WAO News and Notes - Medical Reviews
Volume 5, Issue 9 Reviews - September 2008
Medical Journal Reviews

Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief, and Guest Editor Mark Glaum MD PhD

1. DEFECTIVE KILLING OF STAPHYLOCOCCUS AUREUS IN ATOPIC DERMATITIS IS ASSOCIATED WITH REDUCED MOBILIZATION OF HUMAN B-DEFENSIN-3 (HBD-3)
Synthesis and mobilization are necessary for the rapid elimination of S aureus. In this study, keratinocytes from skin biopsies from subjects with AD vs normals were compared. AD vs normal individual keratinocytes were defective in killing S aureus (P < .001). The constitutive levels of HBD-3 in the epidermal keratinocytes were similar in the 2 groups. However, AD cells were unable to mobilize HBD-3 efficiently to kill S aureus. HBD-3 mobilization and the ability to kill S aureus were significantly inhibited by IL-4 and IL-13 (P < .05). Antagonism of IL-4/10/13 with antibodies significantly improved mobilization of HBD-3 onto the surface of S aureus by skin from patients with AD (P < .01). The authors conclude that AD subjects have problems with S aureus skin infections as a result of increased levels of TH2 cytokines, which inhibit keratinocyte mobilization of HBD-3. Editor's comment: The vexing problem of atopic dermatitis becomes more complex. Perhaps methods to interfere with IL-4 and IL-13 would be beneficial for patients with this disease. Kisich KO, et al., JACI 2008; 122:62.

特应性皮炎患者对金黄色葡萄球菌的清除存在缺陷,这与人B-防护素3(HBD-3)动员减少相关

快速清除金黄色葡萄球菌必需有HBD-3的合成及动员。本研究比较了正常人及AD患者皮肤活检组织中的角质细胞。比起正常人,AD患者角质细胞对金黄色葡萄球菌的清除存在缺陷 (P < .001)。两组人群上皮角质细胞中HBD-3的结构水平相似。然而,AD患者的细胞不能有效动员HBD-3以清除金黄色葡萄球菌。HBD-3的动员及其清除金黄色葡萄球菌的能力显著受到IL-4IL-13的抑制 (P < .05)。用抗体拮抗IL-4/10/13能显著促进AD患者HBD-3动员到金黄色葡萄球菌表面(P < .01)。作者的结论是由于Th2细胞因子水平增加,抑制了角质细胞HBD-3的动员,使得AD患者容易有皮肤金黄色葡萄球菌的感染。编者点评:特应性皮炎病理复杂。干扰Il-4Il-13可能让该病的患者受益。Kisich KO, et al., JACI 2008; 122:62.

2. RITUXIMAB (R) AND INTRAVENOUS IMMUNE GLOBULIN (IVIG) FOR DESENSITIZATION
20 highly sensitized (high HLA antibody titers or with donor-specific antibodies) received RX with IVIG and R (a chimeric anti-CD20 monoclonal antibody that reduces B cell and antibody levels). The mean panel-reactive antibody level was 44±30% after the second infusion of IVIG vs a 77±19% pretreatment level (P < 0.001). 16 of the 20 patients (80%) received a transplant, and at 12 months, the mean creatinine level was 1.5±1.1 mg per deciliter and the mean survival rates of patients and grafts were 100% and 94%, respectively. At study entry, the mean dialysis time for recipients to receive a transplant from a deceased donor was decreased from 144±89 months to 5±6 months. There were no serious adverse events, infections, or neurologic problems. This approach may represent a breakthrough in the care of sensitized persons awaiting transplantation who are currently on a much longer waiting list than non-sensitized patients and who often die because of this problem. Editor's comment: This appears to be a major breakthrough for patients who until now have been the least likely to receive renal transplants. Vo AA, et al., N Engl J Med 2008; 359:242. (editorial: Shapiro, pp. 305).

