露可能减轻猫的肝毒性复发。26在本病例中，虽然无法明确确认伊曲康唑相关肝毒性，但它被认为是肝胆酶活性升高的主要鉴别诊断，停药后该升高消退，支持药物不良反应。第二次手术清创后，伊曲康唑以降低的剂量重新开始，为5 mg/kg每日一次，而初始方案为5 mg/kg每日两次。提供了延长的6个月疗程以预防疾病复发，且耐受良好。第二次疗程伴随严格的治疗监测，每2个月进行血清生化检查。这样做有助于早期发现潜在的药物相关不良反应并确保治疗依从性，强调了在长期抗真菌治疗期间持续生化监测的重要性。26
本病例的另一局限性在于缺乏腹部影像学检查，无法筛查可能促成免疫抑制或影响治疗反应的合并症。尽管初诊时血液学、生化和逆转录病毒检测均无异常，但CT仅局限于头、颈和胸部，无法排除潜在的腹部病变。在发现肝病后这一局限性尤为突出，此时腹部影像学可能有助于深入了解影响免疫功能、抗真菌药物耐受性和疾病进展的潜在肝脏或腹部病变。
现行指南建议术后进行长期抗真菌治疗以降低暗色丝孢霉病复发的风险。26在本病例中，由于患猫有疑似肝毒性病史且首次手术进行了积极的清创，因此未在首次手术后进行延长的术后抗真菌治疗。随后的疾病复发强调了过早停用全身性抗真菌药物的潜在后果，尤其是对于诸如C. boppii等侵袭性真菌病原体。
本病例支持对暗色丝孢霉感染进行早期、积极且持续干预的必要性。更早的根治性手术切除和适当的抗真菌治疗可能已最大限度地减少了手术并发症、疾病负担和重复干预的需求。本报告强调了早期准确诊断及真菌菌种鉴定，结合手术清创、仔细监测和个体化抗真菌治疗在管理猫侵袭性真菌感染中的重要性。
已有九篇病例报告描述了C. boppii在人类中引起不同程度的疾病严重程度。在较轻的一端，皮肤和甲病对 varying 疗程的口服terbinafine或itraconazole联合辅助局部抗真菌药（如ciclopiroxolamine用于甲真菌病管理）有反应。8,9,28一例较深的皮肤感染通过手术切除和3周口服itraconazole成功治愈。29在严重的一端，一篇报告详述了眼部疾病，另一篇报告详述了移植受者的肺部疾病，两者对治疗反应均不佳且伴有显著发病率。10,11本文报告的病例似乎代表了该谱系中的中间表型。与严重病例不同，该病最终通过2次手术清创及随后的延长itraconazole治疗得到控制。局部terbinafine的影响无法确定，可能是一个潜在的混杂因素。由于制剂和剂量未知，其临床效果无法评估。坏死性鼻镜脱落更可能归因于进行性缺血性组织坏死，而非治疗反应。
有记录的侵袭性真菌病病例有所增加。2–6这种情况可能是多因素的，可能反映了地理分布的扩大和高危人群的增加。致病真菌地理分布的扩大被认为是由气候变化引起的，包括气温升高、降水趋势波动和生态不稳定。4免疫功能低下的个体，包括接受器官移植、化疗、侵入性医疗干预以及因COVID-19接受免疫调节的患者，尤其易感。3–6尽管目前有有效的抗真菌药物可用，但抗真菌耐药性的增加以及真菌学和抗真菌治疗方面相对有限的医学和兽医研究仍然是重要关切。26
总之，我们的报告记录了一例猫C. boppii感染病例，并为这一新兴病原体的管理提供了见解。无论免疫状态如何，暗色丝孢霉病应作为猫色素性鼻部和皮肤病变的鉴别诊断之一。成功的结果需要早期、积极的手术清创以及长期、仔细监测的抗真菌治疗。鉴于治疗延迟或中断常导致疾病进展或复发，临床警惕对于应对这些真菌感染相关的显著发病率至关重要。
补充材料
[内容请查看原文]
致谢
作者感谢都柏林大学兽医学院所有参与该患者护理的同事，包括小动物外科、形态病理学、临床病理学、微生物学和诊断影像部门。我们还感谢Brian Cloak和Pamela Kelly博士，BSc (hons), MVB, PhD, FRCPath, DCVP, ProfDipUTL, MRCVS，感谢他们在准备组织病理学图像方面的贡献。
缩写
体况评分
每分钟心跳次数
计算机断层扫描
最低抑菌浓度
曼彻斯特真菌学参考中心
参考区间
沙氏葡萄糖琼脂
贡献者信息
Julia McCarthy，都柏林大学兽医学院，爱尔兰都柏林D04 W6F6。
Monica Augusto，都柏林大学兽医学院，爱尔兰都柏林D04 W6F6。
Emma O'Neill，都柏林大学兽医学院，爱尔兰都柏林D04 W6F6。
Ignacio Otero Balda，都柏林大学兽医学院，爱尔兰都柏林D04 W6F6。
Eleanor Wyatt，Northwest Veterinary Specialists，Linnaeus Ltd 旗下机构，英国朗科恩 WA7 3FW。
作者贡献
Julia McCarthy（研究实施、可视化、撰写—初稿、撰写—审阅与编辑）、Monica Augusto（撰写—审阅与编辑）、Emma Jane O’Neill（撰写—审阅与编辑）、Ignacio Otero Balda（撰写—审阅与编辑）、Eleanor K. Wyatt（撰写—审阅与编辑）
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已就本研究所涉及的全部治疗与操作，取得本研究所描述动物所有者的知情同意（口头及书面）。
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Introduction
Phaeohyphomycoses refers to a diverse group of infections caused by darkly pigmented (melanized) filamentous fungi proliferating within host tissues.1 Numerous genera have been implicated, most commonly Alternaria, Cladophialophora, Microsphaeropsis, Lomento-spora, and Exophiala species.2 This class of saprophytic organisms is ubiquitous in the environment and has a worldwide distribution. Although disease remains uncommon, the incidence of infection continues to increase in humans and animals.2–6 Infections are typically opportunistic and occur as a result of traumatic inoculation from the environment (soil, wood, and decomposed plants). Predilection sites include the facial region (nose) and distal extremities (digits) because they are most frequently in contact with the surrounding environment.1 The distribution is usually focal or multifocal local invasion within cutaneous or subcutaneous tissues, but disseminated disease has been described.1 Both immunocompetent and immunocompromised cats may be affected, with immunosuppression recognized as a risk factor for disease development and hematogenous spread.1,2
