原標題：過敏和呼吸道病原體對哮喘形成的影響
　　過敏，尤其是對常年的空氣變應原過敏，已被確定為哮喘的一個關鍵危險因素。最近證實，致敏的時間和致敏的數(shù)量都是重要的預后指標。辛普森等人已經確定了兒童的一種特應性表型，他們稱之為“多重早期致敏”。辛普森等人報告說，在那些早年對多種氣傳變應原過敏的兒童中，哮喘發(fā)作的風險顯著增加，嚴重惡化導致需要住院治療，以及肺功能受損。在其他隊列研究中也證實了早期對多種過敏原的敏感與哮喘風險增加之間的相關性。
　　觀察到的早期對氣傳變應原過敏與哮喘風險之間的相關性，部分是由于過敏性炎癥和病毒感染（最常見的是鼻病毒）之間的協(xié)同作用。事實上，在哮喘的兒童期起源（COAST）研究中，對氣傳變應原過敏并在出生后三年內被鼻病毒感染的兒童患哮喘的風險最大。這就引出了這樣一個問題：早期的病毒性疾病是否會導致過敏，或者反過來是否正確。Jackson等人在COAST研究中使用縱向多狀態(tài)馬爾可夫模型，確定了過敏導致病毒性喘息的順序關系。這種關系在鼻病毒引起的喘息中最強，沒有證據表明病毒性喘息導致過敏。
　　也有強有力的證據表明，致敏和過敏原暴露是兒童晚期由普通感冒引起的喘息的風險因素。在急診科的研究中發(fā)現(xiàn)，呼吸道病毒（最常見的是鼻病毒）、可檢測到過敏原特異性IgE和/或存在嗜酸性炎癥，都被確定為急性喘息發(fā)作的危險因素。值得注意的是，病毒感染和過敏性炎癥協(xié)同增加了喘息的風險，過敏原特異性IgE水平越高風險越大。這種協(xié)同作用可能對鼻病毒C患者尤其顯著，最近有報道稱，在這些患者中，氣傳變應原致敏是復發(fā)性嚴重惡化的危險因素之一，可導致急診就診和住院。
　　過敏病毒相互作用的機制
　　有多種機制認為病毒感染與過敏性炎癥相互作用，從而導致下呼吸道功能障礙、喘息和哮喘。首先，潛在的過敏性炎癥可以直接增強氣道對鼻病毒感染的反應性。此外，病毒感染可損害氣道上皮的屏障功能，導致氣道壁對氣傳過敏原的吸收增加和炎癥反應增強，而潛在的過敏性炎癥也可能導致病毒復制增強。值得注意的是，鼻病毒感染和變應原均可促進氣道上皮細胞產生IL-33, IL-33是最近發(fā)現(xiàn)的一種先天細胞因子，可促進2型氣道炎癥和重塑。據報道，這種類固醇耐藥途徑在難以控制哮喘的兒童中上調。有趣的是，IL-33多聚物與中晚期發(fā)作的喘息有關，而中晚期發(fā)作的喘息與早期生活中的過敏反應密切相關。 另一種先天上皮細胞因子IL-25也由鼻病毒誘導，在過敏患者鼻病毒感染的情況下，IL-25可能加重過敏性氣道炎癥。
　　最后，有重要證據表明，過敏性哮喘兒童的抗病毒反應受損。確實，過敏原暴露和高親和力IgE受體交聯(lián)已被證明會影響病毒誘導的I型和III型干擾素在外周血細胞中的產生(圖1)。其結果將是病毒復制能力增強和氣道中2型炎癥的加重。
　　最近的一項臨床試驗證實，變應原-病毒相互作用在喘息和哮喘加重過程中起重要作用，即奧馬珠單抗(抗IgE)預防季節(jié)性病毒引起的哮喘加重。在本試驗中，奧馬珠單抗顯著降低了病毒引起的病情惡化，并且這種減輕與在鼻病毒刺激的單核細胞體內增強的I型干擾素反應相一致。值得注意的是，那些接受奧馬單抗治療后I型干擾素應答增強較大的受試者對病毒引起的病情惡化具有最大的保護作用。
　　結論
　　兒童哮喘發(fā)生的兩個關鍵危險因素是早期過敏反應的發(fā)生和主要由病毒引起的喘息性呼吸道疾病，也可由細菌單獨或作為病毒引起的疾病的并發(fā)感染引起。單獨或聯(lián)合針對這兩種危險因素的治療似乎是制定兒童哮喘一級預防有效方法的重要組成部分。
延伸閱讀
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
　　創(chuàng)建過敏性疾病的科研、科普知識交流平臺，為過敏患者提供專業(yè)診斷、治療、預防的共享平臺。