美罗华(R)及静脉免疫球蛋白(IVIG)在肾移植中的减敏作用

20名高度敏感的患者(有高滴度HLA抗体或有供者特异性抗体)在肾移植时接受了静脉免疫球蛋白及美罗华(嵌合性抗CD20单克隆抗体,可降低B细胞及抗体水平)治疗。第二次输入IVIG后,平均群体反应性抗体水平为44±30%,而治疗前为77±19%P<0.001)20名患者中的16(80%) 接受了肾移植,术后第12个月的平均肌苷水平为1.5±1.1mg/dl,患者及移植肾的平均存活率分别为100%94%。研究开始时,受者在接受死去的供者的移植肾之前所需的平均透析时间从144±89 个月下降到了5±6个月。未发生严重不良事件,感染,或神经系统的问题。该研究结果对于等待肾移植的敏感患者而言是一个突破性的进展;目前这些敏感患者比不敏感的患者需要等待更长的时间才能得到一个移植肾,而他们往往因为长时间的等待而死亡。编者点评:该研究对于至今几乎还没有机会接受肾移植的患者而言是一个福音。Vo AA, et al., N Engl J Med 2008; 359:242. (editorial: Shapiro, pp. 305).

3. MAST CELL (MC) ACTIVATORS: A NEW CLASS OF HIGHLY EFFECTIVE VACCINE ADJUVANTS
Reviewed by Mark C. Glaum, MD, PhD
MCs have emerged as prominent effectors of lymphocyte activation and immune cell migration to draining lymph nodes. To explore the role of MC in the development of humoral immune responses, investigators combined small-molecule MC activators with vaccine antigens and measured changes in antigen-specific immunoglobulin responses. Subcutaneous and intranasal administration of these combined formulations induces large antigen-specific immunoglobulin G and A responses in vaccinated animals, and this effect appears to depend on MC-dendritic cell interaction and tumor necrosis factor (TNF). Intranasal administration of these formulations provides protection against anthrax lethal toxin challenge in vitro and against vaccinia virus challenge in vivo. Editor's comment: MC activators may function as vaccine adjuvants by promoting MC-dendritic cell interaction thus boosting protective antigen-specific antibody responses. McLachlan JB, et al., Nat Med 2008;14:536.

肥大细胞激活剂:新一类高效免疫佐剂

肥大细胞对淋巴细胞活化及免疫细胞迁移到引流淋巴结有显著效果。为研究体液免疫系统发育过程中肥大细胞的作用,研究者将小分子的肥大细胞活化物与疫苗抗原连接,测定了抗原特异性免疫球蛋白应答的变化。皮下及鼻内接种该复方制剂诱导接种动物体内抗原特异性免疫球蛋白GA应答,该效应依赖肥大细胞-树突细胞相互作用以及肿瘤坏死因子(TNF)。鼻内接种该制剂后动物对体外炭疽毒素及体内病毒疫苗的攻击产生了防御功能。编者点评:肥大细胞激活剂因为能改善肥大细胞-树突细胞相互作用而被用做疫苗佐剂,从而提高保护性抗原抗体反应。McLachlan JB, et al., Nat Med 2008;14:536.

4. EPINEPHRINE: THE DRUG OF CHOICE FOR ANAPHYLAXIS - A STATEMENT OF THE WORLD ALLERGY ORGANIZATION (WAO)
WAO has targeted anaphylaxis as a disease which is inappropriately and under treated. This statement discusses the definition of anaphylaxis, following WAO nomenclature, and emphasizes the absolute need for epinephrine to treat this acute allergic emergency. There is some disagreement among the panel members who contributed to this paper about when epinephrine should be given in the course of progressive anaphylaxis. The majority of authors thought it should be given at the earliest sign or symptom of anaphylaxis, particularly, when associated with SCIT, while others felt that such treatment could be delayed until more definitive signs of anaphylaxis are present. Editor's comment: This article will help each physician understand the pharmacology of epinephrine, why it is essential for the successful treatment of anaphylaxis, and when it should be administered. Kemp SF, et al., WAO Journal 2008; Suppl 2: S18. Conflict: the Editor is one of the senior authors.

肾上腺素:过敏性休克的首选用药-世界变态反应组织(WAO)报告

WAO认为过敏性休克没有得到适当充分的治疗。该报告依据WAO词汇表讨论了过敏性休克的定义,强调肾上腺素对过敏性急症的必要性。制定报告的WAO委员对于过敏性休克发展过程中使用肾上腺素的时机有不同的看法。多数作者认为应该在过敏性休克发生的早期用药,尤其是因皮下免疫治疗引起的严重过敏反应;而其它人认为应该在具备更为明确的过敏性休克征象时才用药。编者点评:该报告有助于医生理解肾上腺素的药理学,知道为何该药对于成功治疗过敏性休克至关重要,以及何时应该用药。Kemp SF, et al., WAO Journal 2008; Suppl 2: S18. Conflict: the Editor is one of the senior authors.