Phaeohyphomycosis typically can be distinguished from other dermatopathies by the presence of lesional pigmentation.1 Their melanin pigment is a key virulence factor, and systemic infections in humans often are associated with a poor prognosis.7 Diagnosis is achieved by visualization of melanized fungal elements on cytology or histopathology. Special stains such as Fontana-Masson, Grocott-Gomori’s methenamine silver or periodic acid-Schiff, highlight fungal cell walls and melanin, thus optimizing diagnostic sensitivity.2 Sabouraud’s dextrose agar (SDA), malt extract agar, inhibitory mold agar and potato dextrose agar, support growth of phaeohyphomycosis, at an optimal temperature of 25-37 °C.2 Identification of phaeohyphomycosis genera and species necessitates molecular testing by panfungal polymerase chain reaction (PCR), preferentially of DNA extracted from fungal culture of diseased tissue, but DNA obtained directly from formalin-fixed paraffin-embedded or fresh or frozen tissue samples also can be used.2 Sequencing of DNA then can be utilized for species confirmation.2
Cladophialophora boppii has been described rarely in humans and to our knowledge not in animals. Previous case reports have detailed cutaneous, nail, ocular, and pulmonary transplant tissue infections.8–11 Thus far, only Cladophialophora bantiana and one case of Cladophialophora carrionii have been documented as pathogenic in cats.12,13 C. bantiana is predominantly neurotropic, classically causing central nervous system disease in cats, dogs, and humans.12,14 However, nasal cutaneous, systemic, pulmonary, and renal disease also have occurred in cats with C. bantiana infection.15–18 Similarly, subcutaneous and systemic disease has been reported in dogs.19,20 The single C. carrionii case in a cat documented fungal peritoneal effusion.13
The identification of a novel species of phaeohyphomycosis (C. boppii) in an animal adds to the growing number of reported cases of invasive mycoses, which may be influenced by environmental change.2–6
Case description
A 7-year-old, 5.6 kg, male neutered domestic shorthair cat was presented with a 4-month history of chronic nonproductive sneezing, stertorous respiratory noises, with dark pigmentation and intermittent ulceration of the dorsal rhinarium. The cat lived in a single cat household, had no travel history, and had access to indoors and outdoors. The severity of the clinical signs had fluctuated over time with a poor response to symptomatic treatment. Concomitant health issues included congenital convergent strabismus. The cat displayed moderate to marked stertorous breathing with referred upper respiratory tract noise on thoracic auscultation. Nasal assessment identified mild protuberance and dark pigmentation of the rostral dorsal rhinarium without ulceration, necrosis, exudation, or nodularity (Figure 1A). Mild bilateral submandibular lymphadenomegaly was noted, but the remaining physical examination was unremarkable.
