杭州浙大迪迅生物基因工程有限公司

　　原标题：过敏和呼吸道病原体对哮喘形成的影响
　　过敏，尤其是对常年的空气变应原过敏，已被确定为哮喘的一个关键危险因素。最近证实，致敏的时间和致敏的数量都是重要的预后指标。辛普森等人已经确定了儿童的一种特应性表型，他们称之为“多重早期致敏”。辛普森等人报告说，在那些早年对多种气传变应原过敏的儿童中，哮喘发作的风险显著增加，严重恶化导致需要住院治疗，以及肺功能受损。在其他队列研究中也证实了早期对多种过敏原的敏感与哮喘风险增加之间的相关性。
　　观察到的早期对气传变应原过敏与哮喘风险之间的相关性，部分是由于过敏性炎症和病毒感染（最常见的是鼻病毒）之间的协同作用。事实上，在哮喘的儿童期起源（COAST）研究中，对气传变应原过敏并在出生后三年内被鼻病毒感染的儿童患哮喘的风险最大。这就引出了这样一个问题：早期的病毒性疾病是否会导致过敏，或者反过来是否正确。Jackson等人在COAST研究中使用纵向多状态马尔可夫模型，确定了过敏导致病毒性喘息的顺序关系。这种关系在鼻病毒引起的喘息中最强，没有证据表明病毒性喘息导致过敏。
　　也有强有力的证据表明，致敏和过敏原暴露是儿童晚期由普通感冒引起的喘息的风险因素。在急诊科的研究中发现，呼吸道病毒（最常见的是鼻病毒）、可检测到过敏原特异性IgE和/或存在嗜酸性炎症，都被确定为急性喘息发作的危险因素。值得注意的是，病毒感染和过敏性炎症协同增加了喘息的风险，过敏原特异性IgE水平越高风险越大。这种协同作用可能对鼻病毒C患者尤其显著，最近有报道称，在这些患者中，气传变应原致敏是复发性严重恶化的危险因素之一，可导致急诊就诊和住院。
　　过敏病毒相互作用的机制
　　有多种机制认为病毒感染与过敏性炎症相互作用，从而导致下呼吸道功能障碍、喘息和哮喘。首先，潜在的过敏性炎症可以直接增强气道对鼻病毒感染的反应性。此外，病毒感染可损害气道上皮的屏障功能，导致气道壁对气传过敏原的吸收增加和炎症反应增强，而潜在的过敏性炎症也可能导致病毒复制增强。值得注意的是，鼻病毒感染和变应原均可促进气道上皮细胞产生IL-33, IL-33是最近发现的一种先天细胞因子，可促进2型气道炎症和重塑。据报道，这种类固醇耐药途径在难以控制哮喘的儿童中上调。有趣的是，IL-33多聚物与中晚期发作的喘息有关，而中晚期发作的喘息与早期生活中的过敏反应密切相关。 另一种先天上皮细胞因子IL-25也由鼻病毒诱导，在过敏患者鼻病毒感染的情况下，IL-25可能加重过敏性气道炎症。
　　最后，有重要证据表明，过敏性哮喘儿童的抗病毒反应受损。确实，过敏原暴露和高亲和力IgE受体交联已被证明会影响病毒诱导的I型和III型干扰素在外周血细胞中的产生(图1)。其结果将是病毒复制能力增强和气道中2型炎症的加重。
　　最近的一项临床试验证实，变应原-病毒相互作用在喘息和哮喘加重过程中起重要作用，即奥马珠单抗(抗IgE)预防季节性病毒引起的哮喘加重。在本试验中，奥马珠单抗显著降低了病毒引起的病情恶化，并且这种减轻与在鼻病毒刺激的单核细胞体内增强的I型干扰素反应相一致。值得注意的是，那些接受奥马单抗治疗后I型干扰素应答增强较大的受试者对病毒引起的病情恶化具有最大的保护作用。
　　结论
　　儿童哮喘发生的两个关键危险因素是早期过敏反应的发生和主要由病毒引起的喘息性呼吸道疾病，也可由细菌单独或作为病毒引起的疾病的并发感染引起。单独或联合针对这两种危险因素的治疗似乎是制定儿童哮喘一级预防有效方法的重要组成部分。
延伸阅读
JACI
The contributions of allergic sensitization and respiratory pathogens to asthma inception(extraction)
DIO:org/10.1016/j.jaci.2016.01.002
INTERACTIONS BETWEEN ALLERGY AND INFECTIONS
Allergic sensitization, most notably to perennial aeroallergens, has been defined as a pivotal risk factor for the development of asthma. Recently, it has become evident that both the timing of allergic sensitization and the quantity of sensitization are impor-tant prognostic indicators. Simpson et al have identified an atopy phenotype in children they termed multiple early sensitization.  In those children sensitized to multiple aeroallergens at an early age, Simpson et al reported a remarkable increase in risk for asthma inception, severe exacerbations leading to hospitalization, and impaired lung function. This link between early-life sensitization to multiple allergens and increased asthma risk has been replicated in additional cohort studies.