5. COMBINATION FLUTICASONE AND SALMETEROL (FP/SAL) VERSUS FIXED DOSE COMBINATION BUDESONIDE AND FORMOTEROL (BUD/F) FOR CHRONIC ASTHMA IN ADULTS AND CHILDREN (REVIEW)
The objective of this paper is to estimate the relative effects of FP/SAL and BUD/F in terms of asthma control, safety and lung function. To do so, randomized studies comparing fixed dose FP/SAL and BUD/F for a minimum of 12 weeks were reviewed for three primary outcomes: i) exacerbations requiring oral glucocorticoid bursts, ii) hospital admission, and iii) serious adverse events. 5537 participants from five studies were analyzed and the odds ratio of exacerbation requiring oral glucocorticoids did not differ significantly between treatments. Likewise, neither did hospital admissions or adverse events. Secondary outcomes also did not differ significantly and include lung function outcomes, symptoms, and rescue medication use. The authors state that the confidence intervals reported do not exclude clinically important differences between treatments in reducing exacerbations or causing adverse events. Likewise, the width of the confidence intervals for the primary outcomes justifies additional trials to better determine the relative effects of these drug combinations. Editor's comment: Thus far, treatment outcomes for fixed combinations of long-acting beta-agonists and ICS do not seem to differ. Lasserson TJ, et al., The Cochrane Collaboration, The Cochrane Library 2008; Issue 3.

成人及儿童哮喘患者用氟替卡松沙美特罗合剂 (FP/SAL)与固定剂量布地耐得氟莫特罗(BUD/F)合剂的疗效比较(复习)

本文目的在于从哮喘控制,安全性及肺功能改善三个方面来评价FP/SALBUD/F的相对疗效。为此,作者根据三个主要结局来评价固定剂量FP/SALBUD/F为期12周以上的随机试验。三个主要结局包括:i) 需要口服糖皮质激素治疗的病情恶化,ii)住院,以及iii)严重不良事件。分析了5项研究共5537名受试者,发现两个治疗组需要紧急口服糖皮质激素的疾病恶化的危险比没有显著差异。同样,住院及不良事件的发生也没有显著差异。次级结局包括肺功能、症状、以及急救药物的使用没有显著差异。作者认为,从置信区间看,研究结果并没有排除治疗组在减少恶化或发生不良事件方面的临床差异。同样,主要结局的置信区间的宽度也表明需要其它试验来验证这两种联合治疗的相对疗效。编者点评:目前为止,不同长效beta受体激动剂及ICS的固定组合在对哮喘的影响方面没有差异。

6. USE OF MULTIPLE DOSES OF EPINEPHRINE (E) IN FOOD-INDUCED ANAPHYLAXIS IN CHILDREN
A total of 413 anonymous questionnaires distributed to families of children with food allergies during allergy outpatient visits were analyzed. 78 children (median, 4.5 yrs of age; range, 0.5 - 17.5 yrs) reported 95 reactions for which E was administered. Two doses of E were given in 12 (13%) and three doses in 6 (6%). Peanut, tree nuts, and cow's milk were responsible for >75% of these reactions requiring E. Patients with asthma were more likely to receive multiple doses of E (P = .027). The amount of food ingested or a delay in the initial E were not risk factors for multiple doses. The second dose was administered by a healthcare professional in 94% of the reactions. The authors conclude that 19% of food-induced anaphylactic reactions were treated with more than one dose of E and that prospective studies are necessary to establish risk factors for prescribing multiple E autoinjectors for children with food allergy. Editor's comment: Multiple E autoinjectors should be prescribed for food-induced anaphylaxis. Järvinen KM, et al., JACI 2008; 122:133.