[图：Progression of nasal phaeohyphomycosis lesion. (A) Pigmented nasal lesion at initial presentation. (B, C) Nasal lesion f]
Hematology and biochemistry identified no clinically relevant abnormalities. Serology for feline immunodeficiency virus antibody and feline leukemia virus antigen (IDEXX-SNAP FIV/FeLV Combo Test) was negative.
On contrast-enhanced CT the left nostril and a portion of the right were completely obliterated by mildly contrast enhancing, soft tissue attenuating material, which extended rostro-caudally into both nasal cavities (Figure 2A-C). The lesion caused dorsal rhinarium deformity with bilateral nasal bone erosion and mild mandibular lymph node enlargement. No cervical or thoracic abnormalities were identified. Abdominal imaging was not performed.
[图：Contrast-enhanced computed tomography of the phaeohyphomycosis-associated nasal lesion (Arrows), shown in sagittal bone ]
Retrograde rhinoscopy was unremarkable. Antegrade rhinoscopy was precluded by the cat’s size. Cytology of a fine-needle aspirate from the nasal lesion identified fungal hyphae and yeast-like elements with marked, mixed, neutrophilic (non-septic), and macrophagic inflammation (Supplementary file; Figure 3). Three punch biopsy samples were obtained from the lesion, one of which was submitted for histopathologic evaluation. Examination indicated severe granulomatous dermatitis with intralesional pigmented fungal yeast and hyphal forms, consistent with cutaneous phaeohyphomycosis (Supplementary material; Figure 4).
[图：Cytology of fine needle aspirates from the phaeohyphomycosis nasal lesion demonstrating fungal hyphae (black arrow) and ]
[图：Histopathology of a biopsy sample from the phaeohyphomycosis nasal lesion. Haired skin with dermal infiltration of numer]
A second biopsy sample was cultured on Sabouraud's dextrose agar (SDA; Oxoid, Thermo Fischer Scientific, Basingstoke, United Kingdom) at the university microbiology laboratory, isolating a slow growing, darkly pigmented fungus after 3 weeks at 25 °C (Figure 5). The third biopsy sample was frozen in phosphate-buffered saline at –80 °C and submitted to the Mycology Reference Centre Manchester (MRCM) for culture and molecular identification. Sequencing was provided by Eurofins Genomics GmbH, Germany. Amplification by PCR and sequencing of the internal transcribed spacers (ITS) and β-tubulin region (using ITS5/4) followed by comparison to reference sequences confirmed the organism as C. boppii 21–23 (Supplementary material). Definitive speciation results became available ten weeks after the cat’s initial presentation. Antifungal susceptibility testing was performed at MRCM, according to the EUCAST guidelines. Testing indicated a minimum inhibitory concentration (MIC) > 8 μg/mL for itraconazole and all other antifungals. Interpretive breakpoints for this species have not been established, and the clinical relevance of these results could not be determined.
