WAO News and Notes - Medical Reviews
Volume 5, Issue 12 Reviews - December 2008
Announcing the WAO Web Site's new look at www.worldallergy.org
Medical Journal Reviews

These reviews of premier medical journal articles for practicing allergiest were conduction by Gary Hellerman, PhD, in collaboration with Richard F. Lockey, MD, WAO Web Chief Editor. 今月の実地医家のための医学雑誌レビューはWAO編集委員長のRichard F. Lockey 教授とGary Hellerman先生によるものです。

To read translations of past Medical Journal Reviews, click here.

1. NANOPARTICLE-MEDIATED CELLULAR RESPONSE IS SIZE-DEPENDENT
Nanoparticles engineered from a variety of polymers and compounds are being tested as carriers for targeted drug and DNA delivery. This report emphasizes that nanoparticles should not be viewed as inert vehicles, but rather as agents that can be fine-tuned to stimulate their entry into targeted cells to modify a specific cell response. Many important cellular processes such as apoptosis are controlled through cell-surface receptors that interact with specific ligands. Here gold nanoparticles (GNPs) 2 to 100 nm in diameter were coated with various amounts of the ErbB2 ligand herceptin. Entry of the multivalent GNPs into cancer cells and intracellular localization was determined. Greatest uptake occurred with 40-50 nm GNPs, and entry was accompanied by a concomitant increase in cancer cell death. Editor's comment: Therapeutic use of nanoparticles will become more and more widespread as their unique properties are better understood. Jiang W, et al., Nature Nanotech 2008; 3:145.

選択的で効率的な薬剤のデリバリーにナノ粒子を用いることが検討されている。この論文では癌治療薬剤であるEGF受容体ErbB2のリガンドであるherceptinにより、2-100 nmの異なる粒子系の金粒子をコートし、癌細胞に対する効果を検討した。その結果、40-50nmの金粒子が最も効率的に癌細胞に取り込まれ細胞死を誘導することがわかった。

2. EFFECT OF 17q21 VARIANTS AND SMOKING EXPOSURE IN EARLY-ONSET ASTHMA
An increased risk of asthma is associated with specific DNA variants at the 17q21 locus. Genetic, medical and demographic data from 1511 subjects were examined for correlations with time of asthma onset. Of the 36 single-nucleotide polymorphisms (SNPs) analyzed, 11 were associated with asthma (p<0.01) and 3 were strongly associated (p<0.001). There was almost a 3-fold increase in risk of early-onset (≤4 yr of age) asthma with the strongest effect in subjects exposed to environmental tobacco smoke. There was no association with late-onset asthma. Editor's comment: The fact that chromosome variants can affect early-onset but not late-onset asthma suggests a difference in the pathogenesis of the two disease types. Bouzigon E et al., New Eng J Med 2008; 359:1.

染色体17q21に存在するORMDL3などの遺伝子群に存在するSNPはゲノムワイドな相関解析により喘息発症との強い関連が見いだされている。筆者らは17q21に存在する36のSNPについて解析した結果、11のSNPで喘息との有意な相関をみとめた。特に間接喫煙暴露に影響を受け4歳以下で発症する喘息に関しては3倍以上のリスクであり、強い相関があった。

3. SPUTUM EOSINOPHILIA, AIRWAY HYPERRESPONSIVENESS AND AIRWAY NARROWING IN YOUNG ADULTS WITH FORMER ASTHMA
Adolescents often outgrow asthma and appear to be symptom-free as young adults, but may later redevelop the disease. The question is whether those in remission are really disease free. Here, a group of 326 adults (age 21-34) were screened for asthma history and categorized according to those with current physician-diagnosed asthma, those with former asthma and those with no history of asthma. Participants who had been free of symptoms and taken no asthma medication for at least 10 years prior to the study were tested for FEV1, PC20, maximal mid-expiratory flow (MMF) and sputum eosinophilia. The results showed that former asthma patients in remission had significantly lower FEV1, PC20 and MMF and greater eosinophilia than subjects with no history of asthma. In addition, 18% of those with no history of asthma also showed decreased FEV1 and PC20. The long-term prognosis of these subjects needs to be examined. Editor's comment: This investigation brings up the question of whether treatment of symptom-free former asthmatics might prevent the reappearance of asthma. Hara J, et al., Allergology Internatl 2008; 57:211.

