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Drug Hypersensitivity Reactions Targeting the Skin in Dogs and Cats
犬猫的皮肤药物过敏反应
作者：K.L. Voie, K.L. Campbell, and S.N. Lavergne
翻译：王思权；校对：王帆
Adverse drug reactions (ADRs) can be dose dependent or idiosyncratic. Most idiosyncratic reactions are believed to be immune-mediated; such drug hypersensitivities and allergies are unpredictable. Cutaneous reactions are the most common presentation of drug allergies. In veterinary medicine it can be difficult to assess the true prevalence of adverse drug reactions, although reports available suggest that they occur quite commonly. There are multiple theories that attempt to explain how drug allergies occur, because the pathogenesis is not yet well understood. These include the (pro)-hapten hypothesis, the Danger Theory, the pi concept, and the viral reactivation theory. Cutaneous drug allergies in veterinary medicine can have a variety of clinical manifestations, ranging from pruritus to often fatal toxic epidermal necrolysis.Diagnosis can be challenging, as the reactions are highly pleomorphic and may be mistaken for other dermatologic diseases. One must rely heavily on history and physical examination to rule out other possibilities. Dechallenge of the drug, histopathology, and other diagnostic tests can help to confirm the diagnosis. New diagnostic tools are beginning to be used, such as antibody or cellular testing, and may be used more in the future. There is much yet to learn about drug allergies, which makes future research vitally important. Treatment of drug allergies involves supportive care, and additional treatments, such as immunosuppressive medications, depend on the manifestation of the disease. Of utmost importance is to avoid the use of the incriminating drug in future treatment of the patient, as subsequent reactions can be worse, and ultimately can prove fatal.
药物不良反应(ADR)可能是剂量依赖性的或特异的（idiosyncratic）。大多数特异反应被认为是免疫介导的，这种药物超敏反应和过敏症是不可预测的。皮肤反应是药物过敏最常见的表现。在兽医学中，很难评估药物不良反应的真实发生率，但现有报告表明非常常见。目前有多种理论试图解释药物过敏是如何发生的，因为发病机制尚未完全清楚。这些理论包括(前)半抗原假说、危险模式理论PI概念和病毒再激活理论。兽药中的皮肤药物过敏可有多种临床表现，从瘙痒到往往会致命的中毒性表皮坏死松解症（TEN）。诊断可能具有挑战性，因为反应是高度多形性的（pleomorphic），可能会被误认为是其他皮肤病。我们必须依靠详细的病史和体格检查来排除其他可能性。停药、组织病理学和其他诊断试验可以帮助确认诊断。新的诊断工具正在投入使用，如抗体或细胞检测，并可能在未来更多地使用。关于药物过敏还有很多需要了解的地方，这使得未来研究变得至关重要。药物过敏的治疗包括支持性护理和其他治疗，如免疫抑制药物，这取决于疾病的表现。最重要的是避免在以后的治疗中使用该药物，因为随后的反应可能会更严重，最终可能是致命的。
Key words: Adverse drug reaction; Allergy; Cutaneous.
关键词：药物不良反应；过敏症；皮肤
Abbreviations: ADR adverse drug reaction BAT basophil activation test DRESS drug rash with eosinophilia and systemic symptoms IDT intradermal testing LTT lymphocyte transformation test MHC major histocompatibility complex MPE maculopapular exanthema SJS Steven-Johnson Syndrome TCR T cell receptors TEN toxic epidermal necrolysis
缩写：ADR-药物不良反应；BAT-粒细胞活化试验；DRESS-药物皮疹伴嗜酸性粒细胞增多和全身症状；IDT-皮内试验；LTT-淋巴细胞转化试验；MHC主要组织相容复合物；MPE-斑丘疹；SJS-史蒂文-约翰逊综合征；TCR-T细胞受体；TEN-中毒性表皮坏死松解症
Introduction
概述
Adverse drug reactions (ADR) occur commonly, and in human patients account for up to 16.8% of all hospitalized cases. Usually self-limiting, most adverse drug reactions resolve upon discontinuation of the offending drug. However, in some cases they can be quite severe, and can lead to fatality. Although the risk of an adverse event with any given individual drug is relatively low, ADRs are seen commonly because of the increasing numbers of patients seen, the increasing number of drugs available, and the increasing use of drug combinations in a given patient.
药物不良反应(ADR)的发生很普遍，在人类患者中占所有住院病例的16.8%。通常是自限性的，大多数药物不良反应在停药后消失。然而，在某些病例中，它们可能相当严重，并可能导致死亡。尽管某一特定药物的不良事件风险相对较低，但由于患者数量的增加，可用药物数量的增加，以及某些患者的药物联合使用的增加，ADR变得很常见。
Adverse drug reactions are divided into 2 categories: dose-dependent or idiosyncratic reactions (Fig 1). In dose-dependent reactions, the onset and the intensity of the clinical signs correlate with the size of the dose received by the patient. These clinical signs are typically known adverse effects of the drug in question or are related to the physical or chemical properties of the parent drug or one of its metabolites. Dose-dependent ADRs therefore are relatively common, predictable, and could in theory happen to any individual. Conversely, idiosyncratic drug reactions occur independently of the dose, and are not directly related to the pharmacologic, physical, or chemical properties of the drug. They are therefore relatively uncommon and unpredictable. The exact mechanisms of idiosyncratic reactions are not well understood, but in the case of drug allergies (or drug hypersensitivities), the immune system is thought to be involved. The remainder of this review will focus on such drug allergies. There are many different manifestations of drug hypersensitivities, including blood dyscrasias, hepatotoxicity, and cutaneous signs. Cutaneous adverse drug reactions are the most common form of hypersensitivity. The focus of this article will be the cutaneous manifestations of drug allergies in dogs and cats.
药物不良反应分为两类：剂量依赖性反应或特异性（idiosyncratic）反应(图1)。在剂量依赖性反应中，临床症状的出现和强度与患者接受的剂量大小相关。这些临床症状通常是已知相关药物的不良反应，或与药物本身或其代谢产物的物理或化学性质有关。因此，依赖剂量ADR相对常见、可预测，理论上可能发生在任何个体。相反，特异性（idiosyncratic）药物反应与剂量无关，与药物的药理、物理或化学特性也没有直接关系。因此，它们相对不常见和不可预测。特异性反应的确切机制尚不清楚，但在药物过敏(或药物超敏反应)的病例中，认为有免疫系统参与其中。这篇综述的其余部分将集中讨论这种药物过敏症。药物超敏反应有许多不同的表现，包括血液病、肝毒性和皮肤症状。皮肤药物不良反应是最常见的超敏反应形式。本文的重点是药物过敏症在犬猫上的皮肤表现。
Fig 1. Classification of cutaneous adverse drug reactions.
图1：皮肤药物不良反应分类。
Incidence of Cutaneous Drug Hypersensitivity Reactions in Veterinary Medicine
兽医学中皮肤药物超敏反应的发生率
It can be challenging to determine the incidence of ADRs, especially drug hypersensitivities. In human medicine, ADRs seem to occur in 10–20% of hospitalized patients and in 7% of the general population. They result in 300,000 hospitalizations annually. These ADRs can be very serious, and are considered to be between the 4th and 6th cause of death in hospitalized patients.In addition, the expense of treatment of drug allergies can be astounding. In human medicine, treatment of adverse drug reactions can cost more than $136 billion per year, adding approximately $8,000 in hospital expenses per case.Most cutaneous drug reactions in human medicine are associated with antibiotics.
确定ADR的发生率，特别是药物超敏反应的发生率是很有挑战性的。在人类医学中，ADR似乎发生在10-20%的住院患者和7%的普通人群中。每年有30万人因此住院治疗。这些不良反应可能非常严重，被认为是引起住院患者死亡的第4至第6大原因。此外，药物过敏的治疗费用也令人震惊。在人类医学领域，治疗药物不良反应的费用每年可超过1360亿美元，每个患者的医疗花费增加约8000美元。人用药中大多数皮肤药物反应都与抗生素有关。
In veterinary medicine, ADR also occur fairly commonly, but their true prevalence is much more challenging to determine. The Veterinary Medicines Doctorate (VMD) in the UK oversees ADR reports, based on the degree of suspicion (“Probable”, “Possible”, “Insufficient Information”, or “Unlikely” to be drug related). Australia uses a similar system.In 2009, the VMD received 3,151 reports of suspected ADR. Of these, 1,486 were classified as serious reactions (fatal, life-threatening, disabling, incapacitating, or those that result in permanent or prolonged signs).In 2003, over 24,000 ADR were reported to the FDA-CVM; this number increased to over 35 000 reports in 2007. Nevertheless, despite the relatively large number of ADR reported, the number is probably an underestimation. This is likely because of lack of recognition of clinical signs, lack of reporting, and misdiagnosis.
在兽医学中，ADR也相当普遍，但其真实患病率的确定是更具有挑战性。英国兽医医学博士(VMD)负责监督ADR报道，与药物相关性根据怀疑程度分为(“非常可能”、“可能”、“信息不足”或“不太可能”)。澳大利亚采用了类似系统。2009年，VMD收到3151份疑似ADR报告。其中，1486例被归类为严重反应(致命、危及生命、致残、丧失能力或导致永久性或长期症状的反应)。2003年，FDA-CVM报告了超过24000例ADR;这一数字在2007年增加到超过3.5万份报告。然而，尽管报告的ADR数量相对较大，但这个数字仍有可能被低估了。可能是因为缺乏对临床症状的认识，缺乏报告和出现误诊。
Estimating the number of reactions targeting the skin among reported reactions is rendered further challenging because the report system does not always have enough information to distinguish which organ was involved. In addition, lack of recognition of cutaneous signs may be quite frequent, because lesions may be mild, and can easily be missed in a haired patient. Because they have a multitude of clinical presentations, cutaneous drug reactions may be misdiagnosed as a number of other more common skin diseases. Veterinarians likely encounter drug allergies far more frequently than recognized.
