Medical Journal Reviews

Gary Hellerman, PhD, in collaboration with Richard Lockey, MD, WAO Web Chief Editor, conducted these reviews of premier medical journal articles for practicing allergists.

1. Predicting worsening asthma control following the common cold.
The effects of rhinovirus infection on asthmatics vary, but upper respiratory infections commonly worsen asthma and lead to exacerbations. In this multicenter study, 413 adult asthmatics were followed for over a year to determine if the severity of a cold could predict loss of asthma control. To quantify the loss of asthma control, subjects completed the mini-Asthma Control Questionnaire (mini-ACQ) and to measure cold severity, the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21). The questionnaires were done about every 8 weeks, and upon the onset of a cold, the WURSS-21 was completed daily for the duration of the cold and the mini-ACQ was done at 7 and 14 days after its onset. Significant loss of asthma control occurred in 134 subjects and the WURSS-21 scores on the second day were predictive of subsequent worsening of asthma. Editor's comment: Documentation of cold symptoms by asthmatics may help reduce the post-cold loss of asthma control. Walter MJ et al., Eur Respir J, 2008; 32: 1548-1554.

预测普通感冒后哮喘控制的恶化

鼻病毒感染对哮喘影响不一，但上呼吸道感染往往导致哮喘恶化。本多中心研究对413个成人哮喘患者进行1年以上的随访，以明确感冒的严重程度能否预测哮喘失控。通过让患者填写简易哮喘控制问卷（mini-ACQ）来定量描述哮喘失控的情况；采用Wisconsin上呼吸道症状研究－21号问卷（WURSS-21）评价感冒的严重性。每8个星期就让患者做一次问卷，若发生感冒，就从起病当天开始每天填写WURSS-21问卷直到感冒结束；同时在感冒期间每7-14天填写mini-ACQ。134名患者出现了明显的哮喘失控；感冒第二天的WURSS-21积分可以预测哮喘恶化。编者点评：哮喘患者记录感冒症状有助于减少感冒后哮喘的失控。 Walter MJ et al., Eur Respir J, 2008; 32: 1548-1554.

2. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis.
Patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MP) can be induced into remission by a course of i.v. corticosteroids and cyclophosphamide. Either methotrexate (Mtx) or azathioprine (Aza) can then be given as an immunosuppressant for post-treatment maintenance. This study compares the efficacy and safety of Mtx vs Aza administered to 126 WG or MP patients in remission. One group of 63 randomized patients received 2.0 mg/kg Aza per day while the other was given 0.3 mg/kg Mtx per week, increased to 25 mg per week, for 12 months. Adverse events (AEs) requiring discontinuation of the drug or causing death were the primary endpoints recorded over a mean period of 29±13 months. During maintenance therapy, 29 Aza patients (46%) and 35 Mtx patients (56%) had one or more AEs and among these individuals, 7 in the Aza group and 12 in the Mtx group had AEs severe enough to cause discontinuation or death. The relapse-free survival rates were 71.8% for Aza compared to 74.5% for Mtx, and the hazard ratio for risk of relapse with Mtx vs Aza was 0.92. The conclusion is that the safety and efficacy of Mtx and Aza are not statistically different. Editor's comment: Given the equivalency of the two medications, the decision of which one to use for maintenance control of ANCA-associated vasculitis can be made based on the individual's tolerance. Pagnoux C, et al. N Engl J Med 2008; 359:2790-2803.