以前に喘息と診断され治療されていた21歳から34歳までの326名の成人について喘息既往のない成人を対照として呼吸機能等の検査を実施した。その結果、喘息の既往のあるものではFEV1, PC20や喀痰好酸球数が有意に増加していた。金沢大学呼吸器内科からに掲載された論文である(訳者注)。

4. RAPID EFFECT OF INHALED CICLESONIDE (CIC) IN ASTHMA
The purpose of this clinical trial was to determine how quickly CIC acted to decrease airway hyperresponsiveness (AHR), exhaled nitric oxide and eosinophilia in subjects with mild persistent asthma (FEV1≥70%). In this double-blind, placebo-controlled, crossover study, CIC was administered at 320 µg qd and 640 µg bid. Single doses of CIC gave significant reductions in AHR within 2.5 hr of administration, and there was no drop in serum cortisol and few oropharyngeal adverse events. Editor's comment: The rapid improvement in FEV1 within a few hours of CIC inhalation by subjects with mild asthma is impressive. Erin EM, et al., Chest 2008; 134:740.

シクレソニドは薬剤が肺で活性化される局所活性化型のプロドラッグである。我が国でも成人喘息に使用されている。この研究では喘息の急性発作に対する影響を検討している。シクレソニド単回投与により気道過敏性の改善が認められた。血清中のコルチゾールなどの副作用も認めなかった。遺伝子転写を介さない効果においてもシクレソニドは十分な抗炎症効果を示した。

5. ADRENAL SUPPRESSION IN BRONCHIECTASIS AND THE IMPACT OF INHALED CORTICOSTEROIDS (ICS)
A potential side effect of ICS is suppression of the hypothalamic-pituitary-adrenal axis resulting in a measurable decrease in serum cortisol. In this study, a group of 50 bronchiectasis patients, 33 of whom were on ICS, were tested for adrenal suppression using the short Synacthen test (SST) and for quality of life by the St George's respiratory questionnaire. Of the patients on ICS, 48.5% had adrenal impairment. These patients were more likely to report fatigue, dizziness, nausea, and vomiting than the non-suppressed group. The authors advocate caution in prescribing ICS for bronchiectasis patients, speculating that the presence of damaged airway walls may enhance systemic drug uptake. The dynamic SST for adrenal insufficiency is simple and effective and should be more widely used to monitor effects of ICS use. Editor's comment: This important finding in patients with bronchiectasis may also be applicable to other inflammatory airway diseases such as COPD and asthma in which ICS are commonly used. Holme J, et al., Eur Resp J 2008; 32:1047.

喘息に対する吸入ステロイドは血清コルチゾールの低下などの副作用もほとんどなく、安全性が高い薬剤と考えられている。しかし、気管支拡張症を合併している患者50名について調査したところ、48.5%の患者において有意な副腎機能低下が認められた。原因は不明だが、気道の障害の程度が強いと想像されている。

6. TOLL-LIKE RECEPTOR 4 POLYMORPHISMS AND ASPERGILLOSIS IN STEM CELL TRANSPLANTATION
Patients receiving allogeneic bone marrow transplant therapy are at increased risk of infection by opportunistic pathogens such as Aspergillus. This report looked at polymorphisms in the TLR-2, -3, -4 and -9 genes of the donors in relation to aspergillosis risk in recipients of allogeneic transplants. Only the TLR-4 SNP was a significant risk factor. TLR-4 recognizes bacterial lipopolysaccharide and the variant allele confers weaker immunoresponsiveness that may make an individual more susceptible to aspergillosis. Presence of the TLR-4 SNP in the recipient did not increase the risk. Editor's comment: The finding of a TLR-4 mutation in transplant donors that increases the incidence of aspergillosis in recipients is surprising because TLR-4 recognizes bacterial lipopolysaccharide. This suggests other microbial products may bind to TLR-4. Bochud P-Y et al., New Eng J Med 2008; 359:1766. (editorial: Pamer, pp. 1836)