在报告的反应中，评估针对皮肤反应的药物不良反应数量变得更加具有挑战性，因为报告系统并不总是有足够的信息来区分涉及哪个器官。此外，常缺乏对皮肤症状的识别，因为病变可能是轻微的，并且在有毛患病动物中很容易被忽略。因为它们有多种临床表现，皮肤药物反应可能被误诊为其他一些更常见的皮肤病。兽医遇到药物过敏的频率可能比人们认识到的要高得多。
Immune-mediated ADR (drug allergies or hypersensitivities) can be especially challenging to diagnose. However, it is necessary to recognize the importance of drug allergies, and realize that potentially they could happen any time a medication is prescribed. Indeed, although drug allergies can be self-resolving, they also can be very severe, and may even lead to fatalities. For example, toxic epidermal necrolysis (TEN), a severe skin disorder that frequently is associated with drug allergies, carries a greater than 30–40% mortality rate in human medicine, and close to a 0% survival rate in veterinary medicine.
免疫介导的ADR(药物过敏或超敏反应)诊断尤其具有挑战性。然而，我们有必要认识到药物过敏的重要性，并意识到药物过敏可能发生在用药的任何时候。事实上，即使药物过敏可以通过机体自我缓解，但它们也会非常严重，甚至可能导致死亡。例如，中毒性表皮坏死松解症(TEN)是一种经常与药物过敏相关的严重皮肤病，在人类医学中死亡率超过30-40%，在兽医学中存活率接近0%。
Different Types of Hypersensitivity Reactions
不同类型的超敏反应
In immunology, Gell and Coombs described 4 main types of hypersensitivity reactions (Fig 1).In the case of drug-induced hypersensitivities, the antigen is thought to be the drug itself, one of its metabolites, or a drug- or metabolite-protein complex.Some attempts have been made to adapt the Gell and Coombs classification to address the variety of lesions that have been associated with drug hypersensitivity reactions (Table 1). It is, however, important to note that it is often difficult to apply this hypersensitivity classification to a patient’s specific clinical signs because the manifestations may not fall neatly into a specific category.
在免疫学方面，Gell和Coombs描述了4种主要的超敏反应类型(图1)。在药物诱导的超敏反应的病例中，抗原被认为是“药物本身”、“药物的某种代谢物”或是“药物/代谢物与蛋白质复合物”。一些人尝试调整Gell和Coombs分类以处理与药物超敏反应相关的各种病变(表1)。然而，重要的是要注意，将这种超敏反应分类应用于患者的特定临床症状通常是困难的，因为其表现可能不能完全恰好归入特定的类别。
Table 1. Extended Coombs and Gell classification of immune hypersensitivity applied to cutaneous drug allergy.
表1。应用于皮肤药物过敏的扩展Coombs和Gell免疫超敏分类。
|
Coombs和Gell分类 |
免疫反应 |
病理学事件 |
皮肤典型临床表现 |
|
I型 |
B细胞（IgE） |
肥大细胞脱颗粒 |
荨麻疹、血管性水肿 |
|
II型 |
B细胞（IgG） |
FcR依赖性细胞裂解 |
天疱疮、天疱疮样反应 |
|
III型 |
B细胞（IgG） |
免疫复合物沉积、补体依赖性细胞裂解 |
狼疮、狼疮样反应、血管炎 |
|
IV型 |
T细胞 |
|
|
|
IVa型 |
Th1（IFNγ） |
单个核细胞活性 |
湿疹 |
|
IVb型 |
Th2（IL-4、IL-5） |
嗜酸性细胞炎症 |
疹 |
|
IVc型 |
细胞毒性T细胞（） |
T细胞介导细胞毒性（CD4+和CD8+） |
疹、TEN |
|
IVd型 |
T细胞（IL-8） |
中性粒细胞（活化和招募） |
脓疱疹 |
Type I Hypersensitivity
I型超敏反应
This immediate type of hypersensitivity is primarily an IgE-mediated reaction, occurring within minutes to hours after antigen exposure. In Type I hypersensitivity, antigen-bound IgE interacts via Fc receptors on mast cells and basophils, causing cell degranulation and inflammation. The mast cells and basophils release leukotrienes, histamine, eosinophilic chemotactic factor, platelet activating factor, kinins, serotonins, and proteolytic enzymes, which cause an inflammatory response and tissue damage. Examples of Type I hypersensitivities include angioedema, urticaria, and anaphylaxis.This type of ADR is relatively common,and has been specifically reported multiple times in the veterinary literature.
这种速发型超敏反应主要是一种IgE介导的反应，在抗原刺激后几分钟到几小时内发生。在I型超敏反应中，抗原结合的IgE通过肥大细胞和嗜碱性粒细胞上的Fc受体相互作用，导致细胞脱颗粒和产生炎症反应。肥大细胞和嗜碱性粒细胞释放白三烯、组胺、嗜酸性趋化因子、血小板活化因子、激肽、血清素和蛋白水解酶，这些可导致炎症反应和组织损伤。I型超敏反应的例子包括血管性水肿、荨麻疹和过敏性休克（anaphylaxis）。这种类型的ADR在兽医文献中多次被特别报道过。
True anaphylactic drug reactions should not be confused with anaphylactoid reactions where a drug directly induces the release of proinflammatory molecules (eg, histamine release by opioids) without the involvement of a drug-specific response from the immune system. Opioids, such as morphine, can induce severe pruritus and skin inflammation by triggering the release of histamine directly from mast cells.In this instance, no drug-specific IgE is present, but the clinical signs are similar to those observed during an anaphylactic reaction; these reactions therefore are called anaphylactoid.
真正的药物反应性过敏性休克（anaphylactic）不应与过敏样（anaphylactoid）反应相混淆，过敏样反应是药物直接诱导促炎分子的释放(如：阿片类药物释放组胺)，而不涉及免疫系统的药物特异性反应。阿片类药物，如吗啡，可以通过直接触发肥大细胞释放组胺来诱导严重的瘙痒和皮肤炎症。在这种情况下，不存在药物特异性IgE，但临床症状与过敏反应期间观察到的症状相似；因此，这些反应被称为过敏样反应。
Type II Hypersensitivity
II型超敏反应
This type of nonimmediate reaction is IgM- and IgG-mediated and is sometimes called “cytotoxic hypersensitivity”. In Type II hypersensitivity reactions, antibodies are thought to bind to the antigen present on the surface of a cell, resulting in cell damage or lysis, sometimes via the complement cascade. Examples of cytotoxic hypersensitivity include drug-induced and drug-triggered pemphigus, immune-mediated hemolytic anemias or thrombocytopenias.
这种类型的非速发反应是由IgM和IgG介导的，有时被称为“细胞毒性超敏反应”。在II型超敏反应中，抗体被认为与细胞表面的抗原结合，导致细胞损伤或分解，有时通过补体级联。细胞毒性超敏反应的例子包括药物诱导（drug-induced）和药物触发（drug-triggered）天疱疮，免疫介导性溶血性贫血或免疫介导性血小板减少症。
Type III Hypersensitivity
III型超敏反应
These reactions are IgG mediated and nonimmediate. The presence of antigen and antibodies can lead to formation of immune complexes (antigen-antibody complexes), which are deposited on the endothelium of blood vessels inducing vasculitis, or nephritis when renal capillaries are involved. Examples of Type III hypersensitivity reaction are systemic lupus erythematosus and other lupoid reactions, vasculitis, or nephritis.
这类反应是由IgG介导的，而且是非速发型。抗原和抗体的存在可导致免疫复合体(抗原-抗体复合物)的形成，这些免疫复合物沉积在血管内皮细胞上，导致血管炎，或当肾毛细血管受累时引起肾炎。III型超敏反应包括系统性红斑狼疮和其他狼疮样反应、血管炎或肾炎。
Type IV Hypersensitivity
IV型超敏反应
These reactions are cell-mediated, and also are usually the most delayed reactions, with a mean time of onset of 2 weeks. T cells bind to antigens and, along with cytokines, induce a cell-mediated tissue destruction involving macrophages, cytotoxic T lymphocytes, or both.Examples include erythema multiforme, TEN, contact dermatitis, and rheumatoid arthritis.
这些反应是细胞介导的，通常也是更迟发性的反应，平均发病时间为2周。T细胞与抗原结合，并与细胞因子一起，诱导由一种细胞介导的组织损伤，涉及巨噬细胞、细胞毒性T淋巴细胞或两种细胞都有。其包括多形红斑、TEN、接触性皮炎和类风湿性关节炎。
Theories of Drug Hypersensitivity Pathogenesis
药物超敏反应的发病机制理论
Despite over half a century of research, the exact pathogenesis of drug hypersensitivity reactions remains unclear. This is why some clinicians and researchers use different words to describe certain reactions: “drug-associated” when the drug is thought to be part of the pathogenesis, but the direct cause-effect with the detected biomarkers or the clinical signs is not established; “drug-induced” when the immune events leading to the clinical signs are thought to be directly related to the drug and therefore expected to disappear when the drug is discontinued; and “drug-triggered” when the immune events leading to the clinical signs are thought to be indirectly related to the drug and therefore expected to continue despite drug withdrawal.
尽管进行了半个多世纪的研究，但药物超敏反应的确切发病机制仍不清楚。这就是为什么一些临床医生和研究人员使用不同的词语来描述某些反应：“药物相关（drug-associated）”-当药物被认为是发病机制的一部分，但与检测到的生物标志物或临床症状的直接因果关系尚未确定；“药物诱导（drug-induced）” -当导致临床症状的免疫事件被认为与药物直接相关，因此预计在停药时消失；“药物触发（drug-triggered）”-当导致临床症状的免疫调动被认为与药物间接相关，因此尽管停药但预计症状仍会继续。
There currently are 4 different theories to describe the mechanism of drug hypersensitivities. It is likely that all theories have some relevance, and that components of each occur in conjunction with one another, depending on the drug and the clinical signs.
