原標(biāo)題：花生提取物和花生組分特異性IgE在預(yù)測花生過敏中的作用
　　花生過敏是最常見、最嚴(yán)重、最常見的終身食物過敏之一，準(zhǔn)確的診斷至關(guān)重要。雙盲、安慰劑對(duì)照的食物激發(fā)試驗(yàn)是診斷花生過敏的金標(biāo)準(zhǔn)，但是這個(gè)過程既耗時(shí)又費(fèi)錢，而且病人可能有嚴(yán)重反應(yīng)的風(fēng)險(xiǎn)。目前，15 kUA/L或更高的花生提取物特異性IgE (sIgE)水平被用來預(yù)測花生過敏，其準(zhǔn)確率大于95%，但有許多花生過敏的受試者sIgE水平較低。
根據(jù)口服食物激發(fā)試驗(yàn)的結(jié)果，我們最近發(fā)現(xiàn)大部分對(duì)花生提取物敏感的兒童并沒有花生過敏。在英國以普通人群為基礎(chǔ)的出生隊(duì)列中，大約有10%的8歲兒童對(duì)花生敏感，但只有大約2%的兒童對(duì)花生過敏，大約8%的兒童對(duì)花生敏感但耐受。通過使用微陣列組分診斷對(duì)花生敏感的兒童進(jìn)行檢測，我們發(fā)現(xiàn)花生過敏者和花生耐受者之間的組分敏感程度存在顯著差異，其中IgE對(duì)Ara h2的反應(yīng)性是過敏最重要的預(yù)測因子。然而，盡管這項(xiàng)技術(shù)取得了進(jìn)步，但由于涉及標(biāo)準(zhǔn)化、成本和解釋方面的問題，這項(xiàng)工具還不能作為常規(guī)使用。在本研究中，我們的目的是使用標(biāo)準(zhǔn)的 ImmunoCAP(Phadia, Uppsala，瑞典)比較花生提取物sIgE與和花生組分Ara h1、2、3、8和9sIgE的定量值，以預(yù)測花生過敏或耐受。
在參與初始研究的花生提取物 sIgE陽性的 81例兒童(7-14歲)中，(29例花生過敏和52例花生耐受性)中，80例Ara h2特異性IgE陽性，66例(27例花生過敏和39例花生耐受性)對(duì)花生所有組分特異性IgE均為陽性。如前所述，花生過敏是通過口服食物激發(fā)來確診的。在出現(xiàn)至少2種客觀癥狀(如皮疹、打噴嚏、嘔吐、咳嗽、喘息、FEV1下降>20%)后，才認(rèn)為是陽性。
我們用ROC曲線分析比較不同組分特異性IgE和提取物特異性IgE測定在區(qū)分花生過敏和花生耐受上的診斷性能(Stata 11.0;StataCorp, College Station, Tex)。圖1顯示了花生組分和提取液sIgE不同cut-off值的真陽性率(靈敏度)與假陽性率(1-特異度)的函數(shù)關(guān)系。ROC曲線上的每個(gè)點(diǎn)代表一個(gè)特定的閾值對(duì)應(yīng)的敏感性/特異性。區(qū)別度最理想的測試的ROC曲線通過左上角(100%敏感性和100%特異性)。因此，ROC曲線越靠近左上角，測試的總體精度越高。根據(jù)這一標(biāo)準(zhǔn)，sIgE對(duì)Ara h2的測定似乎是區(qū)分過敏和耐受的準(zhǔn)確性最高的測試。
我們使用ROC曲線下的估算面積作為診斷準(zhǔn)確性的指標(biāo)，觀察到不同測試之間的顯著差異(χ2 = 61.59,P <0.001)。如ROC曲線下的估算面積所示，,Ara h 2特異性IgE在區(qū)分花生過敏和花生耐受兒童上有最高的準(zhǔn)確度：面積（95% CI）, Ara h 2 0.99(0.99 - -1.00),花生提取0.85 (0.74 - -0.96),Ara h 1 0.84 (0.73 - -0.95), Ara h 3 0.77 (0.64 - -0.89), Ara h 9 0.52(0.37 - -0.66),和Ara h 8 0.50 (0.36 - -0.65)。
表I顯示了基于靈敏度和特異性的Ara h2組分和花生提取物的cut-off值的范圍，因?yàn)閷?duì)單個(gè)cut-off值的靈敏度和特異性的測量可能不足以評(píng)估最佳診斷試驗(yàn)。作為一個(gè)例子，我們考慮了一個(gè)假設(shè)的場景，我們試圖在100名對(duì)花生敏感的兒童中區(qū)分花生過敏和耐受，其中50名兒童對(duì)花生過敏，50名兒童對(duì)花生耐受。以0.35 kUA/L為分界點(diǎn)，用sIgE對(duì)Ara h2進(jìn)行分界，可對(duì)所有花生過敏兒童進(jìn)行正確分類。本試驗(yàn)的特異性為96.1%(表一)。在本例中，我們預(yù)計(jì)有2名對(duì)花生不過敏的兒童被誤診為花生過敏，另外48名兒童為陰性。通過使用這個(gè)分界點(diǎn)，97.5%的人被正確區(qū)分。
使用0.55 kUA/L的cut-off值可以正確地分類類似比例的兒童;然而，在這種情況下，3名花生過敏的兒童將被誤認(rèn)為耐受性。這個(gè)cut-off值對(duì)應(yīng)的是特異性增加(100%)，而敏感性減少(93.1%)。考慮到不要將花生過敏兒童誤診為具有耐受性的重要性，我們建議我們?nèi)巳旱淖罴雅R界值（cutoff值）為0.35 kUA/L。
5.30 kUA/L作為花生全提物sIgE的cut-off值，正確區(qū)分受試者比例最高(87.6%)，敏感性為75.9%，特異性為94.2%。然而，約24%的花生過敏兒童將被不恰當(dāng)?shù)貧w類為花生耐受。15 kUA/L的臨界值具有良好的特異性，96.2%高于此水平的兒童被正確歸類為花生過敏;然而，這個(gè)cut-off值的敏感性相對(duì)較差，幾乎一半的花生過敏者被歸類為耐受。這些數(shù)據(jù)表明，在我們的人群中，花生全提液sIgE的定量與Ara h2 sIgE定量相比，在鑒別花生過敏和耐受方面的準(zhǔn)確性較低。
綜上所述，利用微陣列技術(shù)檢測 Ara h2 sIgE 是預(yù)測花生臨床反應(yīng)性的重要因子，我們現(xiàn)在通過常規(guī)的實(shí)驗(yàn)室檢測證實(shí)了 Ara h2 sIgE 定量的價(jià)值。在英國學(xué)齡兒童中，0.35 kUA/L Ara h2 IgE的cut-off值為100%的敏感性和96.1%的特異性。使用這個(gè)cutoff值，我們的研究人群中97.5%的受試者被正確區(qū)分，所有花生過敏兒童都被正確的歸類。來自其它中歐和北歐國家的研究也表明Ara h2的重要性;然而，在其他人群和地理區(qū)域，IgE可能與其他組分相關(guān)(例如，地中海地區(qū)為Ara h9)。我們的發(fā)現(xiàn)需要在其他人群和年齡組中進(jìn)行重復(fù)，然后才能普遍應(yīng)用。