[图：The slow growing, darkly pigmented fungus isolated on Sabouraud dextrose agar at the university microbiology laboratory ]
Oral itraconazole (Intrafungol 10 mg/mL, Lusomedicamenta, Sociedade Técnica Farmacêutica, S.A., Barcarena, Portugal; 5 mg/kg PO q12h) was empirically started based on the histopathologic diagnosis of phaeohyphomycosis, while pending species identification and susceptibility testing. Surgical debridement initially was declined by the owners. At 7 weeks, clinical signs remained static, but by week 15, the lesion had progressed substantially (Figure 1B and C). The cat developed severe necrosis of the nasal planum, pronounced stertor, anorexia, and marked weight loss (approximately 2 kg; body condition score [BCS], 2/9). Clinical examination identified jaundice, dry mucous membranes, prolonged capillary refill time, weak pulses, moderate tachycardia (200 bpm), and enophthalmos. Hematology was unremarkable. Biochemistry identified mild hyperbilirubinemia (1.87 mg/dL; reference interval [RI], 0.1-0.3) and marked increases in alkaline phosphatase (433.8 U/L; RI, 0-66), alanine aminotransferase (381 U/L; RI, 0-45), and aspartate transferase (142 U/L; RI, 0-70) activities. Further diagnostics, including abdominal ultrasonography and a bile acid stimulation test, were not pursued because the results were unlikely to alter the treatment plan given the advanced stage of disease.
The cat was hospitalized and treated with compounded sodium lactate IV fluid therapy (Aqupharm 11, Infomed Fluids SRL, Bucharest, Romania; 5 mL/kg/h), buprenorphine (Buprecare Multidose .3 mg/mL, Produlab Pharma B.V., Raamsdonksveer, the Netherlands; 20 μg/kg IV q8h), maropitant (Vominil 10 mg/mL, VetViva Richter GmbH, Wels, Austria; 1 mg/kg IV q24h), and topical mirtazapine (Mirtaz 20 mg/g, Genera Inc, Rakov Potok, Croatia; 3.8 cm applied to the inner pinna q24h). Because of increased hepatobiliary enzyme activity and hyperbilirubinemia, itraconazole was discontinued. The owner subsequently applied an unspecified formulation and dose of topical terbinafine to the nasal lesion for 2 weeks. During this period, the cat remained hyporexic despite continued topical mirtazapine administration. Terbinafine was discontinued after spontaneous sloughing of the most necrotic aspect of the lesion. Twenty-three weeks after initial presentation, the cat was re-evaluated. Despite marked systemic improvement, the localized nasal lesion remained clinically important. The cat exhibited marked inspiratory dyspnea because of collapse of the nasal planum on inhalation, secondary to destruction of the underlying bony structures (Video 1). At this point, the owner elected to pursue surgical intervention and biochemistry showed resolution of previous hepatobiliary abnormalities.
A second CT of the head, neck, and thorax was performed to assess disease extent and guide surgical planning (Figure 2D-F). Intraoperatively, the infection demonstrated deep tissue invasion, with necrosis of the nasal bone and turbinates. Given the severity of involvement, radical surgical debridement with nasal planectomy was performed instead of a more conservative procedure. Post-operative recovery was uneventful.
Three weeks postoperatively, the surgical site was healed, and the cat had regained normal appetite and weight (4.5 kg; BCS, 4/9). The cat remained disease-free for 5 months before recurrence of phaeohyphomycosis as isolated small brown necrotic plaques on the dorsolateral aspect of the nasal reconstruction. The lesions were surgically debrided and PO itraconazole was reintroduced at a lower dosage (5 mg/kg PO q24h; Figure 1D). Biochemistry for therapeutic monitoring was performed at the primary practice every 2 months and no increase in hepatobiliary enzyme activity was noted.
Ultimately, the fungal infection and associated respiratory signs resolved. Antifungal treatment was provided for 6 months to prevent disease recrudescence after repeat surgical debridement. Despite a complex and protracted clinical course, the outcome was favorable, with substantial improvement in the cat’s quality of life. The cat was alive with no disease recurrence 2 years after initial presentation.
