犬猫的蠕形螨病的诊断和治疗-2020版指南（机理、种类）

王帆

Diagnosis and treatment of demodicosis in dogs and cats

犬猫的蠕形螨病的诊断和治疗

Clinical consensus guidelines of the World Association for Veterinary Dermatology

世界兽医协会皮肤病临床治疗指南

翻译：蔡欢 校对：王帆

1 Introduction

1介绍

In previous clinical consensus guidelines, the World Association of Veterinary Dermatology (WAVD) has made an effort to provide up-to-date and relevant information about certain topics available worldwide, written by international panels reflecting expert opinions from several parts of the world and accessible to everybody worldwide. The WAVD invited the authors of this manuscript to contribute to clinical consensus guidelines about demodicosis. Authors initially agreed on responsibilities of each individual for specific sections of the manuscript, then performed a literature search and gathered published evidence for their individual sections. Where published studies were lacking, textbooks, abstracts presented at veterinary meetings and expert opinions were used. After each section was drafted, the complete manuscript was reviewed by each author. Comments on the whole manuscript were discussed and a preliminary draft of the complete manuscript was posted on the WAVD website and presented at the North American Veterinary Dermatology Forum meeting in Maui, HI, USA, 2018 and the European Veterinary Dermatology Congress in Dubrovnik, Croatia, 2018 where feedback was requested. This feedback was discussed and a final version of the manuscript was agreed on by all authors before submission to the journal.

在以前的临床共识指南中，世界兽医皮肤病学协会（WAVD）致力于提供有关全球某些可用主题的最新信息，这些信息由国际专家小组撰写，反映了来自世界各地的专家意见并且对全世界的每个人公开。WAVD邀请该手稿的作者为有关蠕形螨病的临床治疗指南做出贡献。作者最初就手稿特定部分的每个人的责任达成了共识，然后进行了文献检索并收集了其各个部分的公开证据。在缺乏已发表研究的地方，使用了教科书，在兽医会议上发表的摘要和专家意见。在起草各部分后，每位作者都要审查完整的手稿。讨论了对整个手稿的意见，完整手稿的初稿已发布在WAVD网站上，并于2018年在美国夏威夷州毛伊岛举行的北美兽医皮肤病学论坛会议上以及在克罗地亚杜布罗夫尼克举行的欧洲兽医皮肤病学大会上进行了介绍并反馈意见。对该手稿进行了讨论，并在所有作者提交期刊之前就其最终版本达成了共识。

2 Pathogenesis

2发病机理

Demodicosis is a common disease in canine practice caused by a proliferation of Demodex mites. These mites are normal commensal organisms in the hair follicles of many mammals. In the dog they are transmitted during the first days of life from the dam to the puppies. In most species, demodicosis occurs only when animals are immunocompromised due to other diseases or undergoing immunosuppressive therapies. Demodicosis in immunosuppressed individuals has been reported in humans, dogs and cats amongst others. With the exception of Demodex gatoi in the cat, the dog is the only species where young and otherwise healthy animals develop demodicosis. This juvenile demodicosis has been presumed to be due to cell-mediated deficiency.  

蠕形螨病是犬临床中的常见疾病，由蠕形螨增殖引起。这些螨虫是许多哺乳动物毛囊中的正常共生生物。在犬中，它们可在幼犬出生的最初几天从母犬传播到幼犬。在大多数物种中，仅当动物因其他疾病而导致免疫受损或接受免疫抑制疗法时，才发生蠕形螨病。机体免疫抑制发生蠕形螨病已在人、犬和猫等动物中报道。除了猫的戈托伊蠕形螨外，犬是唯一的在幼犬和健康犬上都会出现蠕形螨病的物种。推测这种幼年蠕形螨病是由于细胞介导缺乏导致。

2.1 Immunology

2.1免疫学

Early studies showed a normal humoral response, but decreased lymphocyte blastogenesis in young dogs with naturally occurring demodicosis. Treatment of puppies with anti-lymphocyte serum led to generalized demodicosis in eight puppies whereas their untreated littermates remained healthy. Subsequently, a T-cell exhaustion characterized by low numbers of circulating CD4+ T cells, together with increased serum concentrations of interleukin (IL)-2, IL-5, IL-6 and IL-18, and the immunosuppressive cytokines IL-10 and TGF-beta were reported in a number of studies comparing dogs with generalized demodicosis to healthy controls. By contrast, the proinflammatory cytokine TNF-alpha was reduced in dogs with demodicosis. The CD4:CD8 ratio was lower and the number of CD8-positive cells was reported to be increased in dogs with generalized demodicosis. However, it is unclear, whether those changes are a consequence of the demodicosis or contribute to the pathogenesis. Histologically, demodicosis is characterized by a mural folliculitis with infiltrating CD8+ cytotoxic T cells, which resolves quickly with resolution of the demodicosis. MHC class II receptors are upregulated in the skin of dogs with demodicosis, particularly in keratinocytes.