儿童发生的食物诱导的过敏性休克该如何用多次肾上腺素注射

研究者在变态反应科门诊对食物过敏患儿家庭进行了413份匿名问卷。78名患儿(平均,4.5岁;0.5-17.5岁)发生了95次反应,并且用到了肾上腺素。12名患儿(13%)用了2次肾上腺素,6(6%)用了3次肾上腺素。75%需要肾上腺素治疗的反应是由于花生,坚果,以及牛奶引起。哮喘患儿更可能需要多次肾上腺素注射 (P = .027)。进食量或拖延用肾上腺素注射的时机并非多剂肾上腺素的危险因素。94%的反应由医务专业人员给第二次肾上腺素。作者结论是19%食物诱导的严重过敏反应需要用1次以上的肾上腺素急救。需要有回顾性的研究来明确食物过敏的患儿有哪些多次用肾上腺素的危险因素。编者点评:食物诱导的严重过敏反应应该多次肾上腺素自注射。Järvinen KM, et al., JACI 2008; 122:133.

7. COMPARISON OF A COMBINATION OF TIOTROPIUM (T) PLUS FORMOTEROL (F) TO SALMETEROL (S) PLUS FLUTICASONE (F) IN MODERATE COPD
605 patients with moderate COPD were randomized and treated in a 6-week multicenter, randomized, double-blind, parallel-group study to compare lung function with T, 18 µg qd, plus f, 12 µg bid, to S, 50 µg bid, plus F, 500 µg bid. A total of 592 patients (baseline FEV1, 1.32 ± 0.43 L/min) were analyzed and the 12-h lung function profiles in the T + F were statistically greater than those in the S + F. Differences in FEV1 and FVC at peak and each individual time point were all statistically significant in favor of TF. Predose FVC was significantly higher with the TF combo. The authors conclude that T + F is superior to S + F in patients with moderate COPD. Editor's comment: S probably should be added to T or vice-versa before adding an inhalational glucocorticosteroid for moderate COPD. Rabe KF, et al., Chest 2008; 134:255

中度COPD用噻托溴铵(T)氟莫特罗(F)联合治疗与沙美特罗(S)氟替卡松(F)联合治疗的疗效比较

605名中度COPD患者参加了该项随机化,6周,多中心,随机双盲平行对照研究,比较T 18ugqd联合f12ugbid,与S50ug bid联合F500ugbid对肺功能的改善情况。共分析了592名患者(基线FEV1 1.32 ± 0.43L/min),T+F组患者的12小时肺功能状况显著好于S+F组。峰态及各时刻的FEV1FVC情况显著支持TF治疗。用药前FVCTF联合用药时显著高。作者的结论是中度COPD患者用T+F治疗优于S+F编者点评中度COPD患者用吸入糖皮质激素之前,也许应该先用S+T联合治疗。Rabe KF, et al., Chest 2008; 134:255 

8. LONG TERM PROGNOSIS IN PRESCHOOL CHILDREN WITH WHEEZE: LONGITUDINAL POSTAL QUESTIONNAIRE STUDY 1993-2004
The object of this study was to follow a population of preschool children with and without a history of wheeze (as reported by their parents) for 6-11 years to determine prognosis and important predictive factors. 628 children aged less than five years at recruitment and with at least six years follow-up data were analyzed from two general practice populations in Great Britain. 201 (32%) parents reported wheeze at baseline, 27% of whom still had the symptom on the second occasion (persistent asthma). Predictors of persistent asthma were exercise induced wheeze (OR 3.94, 95% CI 1.72 to 9.00) and a history of atopic disorders (OR 4.44, 95% CI 1.94 to 10.13). If both predictors were present, it indicates a likelihood of 53.2% of developing asthma; whereas if one was present, the likelihood decreased to 17.2%, and neither present, the likelihood decreased even further to 10.9%. Family history was not predictive of persistent asthma. The authors conclude that a history of atopic disorders and exercise induced asthma are good predictors of asthma persisting into the future. Editor's comment: Here's new data indicating that exercise induced asthma and atopic disease early in life are good predictors of asthma in the future. Frank PI, et al., BMJ 2008; 336:1423.