目前有4种不同的理论来描述药物超敏反应的机制。很可能所有的理论都有一定的相关性，而且每个理论的组成部分都是相互关联的，这取决于药物和临床症状。
(Pro-)Hapten Hypothesis
(前)半抗原假说
The hapten-prohapten hypothesis is based on the thought that drugs that are too small themselves to elicit an immune response bind to tissue proteins, thereby making the protein-drug complexes immunogenic. Haptens are chemically reactive small molecules (eg, penicillins) that bind to proteins. Prohaptens are drugs that are inert, but become protein-reactive after undergoing metabolic bioactivation (eg, sulfonamides, acetaminophen). Hapten-protein complexes are taken up by antigen presenting cells (APCs), and presented by the major histocompatability complex (MHCs) to T cells. This elicits an inflammatory immune response and T-cell proliferation.
半抗原-前半抗原假说是基于这样一种想法，即药物本身太小而不能引起免疫反应，故与组织蛋白结合，从而使蛋白质-药物复合物具有免疫原性。半抗原是与蛋白质结合的化学反应性小分子(如青霉素)。前半抗原是惰性药物，但经过代谢生物活化后会产生蛋白质反应(如磺胺类、对乙酰氨基酚)。半抗原蛋白复合物由抗原提呈细胞(APC)摄取，并由主要组织相容性复合体(MHC)呈递给T细胞。这会引发炎症免疫反应和T细胞增殖。
A study by Lavergne et al investigated the presence of antidrug antibodies in 34 dogs with a history of hypersensitivity to sulfonamides. Sulfonamide serum adducts and antisulfonamide IgG antibodies were found in 50% of the hypersensitive dogs, and the presence of antidrug antibodies correlated with the presence of drug protein adducts. This provided the first evidence in veterinary medicine for the (pro-)hapten hypothesis.
Lavergne等人的一项研究调查了34只对磺胺类药物过敏的犬的抗药物抗体的存在情况。50%的超敏反应犬存在磺胺血清加合物（adducts）和抗磺胺IgG抗体，并且抗药物抗体的存在与药物蛋白加合物的存在相关。这在兽医学中为（前）半抗原假说提供了第一个证据。
Danger Theory
危险理论
The original theories of immunity were based on the idea of self versus nonself. The Danger Theory was developed because these theories failed to answer why autoimmunity or neoplasia was allowed to occur, or why the immune system failed to respond to many “foreign” molecules encountered in daily life, such as the intestinal microflora. The main concept is that the immune system is reactive not toward “foreignness” per se, but rather to “danger”, such as cell debris, oxidative stress, or inflammation.
最初的免疫理论是基于自我与非我的观点。危险理论之所以被提出，是因为这些理论未能回答为什么允许发生自体免疫或肿瘤，或者为什么免疫系统对日常生活中遇到的许多“外来”分子没有反应，比如肠道微生物群。其主要的概念是，免疫系统的反应不是针对“外来物”，而是对“危险”的反应，如细胞碎片、氧化应激或炎症。
This relatively new theory is thought to play an important role in drug allergies. The mechanisms by which a drug or its metabolites could trigger such a “danger cascade” are not yet well established. Many of the drugs that are associated with drug hypersensitivity, however, are known to cause cell damage via oxidative stress. It is therefore reasonable to assume that some drugs or their reactive metabolites could induce some “danger signals”. In any case, the disease treated by the drug also would be associated with various types of danger signals (eg, microbial pathogenic molecules in infections treated with antimicrobials, proinflammatory prostaglandins in inflammatory diseases treated with anti-inflammatory drugs). Indeed, “danger” signals commonly encountered in infectious diseases have been shown to increase the formation of intracellular drug-protein adducts thought to be toxic or immunogenic or both.
这一相对较新的理论被认为在药物过敏中发挥了重要作用。药物或其代谢物引发这种“危险级联反应”的机制尚未得到很好的确立。然而，已知许多与药物过敏有关的药物都会通过氧化应激导致细胞损伤。因此，我们有理由认为，某些药物或其活性代谢物可能会引发一些“危险信号”。无论如何，药物治疗的疾病也会与各种危险信号有关(例如，用抗生素治疗感染中的微生物致病分子，用抗炎药物治疗炎症性疾病中的前列腺素)。事实上，感染性疾病中常见的“危险”信号已被证明会增加细胞内药物-蛋白质加合物的形成，这些加合物被认为是有毒的或具有免疫原性的，或者两者兼而有之。
PI Concept
PI概念
The Pharmacological Interaction (PI) concept proposes that a drug itself can directly interact noncovalently with the major histocompatibility complex (MHC) or T cell receptors (TCR) or both to induce an immune response. This was based on the observation that the T cells of certain patients with a history of hypersensitivity to certain drugs could proliferate in response to drugs, without apparent drug metabolism or protein binding. This phenomenon is similar to how microbial superantigens nonspecifically activate the immune system, but in the case of the PI concept, there appears to be a certain level of specificity because not all T cell subsets are stimulated.
药理学相互作用(PI)的概念认为，药物本身可以直接非共价地与主要组织相容性复合体(MHC)或T细胞受体(TCR)或两者相互作用，以诱导免疫反应。这是基于观察到对某些药物过敏的某些患者的T细胞可以在药物反应中增殖，而没有明显的药物代谢或蛋白质结合的现象。这种现象类似于微生物超级抗原非特异性地激活免疫系统，但在PI概念的病例中，似乎有一定程度的特异性，因为不是所有的T细胞亚群都被刺激。
Viral Reactivation
病毒再激活理论
A newer theory is the viral reactivation theory, which postulates that a relationship exists between viral diseases and drug allergies. Underlying viral infections, such as Epstein–Barr virus or herpes virus, may increase susceptibility of patients to adverse drug reactions. Antiviral T cells may be implicated in stimulating an immune response that causes drug hypersensitivity.
一个较新的理论是病毒再激活理论，它假定病毒性疾病和药物过敏之间存在关系。潜在的病毒感染，如EB病毒（Epstein–Barr virus）或疱疹病毒，可能会增加患者对药物不良反应的易感性。抗病毒T细胞可能涉及到刺激导致药物过敏的免疫反应。
Common Clinical Patterns Associated with Drug Allergies
与药物过敏相关的常见临床模式
There are some differences in nomenclature between human and veterinary dermatology. For the most part, this is likely attributable to increased knowledge in the human medical field, and therefore more detailed description of reactions seen in human medicine. In this section, we describe different cutaneous reaction patterns that are seen as a result of adverse drug reactions, but it is important to remember that cutaneous drug hypersensitivity reactions can look like any known dermatology lesions and affect any part of the body (Table 2). Specific clinical signs cannot be attributed to specific drugs because each drug can induce different clinical signs, both qualitatively and quantitatively, depending on the individual patient (eg, Fig 2B and C).
人类皮肤病学和兽医皮肤病学在命名上有一些不同。在很大程度上，这可能归因于人类医学领域知识的增长，因此人类医学对看到的反应进行了更详细的描述。在本节中,我们描述不同皮肤的反应模式，被认为是药物不良反应的结果，但重要的是要记住，皮肤的药物过敏反应可以与任何已知的皮肤病变相似，发生于身体的任何部分(表2)。具体的临床症状不能归因于特定药物，因为不论如何定性和定量，每个药物可以引起不同的临床症状，这取决于患者个体的反应(例如,图2 B和C)。
Table 2. Notable histopathologic findings in reaction patterns of cutaneous drug allergies.
表2。皮肤药物过敏反应模式的显著组织病理学发现。
|
血管性水肿/荨麻疹 |
血管性水肿/荨麻疹的组织病理学特征是水肿。荨麻疹病变会有真皮水肿，而血管性水肿则是严重的水肿，从真皮延伸到皮下组织。 |
|
浅表脓疱性皮炎 |
在组织病理学上发现无明显棘层松懈的浅表脓疱。可能存在可变的细胞凋亡。 |
|
狼疮样药物反应 |
狼疮样药物反应的组织病理学可能难以与SLE鉴别，需要临床表现和免疫鉴别。典型的组织病理表现为界面性皮炎，多数病例出现基底细胞空泡化、凋亡、真表皮分离和溃疡。也可发生血管炎 |
|
PF样药物发应 |
典型的组织病理学病变是角质层下的脓疱，伴有明显的棘层松懈细胞。 |
|
多形红斑 |
多形红斑的特征性表现为角质形成细胞凋亡伴淋巴细胞卫星现象。界面性皮炎也存在;淋巴细胞和巨噬细胞掩盖了真皮表皮交界处。 |
|
TEN |
中毒性表皮坏死松解的特征是全层凝固性坏死，真皮层炎症最小。 |
Fig 2. A dog featuring the classic target lesions of erythema multiforme, secondary to drug administration (Panel A). Erosions and ulcerations on the scrotum of a Doberman following administration of ampicillin/sulbactam (Panel B). A DSH cat is affected by ulcerations, crusting, and pruritus on the head following a course of amoxicillin/clavulanic acid (Panel C). Pemphigus-foliaceus was induced in this dog by application of the topical parasiticide Promeris Duo (metaflumizone/amitraz) (Panel D).
图2。一只多形红斑患犬的经典靶形病变,继发于药物管理(图A)。一只杜宾犬的糜烂和溃疡的阴囊，氨苄西林/舒巴坦治疗后(图B)。一只DSH猫头部的溃疡、结痂和瘙痒，阿莫西林/克拉维酸治疗后(图C)。一只外用驱虫剂复方(氰氟虫腙/双甲脒)后诱导的PF患犬(图D)。
Urticaria and Angioedema
荨麻疹和血管性水肿
Seen both in animals and humans, these are edematous cutaneous reactions that result from mast cell or basophil degranulation because of Type I hypersensitivity reactions. The characteristic lesion is a hive, or wheal. In the case of urticaria, the edema is confined to the dermis, whereas in angioedema the edema spreads to the subcutaneous tissue, which makes lesions less distinct. Wheals are most commonly seen on the glabrous skin, often the ventral abdomen, and lesions often persist for <24 hours after drug discontinuation. Angioedema typically is noted on the head and face, and pruritus is variable. Chronic urticaria has been reported in a case of diethylcarbamezine reaction in a dog.2Other drugs that have been reported to cause urticaria and angioedema in veterinary patients include penicillin, ampicillin, tetracycline, vitamin K, propylthiouracil, amitraz, ivermectin, moxidectin, radiocontrast agents, and HyLyt efa shampoo.Urticaria seems to be extremely rare in cats.