早期的研究表明，在自然发病的幼犬蠕形螨病中，体液反应正常，但淋巴细胞转化减少。用抗淋巴细胞血清处理八只幼犬，会导致八只幼犬全身性蠕形螨病，而未处理的同窝幼犬仍然健康。随后，一些研究报道了T细胞衰竭，其特征是循环中的CD4+ T细胞数量减少，血清白细胞介素（IL）-2、IL-5、IL-6和IL-18，以及免疫抑制细胞因子IL-10和TGF-β的浓度增加，这些研究将全身性蠕形螨病患犬与健康犬进行了比较。相比之下，蠕形螨病患犬的促炎细胞因子TNF-α降低。据报道，全身性蠕形螨病患犬的CD4：CD8比值较低，CD8阳性细胞的数量增加。但是，目前尚不清楚这些变化是蠕形螨病的结果还是发病机理。从组织学上讲，蠕形螨病的特征是毛囊壁炎，伴有CD8+细胞毒性T细胞浸润，该细胞可通过蠕形螨病的消退迅速消失。MHC II类受体在蠕形螨病患犬的皮肤中上调，特别是在角质形成细胞中增加。

The presumption that immunosuppression is the cause of the demodicosis is further supported by a severe combined immunodeficiency (SCID) mouse model. SCID mice, which have no B and T cells, received skin grafts from dogs which were later infected with D. canis collected from a dog with demodicosis. Within one to three months, mites proliferated in the grafted canine skin and not the surrounding murine skin. In another immunedeficient double knock-out mouse model lacking CD28 (a co-stimulatory molecule involved in T-cell activation) and STAT6 (essential for a pathway that plays a role in IL-4 signal transduction and Th2 differentiation), mice developed a severe dermatitis due to a proliferation of Demodex mites. However, in this model, demodicosis was accompanied by a prominent dermal infiltration of CD4+ and CD8+ T cells, increased concentrations of IL-12, IFN-gamma and IgG2 indicating a prominent Th1 response, that was markedly reduced once the Demodex mites were treated with amitraz. The alleviation of the Th1 response with miticidal treatment in the double knock-out mouse model does not seem to be in concordance with a defect of cell-mediated immunity as a cause of demodicosis. In another study, canine skin grafts on Rag2 knockout mice were infected with D. Canis mites. Mites proliferated in the grafts, but clinical lesions did not develop. Nine weeks after infection, some grafts were injected with canine peripheral blood mononuclear cells (either nonstimulated or stimulated with phytohaemagglutinin and IL-2). One month later, mite numbers were highest in the grafts injected with stimulated PBMCs (those mice also developed canine serum IgG antibodies), lower in grafts not injected at all with PBMCs and lowest in the grafts injected with nonstimulated PBMCs.

严重的联合免疫缺陷（SCID）小鼠模型进一步支持了免疫抑制是蠕形螨病的原因的推测。没有B细胞和T细胞的SCID小鼠接受了犬的皮肤移植，这些犬皮肤随后感染了从有蠕形螨病的犬身上采集的犬蠕形螨。在1-3个月内，蠕形螨在移植的犬皮肤而非周围的小鼠皮肤中增殖。在另一个缺少CD28（参与T细胞活化的共刺激分子）和STAT6（对于在IL-4信号转导和Th2分化中起作用的途径必不可少）的免疫缺陷的双敲除小鼠模型中，小鼠出现了严重的蠕形螨增殖引起的皮肤病。然而，在该模型中，蠕形螨病伴随着CD4 +和CD8 + T细胞的显着皮肤浸润，IL-12、IFN-γ和IgG2浓度升高，表明Th1显着应答，但一旦用双甲脒治疗了蠕形螨，其显着降低。在双基因敲除小鼠模型中，杀螨治疗对Th1反应的降低似乎与导致蠕形螨病的细胞介导的免疫缺陷不符。在另一项研究中，Rag2基因敲除小鼠的犬皮肤移植物被犬蠕形螨感染。螨虫在移植皮肤中增殖，但未出现临床病变。感染后九周，向部分移植皮肤注射犬外周血单核细胞（包括无刺激或有刺激的植物血凝素和IL-2）。一个月后，螨虫数量在注射刺激的PBMC的移植物中最高（那些小鼠也出现犬血清IgG抗体），在完全未注射PBMC的移植物中较低，而在注射无刺激的PBMC的移植物中最低。