ANCA相关性血管炎用硫唑嘌呤或甲氨蝶呤维持治疗
一个疗程的静脉糖皮质激素及环磷酰胺可以诱导韦格纳肉芽肿（WG）或显微镜下多血管炎（MP）的患者病情缓解。甲氨蝶呤（Mtx）或硫唑嘌呤（Aza）能够作为免疫抑制药物进行后续维持治疗。本研究比较了126名WG或MP患者在缓解阶段用Mtx及Aza的疗效及安全性。随机给一组63名患者每天2.0mg/kg的Aza，而另一组每周用0.3mg/kg的Mtx并增加到每周25mg，共治疗12个月。观察期为29±13个月，需要中断药物治疗的不良事件（AEs）或导致死亡的不良事件是主要终点指标。在维持治疗过程中，29例Aza患者（46%）及35例Mtx患者（56%）有一次或多次不良事件。其中，Aza组有7例，而Mtx组中有12例发生了必须中断治疗或导致死亡的严重AE。Aza组无复发的存活率为71.8%，而Mtx组为74.5%，Mtx对Aza的复发危险比是0.92。结论是Mtx及Aza的安全性及有效性没有统计学差异。编者点评：考虑到这两种药物的等效性，选择哪一个作为ANCA相关的血管炎的维持治疗药物可以根据个体的耐受性决定。 Pagnoux C, et al. N Engl J Med 2008; 359:2790-2803.

3. A syndrome with congenital neutropenia and mutations in G6PC3.
Mutations in several different genes are linked to severe congenital neutropenia (SCN) with susceptibility to bacterial infection, lack of mature neutrophils, heart and urogenital defects and increased risk of leukemia. A genome-wide linkage analysis of two consanguineous families of children with SCN resulted in the identification of a homozygous mutation in the gene for glucose-6-phosphatase, G6PC3, that abolished G6P activity. The parents were heterozygous for the mutation. An additional seven unrelated SCN patients were found to have biallelic G6PC3 mutations. None had hypoglycemia commonly seen in glycogen storage disorders also associated with neutropenia. The defect in glucose-6-phosphatase caused loss of mature neutrophils through apoptosis and was associated with increased susceptibility to infection, heart defects, superficial vein prominence and urogenital abnormalities. Mutant G6PC3 activity measured by in vitro glucose production was at background levels compared to the wild type enzyme. Neutrophils, hematopoietic progenitor cells and other cells such as fibroblasts from SCN patients showed an increased rate of spontaneous and induced apoptosis. The tendency to apoptosis in myeloid progenitor cells was reversed by transfection with a plasmid expressing wild type G6PC3. Enzymatic analysis of neutrophils from SCN patients revealed a decrease in the anti-apoptotic protein Mcl-1 which may account for the increased apoptosis. Editor's comment: This paper should be read as a model for excellence in experimental design, data analysis and presentation. Boztug K et al. New Engl J Med 2009; 360:32-43. (also see the editorial by Dale and Link, pp 3-5

先天性中性粒细胞减少综合征以及G6PC3缺陷
几个不同基因的突变与严重的先天性中性粒细胞减少症有关。患者易发生细菌感染，缺乏成熟的中性粒细胞，存在心脏及泌尿生殖系统缺陷，且白血病发病危险增高。对两个同血缘家族的SCN患儿进行全基因组连锁分析，发现编码葡萄糖－6-磷酸的基因G6PC3的纯合突变，该突变使得G6P失去活性。另外7个没有血缘关系的SCN患儿的父母有G6PC3突变的二等位基因。没有患儿出现与中性粒细胞减少相关的糖原储备障碍导致的低血糖。葡萄糖－6-磷酸的缺陷导致中性粒细胞因凋亡而丢失，与易发生感染，心脏缺陷，浅表静脉突出以及泌尿生殖系统异常有关。与野生型酶活性相比，通过葡萄糖体外生成测定到的突变后G6PC3的活性仅为基线水平。SCN患者的中性粒细胞，造血祖细胞以及其它细胞如纤维母细胞的自发凋亡及诱导凋亡的速度增高。转染表达野生型G6PC3的质粒可以逆转骨髓祖细胞凋亡倾向。SCN患者中性粒细胞酶分析结果显示抗凋亡蛋白Mcl-1减少，这可能是凋亡增加的原因。编者点评：本文的实验设计，数据分析以及结果陈述都是优秀中的典型。 Boztug K et al. New Engl J Med 2009; 360:32-43. (also see the editorial by Dale and Link, pp 3-5

4. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States.
The over-55 group has the highest per capita rate of prescription use and is most at risk for drug-related adverse events. At least one in 25 older Americans is at risk of a major drug-drug interaction because of the combination of medications and supplements. This report utilized a representative probability survey of 3305 noninstitutionalized U.S. individuals 57 to 85 years of age to determine patterns of medication use and potential drug interactions. Professional interviews were conducted in-home and all regular (daily or weekly) use of prescription and over-the-counter (OTC) drugs, as well as supplements, herbals and alternative medicines was verified by the interviewer. 81% of the sample population used at least one prescription drug while about half used at least one OTC drug. Women were more likely than men to use a prescription drug or dietary supplement. The use of more than five prescription or OTC drugs or supplements was observed in more than half of older adults and 68% of prescription users also used OTC drugs or supplements. 46 potential interactions between the 20 most common drugs and the 20 most common dietary supplements were identified, 11 of which could cause severe reactions. Editor's comment: This study emphasizes the importance for the physician to be aware of all medications and supplements taken by their patients. Qato DM et al. J Am Med Assoc 2008; 300:2867-2878.

美国老年人处方药，非处方药以及营养补充品的使用情况

55岁以上人群的人均处方使用率最高，发生药物相关不良事件的危险也最高。由于合并用药及辅助营养品的使用，每25名美国人中至少有1名有发生严重药物相互作用的危险。本研究采用了典型概率调查，研究3305名年龄在57-85岁非专门机构的US成人的药物使用形式及潜在的药物相互作用。专业人士对研究对象进行上门访问，由访问者证实所有日常使用（每天或每周）的处方药及非处方药，营养补充品，草药以及其它药物。81%的研究对象用了至少一种处方药，一半人用着至少一种非处方药。女性比男性更易用处方药或营养补充品。超过一半的老年人用了5种以上的处方药或非处方药或营养补充品；68%的处方药使用者也用着OTC药品或营养补充品。在20种最常见的药物以及20种最常见的营养补充品之间发现了46种可能的相互作用，其中的11种可能导致严重反应。编者点评：本研究强调了医生应该警惕其患者所服用的所有药物及营养补充品。 Qato DM et al. J Am Med Assoc 2008; 300:2867-2878.

5. Viral infection in adults hospitalized with community-acquired pneumonia (CAP)-prevalence, pathogens, and presentation.
The viral etiology of CAP has not been studied extensively and treatment guidelines are not as complete as those for bacterial pneumonia. Nasal swab secretions were acquired from 193 individuals hospitalized with CAP and analyzed by the nucleic acid amplification test (NAT) for influenza, rhinovirus (RV), human metapneumovirus (hMPV), respiratory syncytial virus (RSV), parainfluenzavirus (PIV), coronavirus and adenovirus. Serum samples were tested for bacterial infection by immunofluorescence methods. Pathogens were identified in 39% and among those, 29 had a viral infection only, 38 had a bacterial infection only, and 8 had both viral and bacterial infections. The most common were influenza, hMPV and RSV. In patients with bacterial infection, Streptococcus pneumoniae was most common (37%). Viral infection occurred more frequently in older patients (median 76 yrs) than younger (median 64 yrs) and was seasonal (October to May), whereas bacterial infections occurred year round. Morbidity and mortality rates were similar for viral and bacterial infections. Editor's comment: The observation that hMPV occurs as frequently as influenza virus in CAP suggests that this pathogen is more common than previously documented. Johnstone J, et al. Chest 2008; 134:1141-1148.