这种情况在动物和人类中均可见，这是由于I型超敏反应导致肥大细胞或嗜碱性粒细胞脱颗粒而引起的皮肤水肿反应。特征性病变为蜂窝状或风疹。在荨麻疹的病例中，水肿局限于真皮层，而在血管性水肿中，水肿扩散到皮下组织，这使得病变不那么明显。风疹最常见于无毛皮肤，通常在腹部腹侧，并且病变在停药后持续时间<24小时。典型的血管性水肿出现在头部和面部，瘙痒是多变的。据报道，在一只犬身上发现了由乙胺嗪（diethylcarbamezine）引起的慢性荨麻疹。其他已报道的引起动物荨麻疹和血管性水肿的药物包括青霉素、氨苄西林、四环素、维生素K、丙基硫氧嘧啶、双甲脒、伊维菌素、莫昔克丁、放射造影剂和HyLyt efa香波。荨麻疹似乎在猫身上极为罕见。
Pruritus
瘙痒
Pruritus is a common manifestation of cutaneous drug reactions, and may be the only clinical sign. It is thought to be particularly intense in cases of drug allergies. It may be mediated by histamines in immediate reactions, and proinflammatory cytokines in delayed reactions. Symmetric pruritus without lesions may be present; the severity of the pruritus can be variable.
瘙痒是皮肤药物反应的常见表现，也可能是唯一的临床症状。在药物过敏的病例，它被认为是特别强烈的。速发反应中可能由组胺介导，迟发反应中由促炎细胞因子介导。可能表现为无病变的对称性瘙痒；瘙痒的严重程度可能是不同的。
In humans, pruritus has been reported with drugs such as NSAIDs, antibiotics, opiates, radiocontrast media, and Vitamin A derivatives. Scott et al found that of 101 dogs with adverse drug reaction, 11.9% had allergic-like dermatoses that presented as pruritus. Pruritus and facial excoriations have been associated with methimazole administration in up to 15% of cats.
据报道，在人类中，非甾体类抗炎药、抗生素、阿片类药物、放射造影剂和维生素A衍生物等药物会导致瘙痒。Scott等人研究发现，在101只出现药物不良反应的犬中，11.9%的犬患有以瘙痒为表现的过敏样皮肤病。在高达15%的猫只中，瘙痒和面部抓痕与甲巯咪唑的用药有关。
Sweet’s Syndrome
斯威特综合征
Sweet’s syndrome, or neutrophilic dermatosis in humans, is characterized by painful, erythematous plaques or nodules with an intense neutrophilic dermatitis, as well as concurrent systemic signs. Clinical signs can include pyrexia, immune-mediated thrombocytopenia, leukocytosis, arthralgia, myalgia, and vasculitis. Although Sweet’s syndrome often is idiopathic, adverse drug reactions have been known to cause this disease. In a case report described by Mellor et al, a 10-month-old Neopolitan Mastiff presented for a 7-day history of sudden-onset extensive skin eruptions, lethargy, weakness, and collapse. The dog had a history of carprofen, cephalexin, and amoxicillinclavulanic acid administration after entropion surgery. Clinical features and skin biopsy results were consistent with Sweet’s syndrome, but lymphocyte transformation tests (LTT) for cephalexin and amoxicillin-clavulanic acid were negative. This indicated that the cause of the clinical signs could have been a result of hypersensitivity to carprofen, although this hypothesis was not tested by LTT. Carprofen also was associated with drug eruption resembling Sweet’s syndrome and death in 2 additional dogs. Firocoxib may have contributed to the development of Sweet’s syndrome in an additional case report.
斯威特综合征，或人类的中性粒细胞皮肤病，以疼痛、皮肤发红或结节为特征，伴有严重的中性粒细胞皮炎，并有全身症状。临床症状包括发热、免疫介导的血小板减少、白细胞增多、关节痛、肌痛和血管炎。虽然Sweet‘s综合征通常是特发性的，但已知药物不良反应会导致这种疾病。在Mellor等人描述的一个病例报告中，一只10个月大的纽波利顿犬（Neopolitan Mastiff）出现了为期7天的突发性广泛皮疹、嗜睡、虚弱和昏厥的病史。这只犬有在眼睑内翻手术后服用卡洛芬、头孢氨苄和阿莫西林克拉维酸的病史。临床特征和皮肤活检结果与Sweet综合征一致，但是淋巴细胞转化试验（lymphocyte transformation tests）显示对头孢氨苄和阿莫西林-克拉维酸检测均为阴性。这表明，出现这些临床症状的原因可能是对卡洛芬过敏的结果，但这一假设没有进行LTT的验证。卡洛芬还与另外2只犬的类似斯威特综合征的药疹和死亡有关。在另一个病例报告中，非罗考昔可能促进了Sweet综合征的发展。
Lupoid Drug Reactions or Lupus-like Drug Reactions
狼疮样药物反应或狼疮样药物反应
Allergic drug reactions may mimic the cutaneous lesions that are seen in systemic lupus erythematosus (SLE). Dermatologic findings may include erythema, depigmentation, scaling, crusting, erosions, and ulceration of the skin, mucocutaneous junctions and mucous membranes, and alopecia. If vasculopathy is a factor, ear tip necrosis, foot pad ulceration, and pressure point ulceration also may be present. As SLE is multisystemic, anemia, thrombocytopenia, polyarthropathy, and protein-losing nephropathy also may be present. In dogs, sulfonamides, hydralazine, primidone, and vaccines have been reported to cause SLE.
药物过敏反应可能与系统性红斑狼疮(SLE)的皮肤病变相似。皮肤病学表现包括皮肤、黏膜皮肤交界处和黏膜的皮肤发红、色素减退、皮屑、结痂、糜烂、溃疡，以及脱毛。如果出现了血管病变，那么耳尖坏死，脚垫溃疡，压力点溃疡也可能还会表现出来。由于SLE是多系统的，也可能出现贫血、血小板减少、多关节病和蛋白丢失肾病。据报道，在犬身上，磺胺类药物、肼酞嗪、扑米酮和疫苗会引起系统性红斑狼疮。
Pemphigoid Reactions or Pemphigus-like Drug Reactions (Fig 2D)
类天疱疮反应或类天疱疮药物反应(图2D)
These terms apply when the drug reaction mimics naturally occurring pemphigus foliaceus. Pemphigus foliaceus-like drug reaction resolves once the offending drug is discontinued (“drug-induced pemphigus”). However, in cases of drug-triggered pemphigus foliaceus, the disease continues despite ceasing the offending drug. Further differentiation from naturally occurring pemphigus foliaceus includes unusually fast onset of clinical signs, unusually early age of onset, and unusual clinical features such as oral lesions (“drugtriggered pemphigus”). White et al presented 4 case reports of dogs with putative drug-related pemphigus foliaceus. These cases involved trimethoprim-sulfamethoxypyridazine, trimethoprim-sulfamethoxazole, cephalexin, and oxacillin. Another puppy that was treated for juvenile cellulitis with amoxicillin-clavulanic acid and topical oxytetracycline developed clinical signs consistent with pemphigus foliaceus. After discontinuation of all medications, the clinical signs resolved, and a diagnosis of pemphigus foliaceus-like drug reaction was made. A case of suspected druginduced pemphigus vulgaris has been reported because of administration of polymyxin-B in a dog. Promeris, an ectoparasiticide containing amitraz and metaflumizone, has been associated with 22 published cases of pemphigus foliaceus-like drug reaction, as well as drug-triggered pemphigus.
这些术语适用于与自然发生的落叶型天疱疮相似的药物反应。一旦停用致敏药物，落叶型天疱疮样药物反应就会消失(“药物诱导性天疱疮”)。但是，在药物触发性落叶型天疱疮的病例，即使停用致敏药物，临床症状仍会继续。与自然发生的落叶型天疱疮的进一步区别包括临床症状发作异常快，发病年龄异常早，以及出现不寻常的临床特征，如口腔病变(“药物触发性天疱疮”)。White等人提出了4例疑似与药物相关的落叶型天疱疮的犬病例报告。这些病例涉及甲氧苄啶-磺胺甲氧哒嗪（trimethoprim-sulfamethoxypyridazine）、甲氧苄啶-磺胺甲恶唑（trimethoprim-sulfamethoxazole）、头孢氨苄和苯唑西林。另一只幼犬用阿莫西林-克拉维酸和外用土霉素治疗幼犬蜂窝织炎，出现了与落叶型天疱疮一致的临床症状。这只幼犬停止所有药物治疗后，临床症状消失，诊断为落叶型天疱疮样药物反应。还有一例疑似药物诱导性寻常型天疱疮，原因是犬使用了多粘菌素-B。Promeris（普罗梅里斯，一个产品商品名）是一种含有双甲脒和氰氟虫腙的体外驱虫剂，其与已发表的22例落叶型天疱疮样药物反应和药物触发性天疱疮有关。
Vasculitis
血管炎
Neutrophilic immunologic vasculitis is a multifactorial disease, and is sometimes a result of drug allergy. Most often it is because of immune complex deposition (Type III hypersensitivity) or may be related to autoantibodies produced against neutrophils. The spectrum of severity can range from single organ vasculitis to multiple organ failure and death. Dermatologic findings include swelling because of subcutaneous edema, erythema, purpura, erythematous plaques, skin necrosis, and ulcerative lesions. Vasculitis often is evident in areas of the skin where there is poor collateral circulation, such as footpads, the tips of the pinnae and tail, and over bony prominences. Pain may be present, and often is seen in conjunction with tissue necrosis. Lavergne et al have identified some anti-neutrophil antibodies in dogs with a history of sulfonamide allergy; their presence correlated with a poorer prognosis. Meloxicam was reported to have induced a neutrophilic vasculitis in a dog that had been treated for cranial cruciate ligament injury.