The pathogenesis of demodicosis may be more complicated or it may be different in the juvenile dog or in different dog breeds. Possibly, a functional Th2 response is more relevant for mite control than thought previously. One study evaluated only pit bull terrier-type dogs with generalized demodicosis with age- and breed-matched controls, and reported significantly higher serum IgA, IL-2, IL-18 and monocyte chemoattractant protein-1 concentrations in affected dogs, also pointing to an at least partially increased immune response in this breed. A further study reported increased Toll-like receptor (TLR)-2 and decreased TLR-4 and TLR-6 in dogs with demodicosis compared to normal controls. The downregulation of TLRs in affected dogs may be induced by the mites as a strategy to decrease the host immune response. Alternatively, it could be a predisposing factor for disease development or an incidental finding not influencing the disease. Further studies are required to define the role of TLRs in the development of canine demodicosis.

蠕形螨病的发病机理可能比较复杂，也可能在幼犬或不同犬种中有不同。可能功能性Th2反应与控制螨虫的关系比以前想象的要重要。一项研究仅评估了患有全身性蠕形螨病且年龄和品种相匹配的比特犬，并报告了患犬的血清IgA、IL-2、IL-18和单核细胞趋化蛋白-1浓度显着升高，还指出该品种的免疫反应至少有部分增强。进一步的研究报道中，与正常对照组相比，蠕形螨病患犬Toll样受体（TLR）-2增加，TLR-4和TLR-6减少。作为降低宿主免疫反应的一种策略，蠕形螨可能会引起患犬TLR的下降。或者，它可能是疾病发展的偶然因素或不影响疾病的偶然发现。需要进一步的研究来确定TLR在犬蠕形螨病发展中的作用。

Initially, there was debate as to whether the secondary bacterial infection seen with generalized demodicosis was contributing to, or in some way causing, those immunological changes. However, based on the published data this seems less likely and at least the decreased lymphoblastogenesis seems to be a consequence rather than a cause of the disease. Not surprisingly, demodicosis is accompanied by an increase in markers for oxidative stress.

最初，关于全身性蠕形螨病所致的继发性细菌感染，还是以其他某种方式导致了这些免疫学变化起了争论。但是，根据已公开的数据，这种可能性似乎较小，至少淋巴细胞转化减少似乎是疾病的结果，而非原因。毫不奇怪，蠕形螨病伴随着氧化应激标志物的增加。

As the overwhelming majority of affected juvenile dogs do not suffer from a recurrence following successful therapy, it seems likely that the presumed immune aberration is a temporary problem.

由于绝大多数患病幼犬在成功治疗后都不会复发，因此推测免疫失常似乎是暂时的问题。

The first clinical signs of juvenile demodicosis in dogs typically occur in the first 18 months of life. Adult-onset demodicosis also exists and is comparable to the demodicosis seen in other species. In the dog, this was reported to be associated with diseases or drugs leading to a compromised immune system such as leishmaniosis, hyperadrenocorticism, hypothyroidism, neoplasia, babesiosis, ehrlichiosis, and glucocorticoid treatment or chemotherapy. Although one report mentioned atopic dermatitis as a frequent concurrent disease, many dogs had received glucocorticoid therapy. In a retrospective study evaluating a large number of dogs with adult-onset demodicosis in two countries and comparing those dogs to a control population, hyperadrenocorticism, hypothyroidism and leishmaniosis, but not neoplasia, predisposed dogs to demodicosis. However, the differentiation of juvenile-and adult-onset demodicosis may be difficult in individual cases. It is more important to identify and correct predisposing factors (such as endoparasitism or underlying diseases) independent of age to achieve the best possible outcome.