骨髄移植を受けた患者ではアスペルギルス症のリスクが高い。その感染リスクとToll様受容体の遺伝子多型との相関を調べたところ、TLR4のSNPに変異のある人ではリスクが高いことが判明した。

7. AGEING AND THE IMMUNE SYSTEM
A series of review articles appeared in the August 2008 Current Allergy & Clinical Immunology that focus on the topics of immunosenescence¹, asthma and allergic diseases in the elderly² and inflammation, immunity and Alzheimer's disease (AD)³. As the average age of the world's population increases, the effects of ageing on the body's systems become more and more important. Immunosenescence, the gradual decline in immune response with advancing years is partly due to thymic insufficiency but also in large part to environment, diet, stress, exercise, infections, smoking and other factors that may be controllable. Improved vaccines are one answer to reduced immunocompetence in the elderly, but studies need to be done to define immunoprotective interventions that can be done to prolong the longevity of the immune system. Asthma and rhinitis present special problems in the elderly because of complications in diagnosis, comorbid conditions and potential drug interactions. Immune components of Alzheimer's disease are still being elucidated. Anti-amyloid therapies are being tested but remain experimental. The one characteristic feature tying immune responsiveness to AD, Parkinson's and other neurodegenerative disorders is the inflammatory status. Inflammation in the brain may be affected by age-related immune system changes in the periphery. Editor's comment: Research focused on understanding the ageing process as it relates to the immune system and new ways to intervene prophylactically and therapeutically should be one of the major goals of medical science in this century. ¹Kalula SZ, et al., Curr Allergy Clin Immunol 2008; 21:126-130. ²De Villiers L, et al., 120. ³Combrinck M, et al., 132.

骨髄移植を受けた患者ではアスペルギルス症のリスクが高い。その感染リスクとToll様受容体の遺伝子多型との相関を調べたところ、TLR4のSNPに変異のある人ではリスクが高いことが判明した。

8. ANALYSIS OF SAFETY, RISK FACTORS AND PRETREATMENT METHODS DURING RUSH HYMENOPTERA VENOM IMMUNOTHERAPY (VIT)
VIT is a safe and effective method of inducing tolerance in persons with a history of sting reactions, but severe adverse events (SAEs) do occur. This retrospective study examined records from a single institution of 118 patients with a history of anaphylactic reaction undergoing a 5-day rush VIT and found side effects in 18 (15.2%) with SAEs in 7 (5.9%). The number of reactions was highest on the 4th day (100 µg/ml allergen) and highest among females. All patients received H1 receptor antagonist and 45 also received H2 antagonist. Those pretreated with H1 antagonist alone had fewer systemic effects than those getting both H1 and H2 antagonists. Editor's comment: Rush VIT is less costly and time-consuming than conventional VIT and warrants additional studies to enhance tolerogenesis without causing potentially severe reactions. Gorska L et al., Internatl Arch Allergy Immunol 2008; 147:241.