中性粒细胞免疫性血管炎是一种多因素疾病，有时是药物过敏导致的。其最常见的原因是免疫复合物沉积(III型超敏反应)，或也可能与自身产生的抗中性粒细胞抗体有关。它的严重程度可从单器官血管炎到多器官衰竭和死亡。皮肤科表现包括皮下组织水肿导致的肿胀、皮肤发红、紫疹、发红斑块、皮肤坏死和溃疡性病变。血管炎通常发生在侧支循环不佳的皮肤区域，如足垫、耳廓尖端和尾部，以及骨骼凸起部位。可能存在疼痛，并且经常与组织坏死一同出现。Lavergne等人在有磺胺类药物过敏病史的犬身上发现了一些抗中性粒细胞抗体；这只抗体的存在提示预后较差。据报道，美洛昔康在一只接受过前十字韧带手术的犬身上诱导过中性粒细胞血管炎。
Fixed Drug Eruption
固定型药疹
Fixed drug eruption lesions are well-circumscribed erythematous lesions that begin as edema and progress to bullae, and may ulcerate as a consequence of bullae rupture. Lesions may be solitary or multiple, and can appear on any site of the skin.The classic feature of fixed drug eruptions is that repeated exposure to the drug results in lesions in identical locations. Satellitosis (lymphocytes adjacent to apoptotic keratinocytes) in histopathology samples indicates keratinocyte necrosis, which suggests a cell-mediated cytotoxic response. Fixed drug eruptions have been noted in dogs with diethylcarbamazine reactions, as well as with 5-fluorocytosine, aurothioglucose, and thiacetarsamide.Scott et al reported 3 dogs with fixed drug eruptions, caused by levo-thyroxine, amoxicillin clavulanate, and cephalexin.
固定型药疹病变是边界清楚的红斑性病变，开始为水肿，发展为大疱，并可能因大疱破裂而溃疡。病变可单发或多发，可出现在皮肤的任何部位。固定药疹的典型特征是反复接触药物会在相同位置造成病变。组织病理学样本中的卫星现象(淋巴细胞毗连于凋亡的角质形成细胞)表明角质形成细胞坏死，这种现象提示细胞介导的细胞毒性反应。据报道，犬在使用乙胺嗪后出现固定型药疹，同样，在使用5-氟胞嘧啶、金硫代葡萄糖和硫胂胺后，也有出现固定型药疹的案例。Scott等报道了3只犬由于使用左旋甲状腺素、阿莫西林克拉维酸和头孢氨苄出现固定型药疹。
Superficial Suppurative Necrolytic Dermatitis
浅表化脓性坏死性皮炎
Superficial suppurative necrolytic dermatitis (SSND) has been described only in Miniature Schnauzers and is associated with shampoos. Clinical signs begin 48 –72 hours after topical application of shampoos, and the condition presents as erythematous papules and plaques, vesicles, and pustules. Most commonly, over-the-counter natural shampoos are implicated. Dogs may have concurrent systemic signs including pyrexia or lethargy. Scott et al reported 2 cases of SSND of 101 dogs with adverse drug reactions, and Murayama et al confirmed shampoo as an etiologic agent of SSND by patch testing in a Miniature Schnauzer.
目前，浅表化脓性坏死性皮炎(SSND)仅在迷你雪纳瑞犬中有报道，与香波有关。临床症状开始于外用香波48 -72小时后，症状表现为发红丘疹和斑块、水疱和脓疱。引起这种现象最常见的香波是非处方天然香波。犬可能同时出现全身症状，包括发热或嗜睡。Scott等报道了101只发生药物不良反应的犬，其中2例SSND，Murayama等通过对一只迷你雪纳瑞进行斑贴试验证实香波是SSND的病因。
Erythema Multiforme (Fig 2A)
多形红斑(图2A)
Erythema multiforme is an uncommon cutaneous reaction pattern that can have variable manifestations and varied etiologies, including drug reaction, although this is controversial. It is believed to be a T cell-mediated hypersensitivity that is mounted against keratinocytes carrying drug-protein complexes, and causing apoptosis. Ulceration may be substantial, and mucosal ulceration can be striking. Pruritus is not a common feature, but cutaneous pain may be evident. In animals, drugs that have been associated with EM include sulfonamides, cephalexin, chloramphenicol, aurothioglucose, diethylcarbamazine, gentamicin, penicillin, levamisole, and levo-thyroxine. One study showed an increased frequency of EM in German Shepherd Dogs, Pembroke Welsh Corgis, Old English Sheepdogs, Chow Chows, Cairn Terriers, and Bearded Collies.
多形红斑是一种不常见的皮肤反应模式，可以有不同的表现和包括药物反应在内的不同病因，但这是有争议的。其被认为是由T细胞介导的超敏反应，针对携带了药物-蛋白复合物的角质形成细胞的相互作用，最终导致细胞凋亡。溃疡可能是牢固的，在黏膜的溃疡会比较明显。瘙痒不是一个常见的特征，但皮肤疼痛可能是明显的。在动物实验中，与EM相关的药物包括磺胺类药物、头孢氨苄、氯霉素、金硫代葡萄糖、乙胺嗪、庆大霉素、青霉素、左旋咪唑和左旋甲状腺素。一项研究表明，EM在德国牧羊犬、彭布罗克威尔士柯基犬、英国古代牧羊犬、松狮犬、凯恩梗和粗毛牧羊犬中发生频率增加。
Toxic Epidermal Necrolysis and Steven–Johnson Syndrome (SJS)
中毒性表皮坏死松解与史提芬强生综合征(SJS)
Steven–Johnson syndrome and TEN both involve the detachment of the epidermis from the dermis over a significant surface of the skin. The SJS is less likely to be associated with systemic signs, and skin detachment (epidermolysis) occurs over less than 10% of the body area, whereas in TEN epidermal detachment encompasses greater than 30% of body surface area. Both are relatively rare, but life-threatening, conditions because of rapid and extensive necrosis of the skin that predisposes the patient to sepsis and fluid loss. In humans, SJS and TEN are associated with drug reactions in 80–95% of cases, and survival rate when the patient can rapidly be admitted to a specialized intensive care unit remains lower than 30–50%. The pathomechanism of these severe skin reactions still remains unclear, but is thought to be caused by widespread, rapid apoptosis of keratinocytes mediated by CD8 T cells and mononuclear cells, with concurrent overexpression of toxic cytokines, such as TNF-a. Widespread erythema progresses to epidermal necrolysis that presents as sloughing of the skin with even gentle contact. Marked cutaneous pain is present.
史提芬强生综合征（SJS）和TEN都涉及皮肤表皮层与真皮层的分离。SJS不太可能与全身症状相关，并且皮肤分离(表皮松解)不超过体表面积的10%，而在TEN中，表皮分离超过体表面积的30%。这两种情况相对罕见，但都有生命危险，因为皮肤迅速广泛坏死，易导致患者出现败血症和体液流失。在人类中，在80-95%的SJS和TEN病例中都与药物反应有关，即使患者可以迅速被送入专科重症监护病房时，但生存率仍低于30-50%。这些严重皮肤反应的病理机制仍不清楚，但被认为是由CD8+ T细胞和单核细胞介导的一种广泛、快速地引起角质形成细胞凋亡的反应，同时其过度表达毒性细胞因子，如TNF-α。广泛性红斑发展为表皮坏死松解，即使是轻微的接触也会出现皮肤脱落。伴有有明显的皮肤疼痛。
Cases in humans have improved success if treated extensively in burn units, yet have a mortality rate of >35% for SJS and 50% for TEN. In veterinary medicine where such specific intensive care is unavailable, the disease usually is rapidly fatal, often within 2 days. Flea dip preparations, both organophosphate dips and d-limonene dips, have been implicated in TEN in both dogs and cats. Other medications reported to have caused TEN in veterinary patients include sulfonamides, penicillin, ampicillin, aurothioglucose, cephalexin, griseofulvin, levamisole, and 5-flurocytosine. In humans, sulfonamides, aminopenicillins, quinolones, cephalosporins, chlormezanone, nevirapine, lamotrigine, sertraline, aromatic epileptics, NSAID, allopurinol, and corticosteroids most often are implicated.
在人类的病例中，如果患者在烧伤病房全力治疗，成功率会有所提高，但SJS的死亡率仍>35%，TEN的死亡率仍为50%。在没有这种特殊重症监护的兽医病例中，这种疾病通常在2天内会快速致命。在犬和猫中都有10个病例，涉及到驱跳蚤的浸泡制剂，包括有机磷酸盐和d-柠檬烯滴剂。据报道，在兽医病例中引起TEN的其余药物最常见的包括磺胺类药物、青霉素、氨苄西林、金硫代葡萄糖、头孢氨苄、灰黄霉素、左旋咪唑和5-氟胞嘧啶。在人类中，磺胺类、氨基青霉素类、喹诺酮类、头孢菌素类、氯嗪酮、奈韦拉平、拉莫三嗪、舍曲林、芳香族癫痫药、非甾体抗炎药、别嘌呤醇和皮质类固醇。
Maculopapular Eruptions and Maculopapular Exanthema (MPE)
斑丘疹(MPE)
Maculopapular exanthema (“skin eruption” or “rash”) is the most commonly seen nonimmediate reaction in humans.Clinical signs include maculopapular erythematous lesions that are variably pruritic. Vesicles and angioedema also may be present.In nonpruritic patients, mild eruptions could go unnoticed, whereas the reactions that are noticed may be mistaken for a more common inflammatory dermatosis. The MPE has been reported in cats treated with ampicillin, cephalexin, penicillin, sulfonamides, and griseofulvin, resulting in miliary dermatitis, or suppurative papules and crusts.