延伸閱讀
JACI                                                           

Quantification of specific IgE to whole peanut extract and peanut components in prediction of peanut allergy

DOI:org/10.1016/j.jaci.2010.12.012

Peanut allergy is one of the most common, severe, and usually lifelong food allergies, and accurate diagnosis is essential.1x1Sicherer, S.H. and Sampson, H.A. Peanut allergy: emerging concepts and approaches for an apparent epidemic. J Allergy Clin Immunol. 2007; 120: 491–503

Abstract | Full Text | Full Text PDF | PubMed | Scopus (265) | Google ScholarSee all References The double–blind, placebo-controlled food challenge is the gold standard for diagnosing peanut allergy, but the procedure is time-consuming and expensive, and patients might be at risk of a severe reaction.2x2Roberts, G. and Lack, G. Diagnosing peanut allergy with skin prick and specific IgE testing. J Allergy Clin Immunol. 2005; 115: 1291–1296

Abstract | Full Text | Full Text PDF | PubMed | Scopus (197) | Google ScholarSee all References Currently, a level of specific IgE (sIgE) to whole peanut extract of 15 kUA/L or higher is used to predict peanut allergy with greater than 95% certainty,2x2Roberts, G. and Lack, G. Diagnosing peanut allergy with skin prick and specific IgE testing. J Allergy Clin Immunol. 2005; 115: 1291–1296

Abstract | Full Text | Full Text PDF | PubMed | Scopus (197) | Google ScholarSee all References, 3x3Sampson, H.A. and Ho, D.G. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol. 1997; 100: 444–451

Abstract | Full Text | Full Text PDF | PubMed | Scopus (914) | Google ScholarSee all References, 4x4van Nieuwaal, N.H., Lasfar, W., Meijer, Y., Kentie, P.A., Flinterman, A.E., Pasmans, S.G. et al. Utility of peanut-specific IgE levels in predicting the outcome of double-blind, placebo-controlled food challenges. J Allergy Clin Immunol. 2010; 125: 1391–1392