ハチ毒に対する急速免疫療法に関して検討した。通常の免疫療法に比べ、時間的にもコスト的にも節約できたとしている。また、注射時にH1アンタゴニストとH2アンタゴニストを服用することが多いが、H1アンタゴニスト単独投与の方が副反応が少なかった。

9. FLUTICASONE PROPIONATE (FP) REDUCES BACTERIAL AIRWAY EPITHELIAL INVASION
COPD patients receiving FP experience less severe bacterial exacerbations but the mechanism is unknown. Both S. pneumoniae (S. p.) and H. influenzae (H. i.) enter bronchial epithelial cells through binding to platelet activating factor receptor (PAFR). PAFR is elevated in the airways of COPD patients. These individuals are also commonly infected with S. p. and H. i. In this study, cultured human epithelial cell lines, A549 and 16HBE14o-, were treated with various doses of FP then challenged with S. p. or H. i. PAFR levels and intracellular bacterial loads were reduced by FP. FP (10 µg/mouse) was also tested on mice prior to inoculation with S. p. and reduced lung colonization nearly 50%. Similar results were obtained when cells or mice were pretreated with a PAFR antagonist rather than FP. Editor's comment: Further studies need to be undertaken to pinpoint the mechanism of FP action on PAFR and to examine long-term effects. Barbier M et al., Eur Resp J 2008; 32:1283.

慢性閉塞性肺疾患COPD患者ではフルチカゾン投与を受けていると感染症が減少した。肺炎球菌やインフルエンザ杆菌は気道上皮の血小板活性化因子PAF受容体を通して肺に進入する。COPD患者ではPAF受容体が増加しているがフルチカゾン投与により肺の細菌の沈着は50%減少した。動物実験においてPAF受容体アンタゴニストよりもフルチカゾン投与を行った方が効果は高かった。

10. THE SAFETY OF LONG-ACTING β-AGONISTS (LABAs) AMONG PATIENTS WITH ASTHMA USING INHALED CORTICOSTEROIDS (ICS)
Several studies support the claim that LABAs increase mortality in asthma patients, but much of these data come from cases in which ICS were not used regularly in combination with LABAs. In this review, a search was done for blinded, randomized, controlled trials of patients using ICS with or without concomitant LABAs. Analysis of 62 such studies involving over 29,000 participants revealed 3 asthma-related deaths and 2 asthma-related intubations, all among those using LABAs. These numbers were too low to permit statistical analysis. The risk of hospitalization or serious adverse affects was not increased with LABA use in those patients regularly using ICS. Editor's comment: Because of the low incidence of mortality, caution is advised in forming conclusions based on these data in comparison to other published analyses. Jaeschke R et al., Am J Respir Crit Care Med 2008; 178: 1009.

LABAの使用は喘息死のリスクを増加させると報告されているが、多くは吸入ステロイドを使用していない患者に対する検討である。本研究では吸入ステロイドを使用した患者に対して比較対照試験を行った。その結果、喘息死は名にみられたが、統計学的な有意差を検討する十分な数に達していなかった。

11. ASSOCIATION OF ANGIOTENSIN I-CONVERTING ENZYME (ACE) GENE POLYMORPHISMS WITH ASPIRIN INTOLERANCE IN ASTHMATICS (AIA)
AIA affects 5-10% of asthmatics and is associated with increased leukotriene levels. An additional pathway involving ACE may contribute to AIA. A cohort of 581 Korean asthmatics (81 with AIA) and 181 healthy controls were screened for a panel of mutations in the ACE gene. No correlation between a specific single nucleotide polymorphism (SNP) in the ACE gene and the presence of asthma was seen. Among those with AIA there was a significantly greater frequency of two ACE promoter mutations. AIA patients homozygous for the promoter SNPs showed a larger drop in FEV1 after aspirin challenge than those with the normal alleles. Fusing the mutant promoter sequence to a luciferase reporter resulted in a significant decrease in luciferase activity compared to a normal promoter, which suggests that those who are homozygous for this mutation produce less ACE and may have accumulations of inflammatory mediators that predispose them to AIA. Editor's comment: This new information on genetic susceptibility to AIA may be useful in designing new therapies. Kim T-H et al., Clin Experimental Allergy 2008; 38:1727.