幼犬蠕形螨病的最初临床症状通常发生在出生的前18个月。成年发病性蠕形螨病也存在，可与其他物种中的蠕形螨病相比较。在犬中，据报道这与导致免疫系统受损的疾病或药物有关，例如利什曼病、肾上腺皮质功能亢进、甲状腺功能低下、肿瘤、巴贝斯虫病、埃里希体病以及糖皮质激素治疗或化疗。虽然在一份报告中提到特应性皮炎是一种常见的并发症，但许多犬都接受了糖皮质激素治疗。在一项回顾性研究中，评估了两个国家中大量成年发病蠕形螨病患犬，并将这些犬与对照组进行比较，发现肾上腺皮质功能亢进、甲状腺功能减退和利什曼病，但没有肿瘤病，这些疾病使这些犬易患蠕形螨病。但是，在个别病例中，很难区分幼年发病和成年发病蠕形螨病。更重要的是识别和纠正与年龄无关的易感因素（例如内寄生虫病或潜在疾病），以得到最佳预后。

In cats, demodicosis has been reported in association with feline immunodeficiency virus, xanthoma and diabetes mellitus. The localized form has been described in lesions of feline squamous cell carcinoma in situ.  

据报道，在猫中，蠕形螨病与猫免疫缺陷病毒、黄瘤和糖尿病有关。已经在猫鳞状细胞癌的原位病变中发现了局部症状。

Consensus Statement 1 In young dogs with generalized demodicosis a temporary immune alteration most likely plays an important role in the pathogenesis. In older dogs, the disease may be associated with an immunosuppressive condition or treatment. However, other hitherto unknown factors also may play a role. In cats, demodicosis usually is associated with other diseases, with exception of the contagious Demodex gatoi that also can affect otherwise healthy cats.  

共识声明1：在幼犬全身性蠕形螨病患犬中，暂时的免疫改变很可能在发病机理中起重要作用。在成年犬中，该疾病可能与免疫抑制疾病或治疗有关。但是，迄今为止其他未知的因素也可能起作用。在猫中，蠕形螨病通常与其他疾病有关，除了具有传染性的蠕形螨病以外，也会影响其他健康猫。

In humans, demodicosis is described as a primary immunosuppressive disorder based on a hereditary T-cell defect or as a consequence of immunosuppression.

在人类中，蠕形螨病被描述为基于遗传性T细胞缺陷或免疫抑制的原发性免疫抑制疾病。

2.2 Genetics of juvenile demodicosis

2.2幼犬蠕形螨病的遗传学

For decades, strong breed predilections were reported for canine juvenile demodicosis. In early reports, those lists were largely anecdotal. One large, well-powered study identified a greater than four-fold increased risk of developing generalized demodicosis for the American Staffordshire terrier, Staffordshire bull terrier, Chinese shar-pei and French bulldog. A further study in the United States identified the English bulldog, pit bull and Sealyham terrier as predisposed breeds for juvenile onset demodicosis.

数十年来，据报道幼年犬蠕形螨病的流行趋势增多。在早期的报告中，这些病例大都是局部的。一项全面大型的研究发现，美国斯塔福德郡㹴、斯塔福斗牛㹴、中国沙皮犬和法国斗牛犬患全身性蠕形螨病的风险比其他品种增加了四倍以上。在美国进行的进一步研究确定，英国斗牛犬、比特犬和锡利哈姆㹴犬是幼年性蠕形螨病的易感品种。

Those breed predilections and the frequent occurrence of juvenile demodicosis in certain lines, sibling puppies and related dogs make a hereditary basis very likely. In addition, there is anecdotal evidence that preventing affected dogs from breeding decreases the frequency of the disease. However, to the best of the authors’ knowledge, only one study has been published evaluating the genetic basis in more detail. In that study, using microsatellite markers, a significant association was found between generalized demodicosis and the DLA haplotypes FH2002, FH2975 and FH2054 in Argentinian mastiffs and boxer dogs.

这些品种的易感性，及同类幼犬和相关犬类中幼年犬蠕形螨病的频繁发生，很可能是遗传因素。此外，有证据表明，防止患病犬繁殖会降低发病率。然而，据作者所知，仅发表了一项研究对遗传因素进行了详细的评估。在那项研究中，使用微卫星标记，发现了在阿根廷獒犬和拳击犬中，全身性蠕形螨病与DLA单倍型FH2002，FH2975和FH2054之间存在显着关联。

Demodicosis in juvenile dogs shows a wide variety of clinical signs, from mild, localized alopecia to severe generalized forms with prominent systemic signs. These variations may be seen within the same litter of puppies. In addition, dogs respond differently to the various therapeutic approaches. Thus, it is likely that several genes are involved in the pathogenesis and, thus, more and larger studies are needed to elucidate the genetic background of the disease. Further support for a multi-gene involvement is the above-mentioned immunodeficient double knock-out mouse strain lacking CD28 and STAT6. By contrast to the double knock-out mice, single knock-out siblings kept in close contact and lacking either CD28 or STAT6 did not show any clinical signs.