有喘鸣的学龄前儿童的长期预后:1993-2004年间的跟踪调查问卷

本研究目的是通过对一组有喘鸣病史及无喘鸣病史的学龄前儿童(该病史由其家长提供)进行6-11年的随访,以明确他们的预后及重要的预测因子。研究对象为英国的628名年龄不足5岁的患儿,随访至少6年。基线期有20132%)名家长说自己的孩子有喘鸣,其中27%在第二次随访时仍有症状(持续性哮喘)。运动诱导的喘鸣 (OR 3.94, 95% CI 1.72 to 9.00)及特异性疾病病史(OR 4.44, 95% CI 1.94 to 10.13)提示可能有持续性哮喘。如果患儿具备两个上述危险因素,那么发生哮喘的可能性达53.2%;若有一个危险因素,可能性降低至17.2%,若没有任何一个因素,可能性降低至10.9%。家族史并非持续哮喘的危险因素。作者的结论是特应性疾病及运动诱发的哮喘是未来发展为持续性哮喘的危险因素。编者点评:这里提出新的数据表明运动诱发的哮喘及早年的特应性疾病是未来发展为哮喘的指征。 Frank PI, et al., BMJ 2008; 336:1423.

9. THE DEVELOPMENT OF ALLERGIC INFLAMMATION
This article in Nature is a superb review of allergic inflammation with the following sections: Allergy and Gene-Environment Interactions; Allergen Sensitization and Epithelial Barriers; Features of Allergic Inflammation; IgE and the Exacerbation of Allergic Disorders; Suppression and Resolution of Allergic Inflammation; and Management of Allergies and Allergic Inflammation. It ends with a section on "What Next?", implying that molecular biology will alter the treatment of allergic diseases. Perhaps the most wonderful thing about this review is the extraordinary six figures included in the article. Editor's comment: This is a wonderful review and update for all physicians, no matter what their degree of knowledge about allergic inflammation. Galli SJ, et al., Nature 2008; 454:445.

过敏性炎症的发生

Nature上的这篇文章是对过敏性炎症的一流综述,包括以下章节:过敏及基因-环境相互作用;过敏原致敏及上皮屏障;过敏性炎症的特点;IgE及过敏性疾病恶化的关系;过敏性炎症的缓解;过敏及过敏性炎症的治疗。本综述以“下一步怎么办”结束,暗示分子生物学会改变过敏性疾病的治疗。也许该综述最大的亮点是文中提到的6大特点。编者点评:对所有医生而言,无论他们对过敏性炎症了解几许,该文都是对过敏性疾病炎症的一篇很好的综述。 

10. SUBLINGUAL IMMUNOTHERAPY (SLIT) FOR LARGE LOCAL REACTIONS CAUSED BY HONEYBEE STING: A DOUBLE-BLIND, PLACEBO-CONTROLLED (DBPC) TRIAL
26 of 30 patients completed a SLIT randomized, DBPC study of large local reactions. After the baseline sting challenge, they were randomized to SLIT or placebo for six months. After a 6-week build-up period, they were maintained with 525 µg (35 µg every other day) of venom monthly. The sting challenge was repeated after six months. The median of the peak maximal diameter of the LLRs decreased from 20.5 to 8.5 cm (P = .014), whereas no change was seen in the placebo group (23.0 vs 20.5 cm, I = ns). There was one dropout in the active and three in the placebo group. No adverse reactions were reported. The authors call for more SLIT dose-ranging studies and studies of systemic reactions. Editor's comment: This study of LLRs is encouraging and may indicate that SLIT could be beneficial for systemic reactions to Hymenoptera insects. Severino MG, et al., JACI 2008; 122:44.

舌下免疫治疗蜜蜂盯蛰引起的大片局部反应(LLRs):双盲,安慰剂对照试验

30名患者中的26名完成了舌下免疫治疗的随机双盲安慰剂对照试验。基线期经蜜蜂盯蛰后,患者随机接受6个月舌下免疫治疗或安慰剂。经过6周的起始阶段,用每月共525ug35ug隔日一次)的毒液维持治疗。6个月后再次被蜜蜂盯蛰。LLRs的最大直径中间值从20.5cm降低至8.5cm(P = .014), 但安慰剂组没有观察到这种反应 (23.0 vs 20.5 cm, I = ns)。试验组没有患者退出,而安慰剂组有三人退出。没有报道不良反应。作者呼吁进行更多不同剂量舌下免疫治疗的研究,并进行有关系统反应的研究。编者点评:这个关于LLRs的研究很让人振奋,该研究可能提示舌下免疫治疗对昆虫毒液盯蛰引起的系统反应有益。Severino MG, et al.JACI 2008; 122:44

Translated by Dr. Qing Manli, PUMCH Allergy Department

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