本研究比较了来自欧洲制造商的5种不同提取物。不同皮肤点刺试验提取物之间的蛋白含量存在20倍的差异，而不同厂家的提取物之间的过敏原Can f 1和 Can f 2含量差异大，5种提取物中有1种检测不到Can f 1和 Can f 2。不同犬类过敏原Can f1、Can f2、Can f4、Can f6的鉴定(属于lipocalin家族);犬血清白蛋白Can f 3;前列腺激肽释放素Can f 5，这些已经改善了对狗敏感病人的诊断方法。
最近鉴定的Can f 7（狗附睾分泌蛋白）的相关性还未知。Can f 1是主要的狗过敏原，能被50%到90%的对狗敏感的病人血清识别，lipocalins（细胞外蛋白家族）Can f 2和Can f 6及血清白蛋白Can f 3与其它皮毛动物存在交叉反应。单独对Can f 5敏感已被认为是对雄狗特异性过敏的标志。应用这一系列过敏原，能区分主要对狗敏感，主要对狗敏感和潜在的交叉反应或与对其它动物的过敏同时存在，或者主要对猫和马过敏同时存在对狗的交叉敏感。目前尚不清楚犬类过敏原组份的致敏性是否与临床相关。通过使用双盲、安慰剂对照的食物挑战，已经表明IgE对花生过敏原组份如Ara h2和Ara h6，可能与儿童对花生敏感的全身反应有关。这类研究尚未涉及吸入性过敏原。
本研究的目的是通过对60例(10-18岁)对犬类过敏的儿童进行鼻腔激发试验，研究敏感程度与犬类过敏临床症状之间的关系。他们发现阳性的鼻腔激发试验结果与对较多的狗过敏原组份敏感有关。lipocalins的致敏，尤其是Can f4和Can f6，与阳性的挑战结果相关。Can f1特异性IgE的存在与阳性激发试验结果无关，可能是因为大多数儿童对Can f1敏感。尽管如此，Can f1的临床相关性通过Can f1特异性IgE水平增加与挑战试验阳性结果之间的密切关系得到了证明。Can f3是最不常见的致敏成分，与阳性检测结果无关。由于 Can f3 特异性IgE多见于对多种过敏原敏感的患者，因此狗血清白蛋白特异性IgE可能是一种更好的交叉反应标志物而不是临床相关过敏标志物。致敏谱之间的关系分析显示，对所有蛋白组(即脂质体、血清白蛋白和前列腺激肽酶)均敏感的患者鼻部刺激试验阳性结果的优势比最高[优势比，5.34;95% CI, 1.01-28.4])，而单独对Can f5敏感与阴性挑战结果相关。
本研究的一个局限性是，鼻腔挑战的程序通常没有很好的标准化。使用症状评分和/或鼻通畅度的客观测量来评估鼻对过敏原的反应性有多种方法，如鼻压测量法、鼻声测量法或鼻吸气流量峰值法。然而，Kack等人使用的方法在不同类型的研究中使用过，最近发表的欧洲过敏和临床免疫学学会(European Academy of Allergy and Clinical Immunology)关于鼻腔激发试验的主旨论文中，这一工具是否已被广泛接受。
治疗过敏性患者面临的主要挑战是区分无关的致敏和临床过敏。如果病史与常规皮肤针刺试验或对粗提物的特异性IgE的联合不能确定诊断，一个好的替代方法是使用暴露试验(鼻腔和结膜激发试验或口腔食物激发试验)。虽然对病人来说，鼻腔和结膜的激发不比食物激发试验费力和繁杂，但在日常生活中并不常用。除了标准化问题之外，缺乏国家监管机构注册的挑战性试验的致敏提取物可能会妨碍这些试验的应用。过敏原组份的可用性为临床医生提供了更好地识别临床相关敏感性的工具。对于儿童的食物过敏尤其如此，但是Kack et el7的研究表明在吸入物过敏的情况中也可以适用。分析过敏原组份IgE模式的作用可能因过敏原而异，但越来越多的研究支持在诊断过程中确定特定过敏原的IgE水平的附加值。尽管这项由Kack等人进行的研究是IgE对犬类组份的致敏模式的确定，可能有助于识别真正的过敏反应，但这并不意味着只有单一的标志物可以检测临床相关性。通过鼻或结膜激发试验比较敏感性和特定组份的方法，对鉴别其他吸入物过敏患者的相关过敏原也有价值。根据可能的过敏原，分析过敏原组份的IgE模式可能有助于过敏的诊断。
Diagnosis of dog allergy: Beware of the dog
October 2018Volume 142, Issue 4, Pages 1058–1059
Exposure to furred pets is high. In Europe dog ownership varies from 9.0% to 34.8%,1
whereas in the United States 30.4% of the households own cats and 36.5% own dogs.2
However, the diagnosis of dog allergy is troublesome. In general, self-reporting misclassifies allergic status in many patients. Even a structured allergy history alone is little better and results in false-positive rates for dog allergy of 27% compared with formal allergy assessment.
In a more recent study, it was found that skin prick test response positivity to dog was associated with a history of symptoms on exposure to dog.4
Although significant, the magnitude of the association was not high. For a positive predictive value of 80%, the wheal diameter cutoff amounted to 10 mm.