Discussion
To our knowledge, this case represents the first report of C. boppii infection in a cat or any other veterinary species. It contributes to emerging evidence of increasing incidence and geographic spread of invasive fungal infections, a pattern that may be influenced by climate change.2–6
Prominent dark nasal pigmentation was an unusual and defining feature of this case. Differential diagnoses included other pigmented fungal infections, such as Aspergillus niger,24 whereas nasal melanoma was considered less likely, given the absence of underlying dermal pigmentation.25
A challenge in this case was the prolonged interval between presentation and molecular identification of the phaeohyphomycosis genus and species, potentially complicating clinical management and delaying targeted treatment. This delay primarily reflected the geographical region, where fungal infections are uncommon, and veterinary resources for fungal molecular testing are limited. This case emphasizes the importance of recognizing phaeohyphomycosis as a differential diagnosis for pigmented nasal lesions to encourage earlier diagnostic and therapeutic intervention in comparable cases. Cytology and histopathology are fundamental to fungal infection diagnosis, particularly when culture and molecular identification are delayed or unavailable. In phaeohyphomycosis, visualization of pigmented fungal elements within pyogranulomatous inflammation on cytology or histology is often sufficient to support a presumptive diagnosis and initiate empirical antifungal treatment, with special stains further enhancing diagnostic sensitivity.2 Best practice, however, dictates rapid and accurate species-level identification to enable appropriate antifungal treatment.26 In view of the existence of over 100 phaeohyphomycosis species with variable virulence, antifungal susceptibility testing should play a central role in therapeutic planning. Even when susceptibility testing is unavailable, molecular identification supports selection of the most appropriate empirical treatment.26 This selection is guided by general information of antifungal susceptibility profiles across different fungal genera and species.2,26 Formal antifungal susceptibility categorization in this case was not possible because of insufficient available data for the C. boppii species. This situation is likely to change if as more cases are recognized and data is gathered. Despite this limitation, the reported MIC of > 8 μg/mL for itraconazole exceeded plasma concentrations typically achievable in cats at a dosage of 5 mg/kg, which may have suggested decreased susceptibility.27 In this context, surgical intervention likely played a key role in successful management of the infection.
Owner compliance, particularly regarding therapeutic drug monitoring, was an additional limitation in this case. Dose reduction is recommended in cases of itraconazole-associated hepatic injury because lower overall exposure may mitigate hepatotoxicity recurrence in cats.26 In this case, although itraconazole-associated hepatotoxicity could not be definitively confirmed, it was considered the primary differential diagnosis for the increased hepatobiliary enzyme activity, which resolved after drug discontinuation, supporting an adverse drug effect. After the second surgical debridement, itraconazole was re-initiated at a decreased dosage of 5 mg/kg once daily, compared with the initial regimen of 5 mg/kg twice daily. An extended 6-month course was provided to prevent disease recrudescence and was well tolerated. Strict therapeutic monitoring accompanied this second course, with serum biochemistry performed every 2 months. Doing so facilitated early detection of potential drug-related adverse effects and ensured treatment adherence, emphasizing the importance of ongoing biochemical monitoring during prolonged antifungal treatment.26
Another limitation of this case was the absence of abdominal imaging to screen for comorbidities that may have contributed to immunosuppression or influenced treatment response. Although hematology, biochemistry, and retroviral testing were unremarkable at initial presentation, CT was limited to the head, neck, and thorax, and potential abdominal pathology could not be excluded. This limitation became particularly relevant after the identification of hepatopathy where abdominal imaging may have provided additional insight into underlying hepatic or abdominal lesions affecting immune function, antifungal tolerance, and disease progression.
Current guidelines recommend prolonged antifungal treatment after surgery to minimize the risk of phaeohyphomycosis recurrence.26 In this case, extended postoperative antifungal treatment was withheld after the first surgery because of the cat’s history of suspected hepatotoxicity and the aggressive surgical debridement performed. The subsequent disease relapse emphasizes the potential consequences of prematurely discontinuing systemic antifungals, particularly with invasive fungal pathogens such as C. boppii.
This case supports the need for early, aggressive, and sustained intervention in phaehyphomycosis infections. Earlier radical surgical excision and appropriate antifungal treatment may have minimized surgical morbidity, disease burden and the need for repeat interventions. This report emphasizes the importance of early accurate diagnosis with fungal species identification, alongside surgical debridement, careful monitoring, and tailored antifungal treatment in managing invasive fungal infections in cats.