幼犬蠕形螨病临床症状多种多样，从轻度局部脱毛到具有全身性症状的严重全身性脱毛。这些变化都可以在同一窝幼犬中看到。此外，犬对各种治疗方法的反应也不同。因此，可能有几个基因与发病机理有关，因此，需要更多和更大的研究来阐明疾病的遗传因素。对多基因参与的进一步证据是上述缺乏CD28和STAT6的免疫缺陷双敲除小鼠。相反双敲除小鼠与缺乏CD28或STAT6基因的单敲除小鼠保持紧密接触，但单敲除小鼠均未显示任何临床症状。

Consensus Statement 2 In young dogs, demodicosis has a genetic basis and most likely multiple genes are involved.

共识声明2：在幼犬中，蠕形螨病具有遗传因素，可能涉及多个基因。

3 Demodex species in the dog and cat

3犬和猫蠕形螨种类

Several mite species have been reported in dogs and cats. In the dog, initially three different species were reported.Demodex canis is the most common demodectic mite of dogs. A longer-bodied mite also was reported and named D. injai("inja" being the Zulu name for "dog"). The female adult mites were approximately 50% longer and males 100% longer than adult D. canis mites respectively. A short-bodied mite was named D. cornei by some authors because it was supposedly found more superficially. Genetic comparisons revealed only one or two different species of Demodex in the dog: D. canis and D. injai. In the genetic studies, the short-bodied mite was considered to be a morphological variant of D. canis. In one report it was suggested that D. cornei are dead or near-dead D. canis mites, further supporting that only two species of mites exist. However, a taxonomic analys is found the short-bodied mite to be a distinct canine species.

犬和猫已报道了多种蠕形螨。在犬中，最初报道了三种不同的种。犬蠕形螨是犬中最常见的螨虫。还报道了一种体形较长的螨，名为隐在蠕形螨（“inja”是祖鲁语中“犬”的意思）。与犬蠕形螨相比，雌螨长50％，雄螨长100％。某些作者将短体螨命名为角质蠕形螨，因为据说是在更浅表发现的。基因研究显示，犬中只有一种或两种不同的蠕形螨：犬蠕形螨和隐在蠕形螨。在遗传研究中，短体螨被认为是犬蠕形螨的形态变异。在一份报告中，有人提出角质蠕形螨是死亡的或濒死的犬蠕形螨，进一步支持仅存在两种螨。然而，分类学分析发现短体螨是独特的犬类品种。

There are three different species of Demodex mites in the cat: D. cati, D. gatoi and a third unnamed species. The unnamed species had a longer gnathosoma and a shorter opisthosoma than D. cati; the length:width ratio of the opisthosoma was approximately 2:1, whereas in D. cati it was approximately 5:1. By contrast to D. cati, D. gatoi is contagious and usually causes intense pruritus. It was considered a very regional disease, predominantly diagnosed in the Southeastern United States. However, more recently there have been reports of D. gatoi infestations in cats from other areas of the world.

猫中有三种不同的蠕形螨：猫蠕形螨、戈托伊蠕形螨和第三种未命名物种。与猫蠕形螨相比，未命名的物种颚体更长和后体部更短。后体部长宽比约为2：1，而在猫蠕形螨中约为5：1。与猫蠕形螨不同，戈托伊蠕形螨具有传染性，通常会引起剧烈瘙痒。它被认为是一种非常有区域性的疾病，主要在美国东南部确诊。但是，最近有报道称，来自世界其他地区的猫感染了戈托伊蠕形螨。

Consensus Statement 3 In dogs, two Demodex species occur, the shorter D. canis and the longer D. injai. In cats, the shorter D. gatoi has a more regional occurrence and different clinical signs than the classical D. cati.

共识声明3：在犬中出现的两种蠕形螨，犬蠕形螨较短，而隐在蠕形螨较长。在猫中，与传统的猫蠕形螨相比，较短的戈托伊蠕形螨更有区域性发病且临床症状不同。