In addition, the diagnosis of dog allergy is hampered by varying levels of allergen content when comparing skin prick test extracts from different sources.5
In this study 5 extracts from European manufacturers were examined. Skin prick test extracts showed a 20-fold variation in protein content, whereas the dog allergens Can f 1 and Can f 2 varied widely between extracts, with undetectable levels in 1 of 5 extracts.
Identification of the distinct dog allergens Can f 1, Can f 2, Can f 4, and Can f 6 (belonging to the lipocalin family); the dog serum albumin Can f 3; and the prostatic kallikrein Can f 5 have improved the diagnostic approach for patients sensitized to dog.6
The relevance of the recently identified Can f 7 (dog epididymal secretory protein) is not known. Can f 1 is a major dog allergen recognized by 50% to 90% of patients sensitized to dog. The lipocalins Can f 2 and Can f 6 and the serum albumin Can f 3 are cross-reactive to other furred animals. Monosensitization to Can f 5 has been suggested as a marker for specific allergy to male dogs. Thus with this set of components, it is possible to discriminate between primary sensitization to dog, primary sensitization to dog and potentially cross-reactivity or cosensitization to another animal, or primary sensitization to cat or horse with cross-sensitization to dog.6
It is not always clear whether sensitization to dog allergen components points to clinical relevance. By using double-blind, placebo-controlled food challenges, it has been shown that IgE to peanut components, such as Ara h 2 and Ara h 6, can be associated with systemic reactions in children sensitized to peanut. Such studies have not been done with inhalant allergens.
aimed to study the association between sensitization and clinical symptoms of dog allergy as assessed by using nasal challenge testing in 60 children (age 10-18 years) sensitized to dog. They found that a positive nasal provocation test result was associated with sensitization to an increasing number of dog allergen components. Sensitization to lipocalins, in particular to Can f 4 and Can f 6, was related to a positive challenge result. The presence of IgE to Can f 1 was not associated with a positive provocation test result, possibly because the majority of children were sensitized to Can f 1. Nevertheless, the clinical relevance of Can f 1 was illustrated by a strong relationship between the increasing level of IgE to Can f 1 and a positive outcome on the challenge test. Can f 3 was the least common sensitizing component and not related to a positive test result. Because IgE to Can f 3 was mostly seen in multisensitized patients, IgE to dog serum albumin is perhaps a better marker for cross-reactivity than for clinically relevant allergy. Analysis of the relation between sensitization profiles showed that the highest odds ratio for a positive nasal provocation test result was found among patients who were sensitized to all protein groups (ie, lipocalins, serum albumin, and prostatic kallikrein [odds ratio, 5.34; 95% CI, 1.01-28.4]), whereas monosensitization to Can f 5 was associated with a negative challenge result.
used the nasal challenge test as the gold standard for assessing clinical allergy to dogs. Nasal provocation tests are not regularly used in daily practice, but they are a valuable tool in research, particularly in clinical trials.
A limitation of this study is that nasal challenge procedures are not well standardized in general. There are a variety of methods to assess nasal reactivity to allergens using symptom scores and/or objective measurements of nasal patency, such as rhinomanometry, acoustic rhinometry, or peak nasal inspiratory flow.8
However, the method used by Käck et al7
has been used in different types of studies and is a well-accepted tool included in a recently published European Academy of Allergy and Clinical Immunology position paper on nasal provocation tests.8
Another drawback of the nasal challenge test is that the limitations of skin testing (ie, variability in allergen content) might also be true for allergenic extracts used for challenge. The allergen solution used in this study was well characterized, with all relevant dog components measured and present in the extract. Finally, taking the inaccuracy of the history into account,3
the challenge test might be the best available reference for evaluating sensitization patterns to different dog allergens.
The major challenge in managing allergic patients is always to differentiate between irrelevant sensitization and clinical allergy. If the combination of a history with conventional skin prick tests or specific IgE to the crude extract is insufficient to establish the diagnosis, a good alternative is use of exposure tests (nasal and conjunctival provocation tests or oral food challenges). Although less laborious and less burdensome for patients than food challenge tests, nasal and conjunctival provocations are not commonly used in daily practice. Apart from standardization issues, lack of allergenic extracts for challenge tests that are registered by national regulators might hamper use of these tests. The availability of allergen components has provided the clinician with tools to better identify clinically relevant sensitizations. This is particularly true for food allergy in children, but the study by Käck et el7 shows that this can also be the case in the setting of inhalant allergy. The effect of analyzing IgE patterns to allergen components might vary per allergen, but an increasing number of studies underwrite the added value of determining levels of IgE to specific allergens in the diagnostic process. Although the study by Käck et al7 does not point to a single marker to detect clinical relevance, determination of the pattern of IgE sensitization to dog components might be helpful in recognizing true allergy. The approach of comparing sensitization to specific components with nasal or conjunctival challenge tests could also be valuable to identify the relevant allergens for patients with other inhalant allergies. Depending on the suspected allergens, analysis of IgE patterns to allergen components may be helpful in the diagnosis of allergy (Fig 1).
MD, PhD Roy Gerth van Wijk