Abstract | Full Text | Full Text PDF | PubMed | Scopus (24) | Google ScholarSee all References but many subjects with peanut allergy have lower sIgE levels.2x2Roberts, G. and Lack, G. Diagnosing peanut allergy with skin prick and specific IgE testing. J Allergy Clin Immunol. 2005; 115: 1291–1296

Abstract | Full Text | Full Text PDF | PubMed | Scopus (197) | Google ScholarSee all References, 5

On the basis of the outcome of oral food challenge, we have recently shown that the majority of children sensitized to whole peanut extract do not have peanut allergy. Approximately 10% of 8-year-old children in our population-based birth cohort in the United Kingdom were sensitized to peanut, but only approximately 2% had peanut allergy, and approximately 8% were sensitized but peanut tolerant.5x5Nicolaou, N., Poorafshar, M., Murray, C., Simpson, A., Winell, H., Kerry, G. et al. Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component-resolved diagnostics. J Allergy Clin Immunol. 2010; 125: 191–197 (e1-13)

Abstract | Full Text | Full Text PDF | PubMed | Scopus (291) | Google ScholarSee all References By using microarray component-resolved diagnostics among peanut-sensitized children, we demonstrated marked differences in the component sensitization profile between subjects with peanut allergy and peanut-tolerant subjects, with IgE response to Ara h 2 being the most important predictor of allergy.5x5Nicolaou, N., Poorafshar, M., Murray, C., Simpson, A., Winell, H., Kerry, G. et al. Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component-resolved diagnostics. J Allergy Clin Immunol. 2010; 125: 191–197 (e1-13)

Abstract | Full Text | Full Text PDF | PubMed | Scopus (291) | Google ScholarSee all References However, despite progress in this technology, because of issues related to standardization, cost, and interpretation, this tool is not as yet ready for routine use. In the current study we aimed to compare the quantification of sIgE to whole peanut extract and the peanut components Ara h 1, 2, 3, 8, and 9 using the standard ImmunoCAP method (Phadia, Uppsala, Sweden) in predicting peanut allergy or tolerance.

Of 81 children (age, 7-14 years) with sIgE to whole peanut extract who participated in the original study (29 with peanut allergy and 52 peanut-tolerant),5x5Nicolaou, N., Poorafshar, M., Murray, C., Simpson, A., Winell, H., Kerry, G. et al. Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component-resolved diagnostics. J Allergy Clin Immunol. 2010; 125: 191–197 (e1-13)

Abstract | Full Text | Full Text PDF | PubMed | Scopus (291) | Google ScholarSee all References 80 had sIgE to Ara h 2, and 66 (27 with peanut allergy and 39 peanut-tolerant) had sIgE to all components. Peanut allergy was confirmed by means of oral food challenge, as previously described.5x5Nicolaou, N., Poorafshar, M., Murray, C., Simpson, A., Winell, H., Kerry, G. et al. Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component-resolved diagnostics. J Allergy Clin Immunol. 2010; 125: 191–197 (e1-13)

Abstract | Full Text | Full Text PDF | PubMed | Scopus (291) | Google ScholarSee all References Challenge was considered positive after development of at least 2 objective signs (eg, skin rash, sneezing, vomiting, cough, wheeze, and >20% decrease in FEV1).5

We compared the diagnostic performance of sIgE measurement to different components and whole extract in discriminating between subjects with peanut allergy and those tolerant to peanut using receiver operating characteristic (ROC) curve analysis6x6Zweig, M.H. and Campbell, G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in Clinical Medicine. Clin Chem. 1993; 39: 561–577

PubMed | Google ScholarSee all References (Stata 11.0; StataCorp, College Station, Tex). Fig?1Fig 1 shows the true-positive rate (sensitivity) plotted in function of the false-positive rate (1-specificity) for different cutoff points for the quantified components and whole peanut extract. Each point on the ROC curve represents a sensitivity/specificity pair corresponding to a particular decision threshold. A test with perfect discrimination has a ROC curve that passes through the upper left corner (100% sensitivity and 100% specificity). Therefore the closer the ROC plot is to the upper left corner, the higher the overall accuracy of the test.6x6Zweig, M.H. and Campbell, G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in Clinical Medicine. Clin Chem. 1993; 39: 561–577

PubMed | Google ScholarSee all References According to this criterion, sIgE measurement to Ara h 2 appears to be the test with the highest accuracy for discriminating allergy from tolerance.