斑丘疹(“皮肤疹”或“皮疹”)是人类最常见的非速发反应。临床症状包括斑疹性红斑病变，并伴有不同程度的瘙痒。水疱和血管性水肿也会出现。在非瘙痒性患者中，轻微的皮疹可能不被注意到，并且被注意到的反应容易被误认为是其他常见的炎性皮肤病。据报道，MPE已在使用氨苄西林、头孢氨苄、青霉素、磺胺类药物和灰黄霉素治疗的猫中出现，导致粟粒性皮炎，或化脓性丘疹和结痂的病变。
Wells’ Syndrome (Eosinophilic Dermatitis)
威尔斯综合征(嗜酸性皮炎)
Wells’ syndrome was first described in the 1970s as a cutaneous eosinophilic disorder. Its pathogenesis remains unknown, but cases often have been related to drugs. Eosinophilic dermatitis with erythematous, edematous, coalescing macules and plaques, resembling human Wells’ syndrome have been reported in dogs, and some cases were suspected to be adverse drug reactions
在20世纪70年代，威尔斯综合征首次被描述为一种皮肤嗜酸性粒细胞疾病。其发病机制尚不清楚，但病例常常与用药有关。犬嗜酸性皮炎的表现有发红、水肿、聚集的斑点和斑块，类似于人类的威尔斯综合征，目前已有报道，其中的一些病例被怀疑是药物不良反应。
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
伴有嗜酸性粒细胞增多症和全身症状的药疹(DRESS)
DRESS also is known as drug-induced hypersensitivity syndrome (DIHS) and is a reaction seen in humans.It includes some combination of clinical signs such as severe cutaneous eruption, lymphadenopathy, hyperthermia, hepatitis, atypical lymphocytes, and characteristic eosinophilia, which can be severely delayed (weeks to months) after institution of the drug.The most common drugs associated with this manifestation of drug allergy are phenytoin, carbamazepine, sulfonamides, allopurinol, gold salts, and dapsone.
DRESS也被称为药物性超敏反应综合征(DIHS)，是一种见于人类的反应。它包括一些临床症状的组合，如严重的皮肤皮疹、淋巴结肿大、高热、肝炎、不典型淋巴细胞和特征性嗜酸性粒细胞增多，这些症状可在用药后严重延迟(数周至数月)。与这种药物过敏表现相关的最常见药物是苯妥英、卡马西平、磺胺类药物、别嘌呤醇、金盐和氨苯砜。
DRESS has not been reported in veterinary medicine thus far. This could be because of the fact that veterinarians usually are not familiar with the existence of this syndrome.
到目前为止，在兽医学中还没有关于DRESS的报道。这可能是因为兽医通常不熟悉这种综合征的存在。
The clinical pattern of a drug hypersensitivity reaction is probably dependent on both the patient and the drug. There may be a range of clinical signs seen in a particular patient. In addition, the clinical manifestations will vary from patient to patient, and among drugs. Because of scant published reports of drug allergies in veterinary medicine, it remains unknown how frequently each of these manifestations of drug allergies occur, and which drugs are most often responsible. The pleomorphic nature of the condition furthermore makes diagnosis and categorization more challenging.
药物超敏反应的临床模式可能取决于患者和药物。在一个特定的病人身上可能会有一系列的临床症状。此外，临床表现也会因患者和药物的不同而有所不同。由于很少有兽药药物过敏的发表报告，目前还不清楚每种药物过敏反应的发生频率，以及哪种药物最常见。病情的多样化使进一步的诊断和分类更具挑战性。
How To Recognize and Diagnose ADR
如何识别和诊断药物不良反应
History and Physical Examination
病史和体格检查
The history and physical examination are very important in diagnosing ADRs or eliminating them from the differential diagnosis. In veterinary medicine, the client should be questioned about any previous drug reactions, any past drug history, and any current medications that the animal may be taking (including nutraceuticals). In particular, the timing between initiating drug treatment and the start of clinical signs should be investigated. Drug allergies may not be immediate, so even drugs that have been used chronically for months may be considered as potential culprits. Furthermore, the client should be questioned about the previous use of the same drug in question, because prior sensitization to the drug may make allergy more likely if the timing between initiating the drug and clinical signs is very rapid.
对药物不良反应来说，病史和体格检查对诊断或排除其他鉴别诊断非常重要。在兽医学中，应询问客户以前所有的药物反应，以往所有的用药史，以及动物目前可能正在使用的所有药物(包括营养品)。特别的是，应该调查开始药物治疗的时间以及临床症状出现的时间。药物过敏可能不是立竿见影的，所以即使是长期服用了几个月的药物也可能被认为是潜在的致敏药。此外，应该询问客户以前是否使用过相同的药物，因为如果开始用药和临床症状之间的时间非常短，那么之前对药物的敏化作用更可能导致过敏。
Another problem confounding the diagnosis of drug allergies is certain biases that clinicians may have. Sulfonamide and penicillin antibiotics, for example, are considered notorious for causing drug allergies. As a result, signs of allergic reactions observed with these drugs are more likely to be noted than with a drug that the clinician does not commonly associate with drug allergy.
另一个混淆药物过敏诊断的问题是临床医生可能存在的某些偏见。比如，磺胺类抗生素和青霉素类抗生素因引起药物过敏而臭名昭著。因此，使用这些药物更有可能被注意到过敏反应，而其他不被临床医生关注的药物过敏反应易被忽视。
Physical examination should include a complete evaluation, with a strong focus on the skin, including haired skin, the mucocutaneous junctions (oral, nasal, ocular, anus, and genital), and oral mucosa. The pleomorphism of cutaneous reaction patterns with drug allergies complicates diagnosis because these drugrelated cutaneous signs can mimic any other cutaneous disease. Ruling out other possible causes is important for diagnosis of drug hypersensitivity.
体格检查应包括详尽的评估，重点放在皮肤上，包括有毛的皮肤、皮肤黏膜交界处(口腔、鼻、眼、肛门和生殖器)以及口腔黏膜。药物过敏的皮肤反应模式的多样性使诊断变得复杂，因为这些与药物相关的皮肤症状可以与任何其他皮肤疾病相似。找出其他可能的病因对于药物过敏的诊断很重要。
The combination of a thorough history and a thorough physical examination may by themselves give a strong suspicion of drug hypersensitivity. Other diagnostic tests then can be performed to help make a definitive diagnosis.
完整的病史结合详尽的体格检查就可对药物过敏产生足够的怀疑。然后可以进行其他检测，以帮助做出明确的诊断。
Complete Blood Count and Serum Biochemistry
全血细胞计数和血清生化
Complete blood work should be performed as part of the diagnostic evaluation. In many cases of ADRs, these laboratory findings will not be instrumental in the diagnosis of cutaneous drug hypersensitivity. However, it will be helpful when the drug allergic reaction is associated with hemolytic anemia, thrombocytopenia, nephritis, or hepatotoxicity. Furthermore, eosinophilia is a common marker of drug allergies in general. In cases of type I reactions, total IgE concentrations can also be increased. In addition, depending on the extent of cutaneous lesions, hypoproteinemia may be present as a result of cutaneous losses.
完整的血液检查应作为诊断评估的一部分。在许多ADR病例中，这些实验室发现对皮肤药物过敏的诊断也许没有帮助。但是，当药物过敏反应与溶血性贫血、血小板减少、肾炎或肝毒性相关时，这将是有帮助的。此外，嗜酸性粒细胞增多通常是药物过敏的常见标志。在I型反应的情况下，总IgE浓度也可以增加。此外，根据皮肤病变的程度，皮肤缺失可能导致低蛋白血症。
Histopathology
组织病理学
Histopathology can be performed when drug allergic reactions seem to target a specific organ (eg, bone marrow histology for blood dyscrasias, skin biopsy for cutaneous manifestations). This is of particular importance with severe cutaneous reactions. Skin punch biopsies can be performed on representative lesions. If there are different stages of a particular lesion (eg, erythema, pustule, crust, ulceration), and finances are limited, obtaining newer lesions is more likely to yield a diagnosis. Ideally, several biopsies should be taken with inclusion of samples of different stages of lesions and also clinically normal skin adjacent to the lesions. Because drug allergies can present in many different ways, histopathology can be useful to differentiate them from other possible differential diagnoses. However, diagnosis cannot be based on histopathology alone, because the reaction patterns seen with drug allergies also can be seen with other etiologies. Skin Diseases of the Dog and Cat: Clinical and Histopathologic Diagnosis by Gross et al is a useful textbook for histopathologic lesions of adverse drug reactions. See Table 2 for a concise table of histopathologic findings.