This observed link between early sensitization to aeroallergens and asthma risk is in part due to synergy between allergic inflammation and viral infections, most commonly rhinovirus. Indeed, children in the COAST study who were sensitized to aeroallergens and wheezed with rhinovirus during the first 3 years of life had the greatest risk for asthma inception. This led to the question of whether viral illnesses in early life lead to allergic sensitization or whether the converse was true. Using a longitudinal multistate Markov model in the COAST study, Jackson et al. identified a sequential relationship whereby allergic sensitization leads to viral wheezing. This relationship was strongest for rhinovirus-induced wheezing, and there was no evidence that viral wheezing led to sensitization.
There is also strong evidence  to implicate allergic sensitization and exposure as a risk factor for wheezing with common cold infections later in childhood. In emergency department studies detection of a respiratory tract virus, most commonly rhinovirus, with detectable allergen-specific IgE and/or the presence of eosinophilic inflammation were all identified as risk factors for acute wheezing episodes. Notably, viral infections and allergic inflammation synergistically enhanced the risk of wheezing, and higher levels of allergen-specific IgE conferred the greatest risk. This synergism might be particularly notable for patients with rhinovirus  C,  in  whom  aeroallergen  sensitization  was  recently reported as a risk factor for recurrent severe exacerbations leading to emergency department visits and hospitalization.
MECHANISMS OF ALLERGY-VIRUS INTERACTIONS
There are multiple mechanisms by which viral infections are thought to interact with allergic inflammation to lead to lower respiratory airway dysfunction, wheezing, and asthma exacerba- tions. First, underlying allergic inflammation can directly enhance airway responsiveness to rhinovirus infection. Additionally, viral infections can damage the barrier function of the airway epithelium, leading to enhanced absorption of aeroallergens across the airway wall and enhanced inflammation, whereas underlying allergic inflammation might also lead to enhanced viral replication. Of interest,  both  rhinovirus  infections and allergens can enhance airway epithelial cell production of IL-33, a recently identified innate cytokine, which promotes type 2 airway inflammation and remodeling. This steroid- resistant pathway has been reported to be upregulated in children with difficult-to-control asthma. Interestingly, IL-33 polymor- phisms have been linked with intermediate and late-onset wheezing, which are strongly linked to early-life allergic sensiti- zation. Another innate epithelial cytokine, IL-25, is also induced by rhinovirus and is likely to accentuate allergic airway inflammation in the context of rhinovirus infections in allergic subjects.
Finally, there is significant evidence that children with allergic asthma have impaired antiviral responses. Indeed, allergen exposure and high-affinity IgE receptor cross-linking has been shown to impair virus-induced type I and III interferon production in peripheral blood cells . The result would be both enhanced viral replication and enhanced type 2 inflammation in the airway.
The most direct evidence to support the importance of allergen- virus interactions in patients with virus-induced wheezing and asthma exacerbations comes from a recent clinical trial of omalizumab (anti-IgE) to prevent seasonal virus-induced asthma exacerbations. In this trial virus-induced exacerbations were significantly reduced by omalizumab, and this reduction coincided with an enhanced type I interferon response ex vivo in  rhinovirus-stimulated mononuclear cells. Of note, those participants who had larger increases in type I interferon response with omalizumab treatment had the greatest protection from virus-induced exacerbations.
CONCLUSION
Two key risk factors for the development of childhood asthma are the development of allergic sensitization in early life and wheezing respiratory tract illnesses caused primarily by viruses but also by bacteria either alone or as coinfections accompanying illnesses of viral cause. Therapies directed at these 2 risk factors, either alone or in combination, appear to be essential components to target for development of effective strategies for the primary prevention of asthma in children.
All Author:
Daniel J. Jackson, MD, James E. Gern, MD,a and Robert F. Lemanske, Jr, MD
　　创建过敏性疾病的科研、科普知识交流平台，为过敏患者提供专业诊断、治疗、预防的共享平台。