We used estimated area under the ROC curves as an indicator of diagnostic accuracy and observed a significant difference between the tests (χ2 = 61.59, P < .001). As indicated by the estimated area under the ROC curves, sIgE to Ara h 2 had the highest accuracy in differentiating between children with peanut allergy and those tolerant to peanut: area (95% CI), Ara h 2 0.99 (0.99-1.00), whole peanut extract 0.85 (0.74-0.96), Ara h 1 0.84 (0.73-0.95), Ara h 3 0.77 (0.64-0.89), Ara h 9 0.52 (0.37-0.66), and Ara h 8 0.50 (0.36-0.65).

Table ITable I shows a range of cutoff points for component Ara h 2 and whole peanut extract based on sensitivity and specificity because the measure of sensitivity and specificity for a single cutoff point might be inadequate for evaluating the optimal diagnostic test. As an example, we considered a hypothetical scenario in which we are seeking to discriminate allergy from tolerance among 100 children sensitized to peanuts, of whom 50 have peanut allergy and 50 are peanut-tolerant. By using sIgE to component Ara h 2 with a cutoff point of 0.35 kUA/L, all children with peanut allergy would be correctly classified. The specificity of this test is given as 96.1% (Table ITable I). In this example we expect 2 children who are not allergic to peanuts to be misclassified as having peanut allergy and the other 48 children to have a negative result. By using this cutoff point, 97.5% of the population is correctly classified.

A similar proportion of children would be correctly classified by using a cutoff point of 0.55 kUA/L; however, in this case 3 children with peanut allergy would be misclassified as tolerant. This cutoff point corresponds to a gain in specificity (100%) but a loss in sensitivity (93.1%). Given the importance of not misdiagnosing children with peanut allergy as being tolerant, we propose that the optimal cutoff point in our population is 0.35 kUA/L.

The cutoff for whole peanut sIgE of 5.30 kUA/L provides the maximum proportion of correctly classified subjects (87.6%), with a sensitivity of 75.9% and a specificity of 94.2%. However, approximately 24% of children with peanut allergy would be inappropriately classified as peanut-tolerant. The cutoff of 15 kUA/L has excellent specificity, with 96.2% of children at greater than this level being correctly classified as allergic; however, this decision point has relatively poor sensitivity, with almost half of the subjects with peanut allergy being classified as tolerant. These data suggest that in our population the quantification of whole peanut sIgE has lower accuracy in discriminating peanut allergy from tolerance compared with quantification of sIgE to Ara h 2.

In conclusion, having identified sIgE to Ara h 2 as an important predictor of clinical reactivity to peanut using microarray technology,5x5Nicolaou, N., Poorafshar, M., Murray, C., Simpson, A., Winell, H., Kerry, G. et al. Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component-resolved diagnostics. J Allergy Clin Immunol. 2010; 125: 191–197 (e1-13)

Abstract | Full Text | Full Text PDF | PubMed | Scopus (291) | Google ScholarSee all References we have now demonstrated the value of its quantification using a routinely available laboratory test. Among school-aged children in the United Kingdom, a cutoff of 0.35 kUA/L Ara h 2 IgE confers 100% sensitivity and 96.1% specificity. By using this cutoff point, 97.5% of the subjects in our study population were correctly classified, with all children with peanut allergy given the correct classification. The importance of Ara h 2 has been suggested in studies from other Central and Northern European countries7x7Astier, C., Morisset, M., Roitel, O., Codreanu, F., Jacquenet, S., Franck, P. et al. Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy. J Allergy Clin Immunol. 2006; 118: 250–256

Abstract | Full Text | Full Text PDF | PubMed | Scopus (163) | Google ScholarSee all References, 8x8Flinterman, A.E., van Hoffen, E., den Hartog Jager, C.F., Koppelman, S., Pasmans, S.G., Hoekstra, M.O. et al. Children with peanut allergy recognize predominantly Ara h2 and Ara h6, which remains stable over time. Clin Exp Allergy. 2007; 37: 1221–1228

Crossref | PubMed | Scopus (101) | Google ScholarSee all References; however, in other populations and geographic areas, IgE to other components might be relevant (eg, Ara h 9 in the Mediterranean9x9Krause, S., Reese, G., Randow, S., Zennaro, D., Quaratino, D., Palazzo, P. et al. Lipid transfer protein (Ara h 9) as a new peanut allergen relevant for a Mediterranean allergic population. J Allergy Clin Immunol. 2009; 124: 771–778 (e5)

Abstract | Full Text | Full Text PDF | PubMed | Scopus (144) | Google ScholarSee all References). Our findings need to be replicated in other populations and age groups before general application.

All Author:

Nicolaos Nicolaou Clare Murray  Maryam Poorafshar Angela Simpson Adnan Custovic


　　創(chuàng)建過敏性疾病的科研、科普知識(shí)交流平臺(tái)，為過敏患者提供專業(yè)診斷、治療、預(yù)防的共享平臺(tái)。