当药物过敏反应看似针对某特定器官时，可以进行组织病理学检查(例如，血凝不良的骨髓组织学检查，皮肤表现的皮肤活检)。这对于严重的皮肤反应尤为重要。皮肤穿刺活检可对有代表性的病变进行。如果一个特定的病变有不同的阶段(如发红、脓疱、结痂、溃疡)，而且资金有限，则获得较新的病变更有可能得到诊断。理想情况下，应进行多次活检，包括不同阶段的病变样本以及病变附近正常的皮肤。因为药物过敏可以有许多不同的表现，组织病理学可以从其他的鉴别诊断中区分它们。然而，诊断不能仅基于组织病理学，因为药物过敏的反应模式也可以在其他病因中看到。Gross等人编写的《猫犬皮肤病:临床和组织病理学诊断》是一本十分有用的介绍药物不良反应组织病理学病变的教科书。组织病理学简表见表2。
Dechallenge and Rechallenge
停药和再用药
The most common test performed is withdrawal of the suspected offending drug (dechallenge). If resolution occurs after withdrawal, then most clinicians presume that their suspicion was correct. In veterinary medicine, especially where other diagnostic tests are less frequently available, this test is the most cost-effective and easiest to perform. If polypharmacy was used on the patient, this can complicate the process. In this case, there are 2 alternatives of how to make a diagnosis. All drugs can be discontinued, and once there is clinical resolution, the medications least likely to have caused a reaction can be reintroduced, one at a time. Alternatively, the clinician may discontinue medications most likely to have incited a reaction 1 at a time. This step-wise approach is useful if the patient is on medications necessary for survival, but is not advised if the clinical signs related to the drug allergy are lifethreatening. Drug provocation tests are considered the gold standard to confirm a drug hypersensitivity reaction and identify the specific culprit drug.6However, ethical considerations come into play when the issue of drug provocation testing (rechallenge) is explored. Re-exposing a patient to a drug that previously caused a hypersensitivity reaction can lead to exacerbated clinical signs, and may be life threatening. Anaphylactic reactions and even death are possible. Therefore, this approach is not recommended. Provocation testing (rechallenge) should only be performed in instances where it is absolutely necessary to determine if the drug was indeed responsible for the clinical signs or which drug was the offending culprit because the patient’s outcome or long-term survival depends on the suspected drug. This is generally performed under strict hospital surveillance by trained personnel in an environment with CPR capabilities, and the drug is administered at increasing doses (starting from a very low dose) every 30–60 minutes.6This test is always contraindicated in patients that have had near-fatal drug reactions, such as anaphylaxis, TEN, or DRESS.
最常见的测试是停药(Dechallenge)。如果停药后症状缓解，那么大多数临床医生认为他们的怀疑是正确的。在兽医学领域，特别是在其他诊断测试不太常见的情况下，这种测试是最成本最低且最容易执行的。如果在患者身上使用了多种治疗药物，可能会使过程变复杂。在这种情况下，有两种诊断方法。第一种方法，所有药物都停用，一旦临床症状缓解，最不可能引起反应的药物可以重新使用，一次增用一种。第二种方法，临床医生停掉一种最有可能引起反应的药物，根据可能性一次停一种。如果用的药物都是生存所必需的药物，这种循序渐进的方法是合适的，但如果与药物过敏相关的临床症状危及生命，则不建议采用这种方法。药物刺激试验被认为是确诊药物超敏反应和确定具体的致敏药物的金标准。然而，当探讨药物激发试验(再用药)的问题时，可能再伦理方面会出现问题。再次让患者接触先前引起超敏反应的药物可能加重临床症状，并可能危及生命。出现过敏反应甚至死亡都是有可能的。因此，不建议采用这种方式。只有在绝对必要的情况下，才应进行激发试验(再用药)以确定药物是否确实导致临床症状，或者是因为患者预后或长期生存取决于这一可疑药物，故一定需要确认这种药是否为致敏药物。这通常是在医院的严格监督下，由训练有素且具有心肺复苏能力的人员操作的，并且以每30-60分钟给药递增的剂量进行 (从非常低的剂量开始)。对曾有过近乎致命的药物反应(如过敏反应、TEN或DRESS)的患者，本试验是禁止操作的。
Skin Tests
皮肤测试
Skin testing (prick testing, patch testing, or intradermal testing) has been used in human patients to diagnose various allergic responses in sensitized patients. There are a limited number of reports of patch testing being performed in veterinary medicine. Prick testing and intradermal testing are used to evaluate immediate reactions caused by IgE allergic reaction, and are evaluated within 24 hours, whereas for delayed reactions both intradermal testing (IDT) or patch testing are options, and require readings up to 72 hours. Anaphylaxis is a possible adverse effect of this test. Skin tests for drug allergy have been used mainly in human medicine where they remain relatively unreliable, especially in delayed type reactions. One explanation is that tests that are conducted with the parent drug are likely to be falsely negative if the immune system is sensitized against a drug metabolite or a drug-protein hapten. These tests are more useful in cases in which the suspicion of drug allergy has been built on strong evidence from the case history and clinical signs, and when specific protocols have been validated for the drug of interest.
皮肤试验(点刺试验、斑贴试验或皮内试验)已用于人类患者诊断致各种过敏反应。在兽医学领域进行的斑贴试验的报告数量有限。点刺试验和皮内试验用于评估IgE过敏反应引起的速发反应，并在24小时内进行评估。而对于迟发反应，皮内试验(IDT)或斑贴试验是可选的，需要长达72小时监测结果。过敏反应是该试验可能产生的不良反应。药物过敏的皮肤试验主要用于人类医学，它们相对不那么可靠，特别是在迟发反应中。一种解释是，如果免疫系统是对药物代谢物或药物-蛋白半抗原致敏，那么用其母体药物进行的测试可能会呈假阴性。当已怀疑药物过敏并且在病史和详尽体格检查都提供了有力证据上，以及当特定检查已经验证了怀疑的药物出现副反应时，这些皮肤测试是更适用的。
Antibody Testing
抗体检测
For Type I Reactions.
对于I型反应
IgE concentrations: Increased total IgE concentrations might indicate a type I hypersensitivity reaction, but they are not specific for drug allergy. Some laboratories have the capacity of measuring drug-specific IgE concentrations for certain specific drug allergies, but these assays often can give false-positive results because of technical artifacts, such as nonspecific binding or cross-reactivity.
IgE浓度检测：总IgE浓度升高可能表明I型超敏反应，但它们不具备药物过敏的特异性。一些实验室有能力检测某些特定过敏药物的特异性IgE浓度，但由于非特异性结合或交叉反应等技术因素，这些检测方法往往会给出假阳性结果。
The basophil activation test (BAT): The BAT is an in vitro test that measures the capacity of basophils to release histamine or upregulate activation markers, such as CD63 and CD203c in the presence of the allergen, the drug itself or one of its metabolites in cases of drug hypersensitivity.6This type of assay appears to be helpful, but is not readily available for veterinary practitioners at this time.
嗜碱性粒细胞激活试验(BAT)：BAT是一种体外试验，它检测嗜碱性粒细胞在过敏原、药物本身或其代谢物存在的情况下释放组胺或上调激活标志物的能力，如CD63和CD203c。这种类型的分析似乎是有帮助的，但目前兽医领域还不容易获得。
For Delayed Reactions
对于迟发反应
Antidrug IgG has been detected in multiple drug allergies in both human and veterinary medicine. Autoantibodies against specific tissues (eg, liver, platelets, neutrophils) also have been identified in human and veterinary patients with a history of delayed drug hypersensitivity. There is very little evidence of antibodies specifically targeting cutaneous proteins in skin drug allergies to date.
在人医和兽医领域的多种药物过敏中都检测到了抗药物IgG。在有迟发药物过敏史的人类和动物中也发现了针对特定组织(如肝脏、血小板、中性粒细胞)的自身抗体。迄今为止，很少有证据表明皮肤药物过敏反应中出现针对皮肤蛋白的抗体。
Antidrug and antitissue antibodies that have been identified in patients with a history of delayed drug hypersensitivity sometimes have also been detected in patients who tolerated the drug normally. It is therefore difficult to consider them as more than diagnostic biomarkers. However, some of these antibodies have been shown to correlate with the prognosis of the drug reaction or its clinical signs. Trying to look for these antibodies more systematically in the future could help researchers characterize their potential diagnostic and clinical roles.
有时也会在正常耐受药物的患者中检测到存在于迟发药物过敏史的患者中的抗药物和抗组织抗体。因此，很难将这些抗体视为用于诊断的生物标记物。然而，这些抗体中的一部分已被证明与药物反应的预后或其临床意义相关。未来尝试更系统地寻找这些抗体可能有助于研究人员确定它们潜在的诊断和临床作用。
Cellular Testing
细胞试验
The lymphocyte transformation test (LTT) is used to evaluate delayed hypersensitivity, because T cells are more likely to be involved in those ADRs. It measures ex vivo T cell proliferation in response to a specific drug antigen. The lymphocytes are obtained from the patient, and cultured with the offending drug. The proliferative response can be measured by radiolabeled thymidine incorporation. This test has been used in veterinary patients with drug allergies on rare occasions, but is more commonly reported in the human literature.
淋巴细胞转化试验(LTT)被用来评估迟发型超敏反应，因为T细胞更有可能参与这些不良反应。它检测T细胞对特定药物抗原的体外增殖反应。淋巴细胞是从患者身上获得的，并与怀疑致敏的药物一起培养。可通过放射性标记的胸苷监测T细胞增殖反应。这项试验很少用于动物的药物过敏，但在人类文献中较为常见。
ADR Logarithms
ADR对数算法
In an attempt to better assign causality to adverse drug events, different algorithms have been used in both human and veterinary medicine. They include multiple factors, such as temporal relationships, dechallenge and rechallenge results, anatomical site, previous ADRs, type of ADRs, drug-drug interactions, or drug dosages. Each factor is given a score. These scores are added up, and the total is compared with a pre-established scale of likelihood of a drug allergic reaction. Because diagnosing a drug hypersensitivity reaction can be such a challenge, some authors recently have suggested that creating computer-based algorithms might be required to improve results.
为了更好地给药物不良事件分配因果关系，人类和兽医都使用了不同的算法。它们包括多个因素，如时间关系、停药和再用药、解剖部位、以前的药物不良反应、不良反应的类型、药物-药物相互作用或药物剂量。每个因素都有一个分值。将这些分值相加，并将总分与预先设定的药物过敏反应可能性量表进行比较。由于诊断药物过敏反应可能是一项挑战，一些作者最近建议，可能需要创建一种基于计算机的算法来完善结果。
Overview of Treatment Options
治疗方案概述
Supportive Care
支持性疗法
The majority of drug allergies are not life threatening and will resolve once the offending medication is discontinued. In these cases, treatment is largely symptomatic. For cases in which the hypersensitivity has caused severe disease, additional treatment may be warranted according to the clinical signs and the clinical pathology results. Supportive care such as IV fluids may be necessary to account for fluid loss through the skin if there are large areas of ulceration. Similarly, cutaneous protein loss may necessitate oncotic support. In diseases, such as pemphigus vulgaris and TEN, where cutaneous pain is a prominent feature, analgesics are warranted. When the integrity of the skin is compromised over a large surface, antibiotic therapy is advised. Depending on the extent of systemic signs associated with the drug allergy, additional therapies also may be implemented (eg, blood products if there is concurrent IMHA, or S-adenosyl methionine in cases of hepatotoxicity).