Nine case reports have described C. boppii causing a spectrum of disease severity in humans. At the milder end, cutaneous and nail disease responded to variable courses of PO terbinafine or itraconazole with adjunctive topical antifungals such as ciclopiroxolamine in onychomycosis management.8,9,28 A deeper cutaneous infection was successfully managed with surgical excision and 3 weeks of PO itraconazole.29 At the severe end, one report detailed ocular disease, and another pulmonary disease in a transplant recipient, both of which were poorly responsive to treatment and associated with substantial morbidity.10,11 The case reported here appears to represent an intermediate phenotype within this spectrum. Unlike the severe cases, disease was ultimately managed with 2 surgical debridements followed by extended itraconazole treatment. The impact of topical terbinafine could not be determined and may represent a potential confounding factor. Because the formulation and dosage were unknown, its clinical effect could not be evaluated. The sloughing of the necrotic nasal planum was more likely attributable to progressive ischemic tissue necrosis rather than a treatment response.
Documented cases of invasive fungal diseases have increased.2–6 This situation is likely multifactorial, potentially reflecting both increases in geographic distribution and a growing population of at-risk individuals. The expanding geographical distribution of pathogenic fungi is thought to result from climate change, through rising temperatures, fluctuating precipitation trends, and ecological instability.4 Immunocompromised individuals including those receiving organ transplantation, chemotherapy, invasive medical interventions, and patients who have received immunomodulation for COVID-19, are particularly susceptible.3–6 Although effective antifungal drugs are currently available, increasing antifungal resistance and relatively limited medical and veterinary research into mycology and antifungal treatment remain important concerns.26
In summary, our report documents a case of C. boppii infection in a cat and provides insight into the management of this emerging pathogen. Phaeohyphomycosis should be considered a differential diagnosis for pigmented nasal and cutaneous lesions in cats, regardless of immunologic status. Successful outcomes necessitate early, aggressive surgical debridement alongside prolonged, carefully monitored antifungal treatment. Given that treatment delays or interruptions frequently lead to disease progression or recurrence, clinical vigilance is essential in addressing the substantial morbidity associated with these fungal infections.
Supplementary Material
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Acknowledgments
The authors thank all colleagues at University College Dublin Veterinary Hospital who were involved in the care of this patient, including small animal surgery, morphological pathology, clinical pathology, microbiology, and diagnostic imaging departments. We also thank Brian Cloak and Dr. Pamela Kelly, BSc (hons), MVB, PhD, FRCPath, DCVP, ProfDipUTL, MRCVS for their contributions in preparing the histopathology images.
Abbreviations
BCSbody condition score
bpmbeats per minute
CTcomputed tomography
MICminimum inhibitory concentration
MRCMMycology Reference Centre Manchester
RIreference interval
SDASabouraud’s dextrose agar
Contributor Information
Julia McCarthy, School of Veterinary Medicine, University College Dublin, Dublin D04 W6F6, Ireland.
Monica Augusto, School of Veterinary Medicine, University College Dublin, Dublin D04 W6F6, Ireland.
Emma O'Neill, School of Veterinary Medicine, University College Dublin, Dublin D04 W6F6, Ireland.
Ignacio Otero Balda, School of Veterinary Medicine, University College Dublin, Dublin D04 W6F6, Ireland.
Eleanor Wyatt, Northwest Veterinary Specialists, Part of Linnaeus Ltd, Runcorn WA7 3FW, United Kingdom.
Author contributions
Julia McCarthy (Investigation, Visualization, Writing—original draft, Writing—review & editing), Monica Augusto (Writing—review & editing), Emma Jane O’Neill (Writing—review & editing), Ignacio Otero Balda (Writing—review & editing), and Eleanor K. Wyatt (Writing—review & editing)
Conflicts of interest
Authors declare no conflicts of interest.
Funding
Authors received no specific funding for this work.
Off-label antimicrobial declaration
Authors declare no off-label use of antimicrobials.
Institutional animal care and use committee or other approval declaration
Informed consent (verbal and written) was obtained from the owner of the animal described in this work for all treatment and procedures undertaken.
Human ethics approval declaration
Authors declare human ethics approval was not needed.
References
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