因社区获得性肺炎（CAP）住院的成人患者的病毒感染情况－发病率，病原学以及临床表现

CAP的病毒学病因尚未得到深入研究，治疗指南不及细菌性肺炎的完整。本研究取得193位CAP住院患者的鼻拭子分泌物，用核酸扩增试验(NAT)检查流感病毒，鼻病毒(RV)，人巨型肺炎病毒(hMPV)，呼吸道合胞病毒(RSV)，副流感病毒(PIV)，冠状病毒以及腺病毒。用免疫荧光技术检测血清标本中的细菌感染。病原检出率为39%，其中，29名患者仅有病毒感染，38名患者仅有细菌感染，8名患者既有病毒又有细菌感染。最常见的病毒是流感病毒，hMPV 以及d RSV。细菌感染的患者，肺炎链球菌最常见（37%）。相对于年轻的患者（中位年龄64岁）病毒感染在年龄大的患者比较常见（中位年龄76岁），且是季节性的（10月到次年5月），而细菌感染呈全年性的发作。病毒感染及细菌感染的致残率及致死率相当。编者点评：CAP患者发生hMPV 感染与与流感病毒感染同样频繁，这个现象提示该病原比以前观察到的更常见。 Johnstone J, et al. Chest 2008; 134:1141-1148.

6. The Brussels Declaration: the need for change in asthma management.
The incidence of asthma, rhinitis and sinusitis continues to increase worldwide and difficulties in diagnosis, lack of effective control and poor education are still serious problems. To address these issues, the Asthma, Allergy and Inflammation Research Charity sponsored a conference that produced the Brussels Declaration which points out the inadequacies in asthma management and urges action on the part of governments and public health groups to recognize these problems and make the necessary changes to improve diagnosis, control and prevention. This paper describes the key points in the declaration and summarizes the evidence supporting the call to action. Areas of focus include the difficulty of accurate diagnosis, the role of inflammation in asthma pathology, the causes of poor asthma control, special problems in pediatric asthma, new areas of research, and the role of public health groups in education and community action. Editor's comment: The emphasis on evidence-based guidelines in developing strategies for improving asthma management is the strong point of this document. Holgate S, et al. Eur Respir J 2008; 32:1433-1442.

布鲁塞尔宣言：哮喘管理方案需要更改

全球哮喘、鼻炎以及鼻窦炎的发病率一直在增长，诊断困难，缺乏有效控制以及教育不好仍然是重要问题。为说明这些问题，哮喘、过敏以及炎症研究基金资助了一个会议，产生了布鲁塞尔宣言，指出哮喘管理的不充分并督促政府及公共卫生机构采取行动，认识现有的问题，进行必要的改变来提高诊断控制及预防。本文陈述了宣言中的重要内容，总结了呼吁行动的证据。重点范围包括正确诊断的困难，炎症在哮喘病理中的角色，哮喘控制不良的原因，儿童哮喘的特殊问题，新的研究领域，以及公共卫生组织在教务及社区行动上的角色。编者点评：这个报告中的重点是强调了提高哮喘管理措施的循证学指南。 Holgate S, et al. Eur Respir J 2008; 32:1433-1442.

7. Treatment with inhaled steroids in patients with symptoms suggestive of asthma but with normal lung function.
The hypothesis of this pilot study was that a pre-asthmatic condition characterized by lung inflammation exists in a significant number of individuals who are not diagnosed with asthma by traditional measures of lung function. This randomized, multicenter, DBPC trial enrolled 144 patients, 12 to 65 years of age, with symptoms suggestive of asthma to undergo treatment with mometasone furoate (MF), 400 µg per day. The subjects scored morning and evening symptoms including cough, sputum production, wheeze, and shortness of breath, among others. An initial 1-2 week screening period was used to insure that those included in the study had an average symptom score >e;1 and that those with diagnosed or verifiable asthma were excluded. Spirometry, eosinophil numbers in induced sputum and airway hyperresponsiveness were also measured. MF or placebo was administered as one puff in the evening from a metered-dose inhaler and salbutamol was used as needed by both groups. The treatment was continued for 4-8 weeks. Despite heterogeneity in the groups, overall symptom scores were lower, eosinophilia decreased and spirometry improved with MF compared to placebo. A short course of inhaled corticosteroids may be beneficial for some patients with symptoms suggestive of asthma , but careful follow-up needs to be done to determine the necessity of continued treatment. Editor's comment: This study provides a useful framework for treating that group of patients with symptoms that may or may not be pre-asthmatic. Rytilä P, et al. Eur Respir J 2008; 32:989-996.