大多数药物过敏不会危及生命，而且一旦致敏药物停止使用，症状就会缓解。在这些病例中，治疗主要是对症治疗。对于过敏疾病严重的病例，可根据临床症状和临床病理结果给予额外治疗。如果有大面积的溃疡，可能需要静脉输液等支持性护理以解决经皮肤液体流失的问题。同样，皮肤蛋白质丢失可能需要胶体液支持（oncotic support）。在皮肤疼痛是明显表现的疾病中，如寻常型天疱疮和TEN，需要使用止痛药。当皮肤存在较大的损伤时，建议使用抗生素治疗。根据与药物过敏相关的全身症状的程度，也可以实施额外的治疗(例如，如果同时存在IMHA，则使用血液制品；如果出现肝毒性，则使用S-腺苷甲硫氨酸)。
Anti-inflammatory and Immunosuppressive Treatment
抗炎和免疫抑制治疗
Antihistamines also may prove beneficial in cases of Type I reactions in which clinical signs are caused by the release of powerful inflammatory mediators such as histamine. Interestingly, reports in the human literature note that the use of histamine H1 and H2 receptor antagonists is more beneficial than H1 receptor antagonist therapy alone. Antihistamines also might help relieve some of the intense pruritus that some drugs can induce during allergic reactions.
抗组胺药也可能被证明对I型反应是有益的，在这种情况下，临床症状是由组胺等强效炎症介质的释放引起的。有趣的是，人类文献报道指出，使用组胺H1和H2受体拮抗剂比单独使用H1受体拮抗剂治疗更有效。抗组胺药也可能有助于缓解某些药物在过敏反应期间引起的强烈瘙痒。
The use of glucocorticoids in drug allergies is controversial. At immunosuppressive dosages (ie, 2–4 mg/ kg of prednisone daily) they are expected to have a major effect on both the humoral and cellular immune system. In human patients with anaphylaxis, their benefit remains unclear. They affect the late phase of anaphylaxis, which could be crucial for the outcome of the drug reaction. In drug-induced pemphigus, treatment with corticosteroids may be necessary to manage the disease until the clinical signs resolve after the discontinuation of the drug. Drug-triggered pemphigus may necessitate chronic treatment with immunosuppressive drugs to manage the disease, because remission will not occur upon discontinuation of the drug.For other types of drug allergies, glucocorticoids have been used with mixed results depending on the patients. If indicated, both systemic and topical corticosteroids can be used to control the immunologic reaction. Dosages, treatment duration and how swiftly corticosteroids can be tapered will depend on many factors, including the disease present, the systemic health of the patient, response to treatment, and the potential for adverse effects from the corticosteroids themselves. Their use also could increase the risk of sepsis encountered in cases of severe skin detachment.
糖皮质激素用于药物过敏是有争议的。在免疫抑制剂量下(即泼尼松2-4 mg/ kg，每日一次)，它们预计会对体液免疫系统和细胞免疫系统产生重大影响。在人类过敏反应患者中，它们的有效性尚不清楚。它们影响过敏反应的晚期，这可能对药物反应的结果至关重要。对于药物诱导性天疱疮，在停药后临床症状消失前，使用糖皮质激素治疗可能是必要的。因为药物触发性天疱疮在停药后不会出现缓解，所以可能需要用免疫抑制药物进行长期治疗。对于其他类型的药物过敏，糖皮质激素的使用效果因患者而异。如果需要，全身和外用皮质类固醇都可以用来控制免疫反应。剂量、治疗时间和糖皮质激素减少的速度取决于许多因素，包括疾病目前情况、患者的全身健康状况、对治疗的反应以及糖皮质激素本身可能产生的不良反应。它们的使用还可能增加严重皮肤分离情况下发生败血症的风险。
Other immunosuppressive drugs, such as cyclosporine or azathioprine may be warranted, more so in severe cases of skin reactions, such as pemphigus, EM or TEN. However, these cases might also be those with the highest risk of secondary bacterial infection. Human IV immunoglobulins (IVIG) have been used in cases of EM and TEN, with some success. There are also reports of human IVIG being used in severe cases of pemphigus foliaceus. One team successfully treated 2 dogs with suspected drug-induced skin lesions with human IVIG.
其他免疫抑制药物（如环孢素或硫唑嘌呤），在皮肤反应严重的病例中（例如：天疱疮，EM或TEN）可能是必要的。然而，这些病例也可能是继发细菌感染风险最高的病例。人IV免疫球蛋白(IVIG)已用于EM和TEN病例，并取得了一些成功。也有报道称人类IVIG被用于严重的落叶型天疱疮病例。一个研究小组成功地用人IVIG治疗了2只怀疑是药物引起的皮肤病变的犬。
These immunosuppressive therapies have been used only in isolated cases of drug hypersensitivity in veterinary medicine, and randomized blinded clinical trials in human medicine are not available to provide true evidence of their efficacy in drug allergic reactions.
在兽医学中，这些免疫抑制疗法仅用于药物过敏的个别病例，人类医学中的随机盲法临床试验无法提供其在药物过敏反应中关于疗效的真实证据。
Future Management
未来的管理
If drug hypersensitivity has been documented, the drug should be avoided for the rest of the patient’s life. Re-exposure to the offending drug, even in minute amounts, can cause similar or substantially worse clinical signs, and these signs can become life-threatening even if the reaction in the 1st episode was relatively benign.
如果有药物过敏记录，在患者的余生中应避免使用该药物。再次接触致敏药物，即使是微量的，也会引起类似或严重的临床症状，即使过敏首次发作的反应相对良性，再次出现的过敏症状也可能危及生命。
In rare instances, desensitization may be performed, if future use of the drug is deemed imperative. This is used occasionally in cases of drug allergy in human medicine, although the protocols can be cumbersome and are not always successful. Furthermore, the potential risks associated with these protocols are great, and may outweigh the indications for use of the drug.
在极少数情况下，如果未来必须使用该药物，可以使用脱敏治疗。在人类医学的药物过敏病例中偶尔会使用这种方法，但这种方法可能很麻烦，而且并不总是成功。此外，与这些方案相关的潜在风险是巨大的，并且可能超过使用该药物的适应症。
In addition, drugs with related structures should be identified and avoided, as there is potential for cross reactivity. For example, cephalosporins and other β-lactam antibiotics often are thought to present a high risk of cross-reactivity because of the presence of the β-lactam ring in all of these antibiotics. However, the risk of cross-reactivity in practice among these antibiotics is low; the rate of cross-reaction between penicillins or among penicillins and cephalosporins has been reported as 5% or less in humans.
此外，应识别和避免具有相关结构的药物，因为存在交叉反应的可能性。例如，头孢菌素和其他β-内酰胺类抗生素通常被认为具有很高的交叉反应风险，因为所有这些抗生素中都存在β-内酰胺环。然而，这些抗生素在实践中发生交叉反应的风险较低；据报道，青霉素类药物之间或青霉素类药物与头孢菌素类药物之间的交叉反应率在人类中为5%或更低。
Reporting
报告
When ADRs have been diagnosed or are strongly suspected, they should be reported to the pharmaceutical company, which is legally obligated to transfer the report to the FDA, and which is likely to have up-to-date information regarding ADRs to the drug of interest. A monitoring and reporting program can provide benefits to clinicians, patients, and pharmacists. Especially in veterinary medicine, where case reports of ADRs are not commonly published in the literature, reporting will be an invaluable means of collecting more information and extending our knowledge about the mechanisms and treatments of these diseases.
当诊断出或强烈怀疑有不良反应时，应向制药公司报告，制药公司在法律上有义务将报告转交给FDA，并且可能拥有有关该药品的不良反应最新信息。监测和报告程序可以为临床医生、患者和药剂师提供信息。特别是在兽医医学领域，药品不良反应的病例报告通常不发表在文献中，报告将是收集更多信息和扩展我们对这些疾病的机制和治疗的知识的宝贵手段。
In an era of translational research in which clinicians and researchers work side-by-side to improve patient care and scientific knowledge, contacting a researcher specialized in veterinary ADRs also could help the clinician establish a diagnosis and manage the clinical signs. Ex vivo experiments on the patient’s samples (eg, blood, skin biopsies) could further advance knowledge of cutaneous drug allergies in veterinary medicine where evidence-based information is very limited.
在一个临床医生和研究人员并肩工作以改善患者护理和科学知识的转化研究时代，联系专门研究兽医学不良反应的研究人员也可以帮助临床医生建立诊断和管理临床症状。因为在兽医学中，循证信息非常有限，因此对患者样本（如血液、皮肤活检）上进行体外实验可以进一步推进兽医学中对皮肤药物过敏的认识。
Conclusion
结论
Drug hypersensitivity reactions are idiosyncratic and immune-mediated. Cutaneous reactions are common manifestations that are easily mistaken for other cutaneous diseases. Very little is known about the pathogenesis of drug hypersensitivity reactions in veterinary medicine, limiting diagnostic and treatment options. Most information is derived from human medicine where knowledge about the pathogenesis of drug hypersensitivity also is relatively limited despite over half a century of research. Increasing awareness among veterinarians and better reporting hopefully will improve this frustrating situation.
药物超敏反应具有特异性和免疫介导性。皮肤反应是常见的表现，很容易被误认为是其他皮肤病。兽医中药物过敏反应的发病机制知之甚少，限制了诊断和治疗选择。尽管经过了半个多世纪的研究，但对药物超敏反应的发病机制的了解也相对有限，大多数信息还是来自人类医学。兽医意识的提高和更好的报道有望改善这一令人沮丧的情况。
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发表于 2024-5-12 01:42:52
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