用吸入激素治疗症状提示哮喘但肺功能正常的患者

该项小规模研究基于一个假设，就是用传统肺功能测定无法诊断哮喘的人，很多都存在以肺部炎症为特点的哮喘前状态。本项随机，多中心，双盲安慰剂对照试验共纳入144名患者，年龄在12-65岁，均有提示哮喘的症状，用糖酸莫美他松（MF）每天400ug治疗。研究对象将晨起及傍晚的症状，包括咳嗽，咳痰，喘鸣以及气短进行评分。最初1-2周的筛选期确保纳入研究的患者平均症状积分能达到>e；且确保没有纳入可以明确诊断哮喘的患者。测定肺功能，诱导痰嗜酸细胞计数以及气道高反应性。每天傍晚用定量吸入装置吸入1喷的MF或安慰剂，并且两组都按需使用沙美特罗。治疗共4-8周。尽管两组有异质性，但MF组较安慰剂组总体症状积分低，MF组嗜酸细胞降低，肺功能改善。短疗程吸入糖皮质激素可能对一些有提示哮喘症状的患者有益，但需要仔细的随访以决定继续治疗的必要性。编者点评：本研究对治疗可能有/无哮喘前症状的患者提出了一个有用的框架。 Rytilä P, et al. Eur Respir J 2008; 32:989-996.

8. Chitosan microparticles loaded with mite group 2 allergen Der f2 alleviate asthma in mice.
Allergen-specific immunotherapy is an effective way to reduce allergy but may cause adverse side effects. This study examined the use of chitosan as a carrier for synthetic allergen peptides that have reduced allergenicity but are still immunogenic. The natural polysaccharide chitosan makes an ideal delivery system because it protects peptides from degradation and enhances their uptake in the mucosa. Mice were sensitized to dust mite by injection of Der f2 and treated with chitosan microparticles loaded with the major epitope peptide, Der f2 (47-67), once daily by i.p. injection for 8 days. One week after the final injection, the mice were challenged with Der f2 and airway hyperresponsiveness (AHR) was measured followed by determination of bronchoalveolar lavage (BAL) cells and lung histology. Mice receiving Der f2 (47-67) chitosan had reduced AHR and BAL eosinophilia, less lung damage and mucus production and lower Der f2-specific serum IgE than mice treated with empty chitosan. Editor's comment: These results in a mouse model suggest that chitosan nanoparticles may be effective as a vehicle in human immunotherapy. Li J, et al. J Investig Allergol Clin Immunol 2008; 18:454-460.

转载尘螨二组变应原Der f2的甲壳胺减轻小鼠的哮喘

变应原特异性免疫治疗是降低过敏的有效方式但可能引起不良反应。本研究探索用甲壳胺作为合成变应原肽段的载体，使得过敏原性降低，但免疫原性依旧。天然多糖甲壳胺是理想的运载系统，因为它保护肽段免受降解，提高黏膜的吸收。通过给小鼠注射Der f2使其对尘螨致敏，然后用装载了主要变应原肽的甲壳胺微颗粒Der f2 (47-67)每天一次皮下注射治疗共8天。最后一次注射后一周，用Der f2激发小鼠，测定气道高反应性，检查支气管肺泡灌洗的细胞及肺的病理。比起用空的甲壳胺治疗的小鼠，接受Der f2 (47-67) 甲壳胺的小鼠AHR及BAL嗜酸细胞降低，肺损伤减轻，黏液产生少，Der f2-特异性血清IgE低。编者点评：小鼠模型中的结果提示甲壳胺微颗粒可能作为人免疫治疗的载体。 Li J, et al. J Investig Allergol Clin Immunol 2008; 18:454-460.

9. Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling.
The enzyme 15-lipoxygenase (15-LO) acts on arachidonic acid to produce immunoactive compounds. 15-LO is induced by the Th2 cytokines IL-4 and IL-13 and is elevated in asthmatics suggesting a possible role in inflammation. Mice deficient in 12/15-LO (the animal ortholog of human 15-LO) were sensitized to ovalbumin (OVA) and responded with normal production of OVA-specific IgE. Upon OVA aerosol challenge, however, the 12/15-LO-/- mice showed fewer eosinophils, lymphocytes and macrophages in the lungs than wild type (WT) and reduced levels of IL-4, IL-5 and IL-13. Goblet cell hyperplasia was present in both WT and 12/15-LO-/-, but mucus production was inhibited in the latter. Measurements of smooth muscle (SM) cell proliferation revealed fewer alpha-SM actin-positive alveolar cells in the peripheral airways in 12/15-LO-/- mice. Taken together, these results suggest that arachidonic acid metabolites produced by 12/15-LO are active in allergic inflammation and remodeling. Editor's comment: Inhibitor's of the 15-LO pathway may afford some protection from allergic airway inflammation. Andersson CK, et al. Am J Respir Cell Mol Biol 2008; 39:648-656.

12/15－脂氧合酶缺陷的小鼠气道过敏性炎症及气道重塑减轻

15-脂氧合酶（15-LO）作用于花生四烯酸，产生免疫活性复合物。15-LO受Th2细胞因子如IL-4，Il-13的诱导，哮喘患者15-LO水平增高，提示其在炎症中可能有一定作用。12/15-LO缺陷的小鼠用卵白蛋白致敏，产生正常水平的OVA-特异性IgE。然而，经OVA气溶胶激发时，12/15-LO-/-小鼠肺内的嗜酸粒细胞、淋巴细胞以及巨噬细胞都比野生型的少，Il-4,IL-5以及IL-13的水平也低。野生型小鼠以及12/15-LO-/-小鼠都有杯状细胞增生，但后者黏液产生受到抑制。测定平滑肌细胞增生显示较少的alpha－SM－actin－阳性的肺泡细胞，在12/15-LO-/-小鼠的周围气道中。总的来说，这些结果提示12/15-LO来源的花生四烯酸代谢产物对过敏性炎症及气道重塑很有意义。编者点评：抑制15-LO途径可以对过敏性气道炎症有一定的保护作用。 Andersson CK, et al. Am J Respir Cell Mol Biol 2008; 39:648-656.

10. Pulmonary fibrosis.
This issue of the European Respiratory Review contains a comprehensive series of articles examining the causes, classification and latest clinical findings in pulmonary fibrosis (PF). The outcomes of recent clinical trials are discussed together with a cross-section of the current research including the role of epithelial fibroblasts in PF, the part played by apoptosis, key interactions involving endothelin, cytokines and chemokines in the lung, and more. A survey of gene expression profiles in PF is also presented. The collection ends with an evaluation of the current progress and the important targets for future study. Editor's comment: This is required reading for anyone desiring an up-to-the-minute survey of the literature on PF. Edited by TE King Jr and RM du Bois, Eur Respir Rev 2008; 17:103-170.

肺纤维化

这一期的欧洲呼吸综述有一系列关于肺纤维化（PF）的病因、分类以及最新临床发现的文章。近期的临床试验的结果也在此进行了讨论，并且有关于目前研究的一个横断面描述，包括上皮纤维母细胞在PF中的作用，凋亡的意义，内皮素，细胞因子以及化学因子在肺内的重要相互作用，还有其它更多的内容。还有PF的基因调查的情况。全刊以评价目前的进展以及将来研究的重要靶向结束。编者点评：所有希望对最新PF文献有认识的人应该阅读该刊。 Edited by TE King Jr and RM du Bois, Eur Respir Rev 2008; 17:103-170.

Translated by Dr. Qing Manli, Allergy department, PUMCH,China