アンジオテンシン転換酵素の遺伝子多型がアスピリン誘発喘息の発症と関連していた。

12. DACLIZUMAB (DAC) IMPROVES ASTHMA CONTROL IN PATIENTS WITH MODERATE TO SEVERE PERSISTENT ASTHMA
DAC is a humanized antibody specific for CD25, the IL-2R alpha subunit. DAC blocks binding of IL-2 to its receptor inhibiting subsequent signaling events. In this randomized, double-blind, placebo-controlled multicenter trial, patients with moderate to severe persistent asthma on ICS were switched to an equivalent dose of triamcinolone acetate acetonide (TAA) during the run-in period and given i.v. injections of DAC (90 subjects) or placebo (30 subjects) every 2 weeks during the study. After the first 12 weeks, the TAA dose was tapered 25% every two weeks for 12-20 weeks. Changes in FEV1, frequency and severity of asthma exacerbations, PEF, use of rescue medication and symptom scores were monitored. DAC treatment resulted in significant improvements in FEV1 and daytime symptom scores, decreased use of rescue meds, lower numbers of peripheral eosinophils and reduced eosinophilic cationic protein. The frequency of common adverse events was similar for DAC and placebo groups; however, 5 of 6 patients experiencing severe adverse events were on DAC. Editor's comment: While DAC improved asthma symptoms, the study needs to be repeated to confirm these results and to evaluate the potential safety issues. Busse WW et al., Am J Resp Crit Care Med 2008; 178:1002.

DACLIZUMABはCD25, IL-2受容体に対するヒト化抗体である。中等症から重症の喘息患者に対して使用したところ、FEV1や昼間の症状などで有意に改善を認めた。しかしキメラ抗体であるため6名で自己抗体が増加し、そのうち5名に強い副反応が見られた。

13. THE OBESITY PARADOX IN PATIENTS WITH PERIPHERAL ARTERY DISEASE (PAD)
In contrast to the general population, overweight patients with PAD have lower mortality than underweight patients. This report classified 2392 PAD patients undergoing vascular surgery into groups according to their BMI and whether they had COPD. Death from all causes was the outcome measured and follow-up was from about 2 to 8 years. Nearly 50% of the patients had evidence of COPD. Underweight patients (2.6% of the total) were more likely to have moderate to severe COPD (40% of the group) and to be smokers. COPD was present in 25% of the overweight group and 22% of the obese group. After adjusting for a number of factors, the underweight subjects were 1.42 times as likely as normal weight subjects to die, while the underweight and obese patients were 0.73 and 0.68 times as likely to die, respectively, than normals. This inverse BMI relationship to mortality was eliminated when the data were corrected for COPD severity. Editor's comment: The results of this interesting study suggest that spirometry measurements on PAD patients might be useful for identifying undiagnosed COPD. Galal W et al., Chest 2008; 134:925.

末梢動脈疾患を合併した肥満患者はCOPDのリスクも1.42倍高かった。しかし、体重の少ない場合は肥満のみの場合は、リスクは0.73, 0.68と低いことがわかった。

World Allergy Congress (WAC) 2009 - Buenos Aires, Argentina,  6-10 December 2009

Deadlines

Abstract Submission: 11 May 2009
Click here to submit your abstract online

Early Registration: 11 May 2009
Online registration will be available soon!


Medical Book Review

Immunology, Infection and Immunity
2004 American Society for Microbiology (ASM) Press
Editors: Gerald B. Pier, Jeffrey B. Lyczak, Lee M. Wetzler
ISBN: 978-1-55581-283-6

今月の書籍紹介は感染と免疫に関する本である。よく書かれているが専門家、研究者向けであり学生には難しい。

Available from: ASM Press
$79.95 or $89.95 when bundled with Digital Learning Guide

Reviewer:
James J. Yun, MBBS
Immunology & Allergy
Campbelltown Hospital
Cambelltown, New South Wales
Australia

Description
While there are many textbooks that attempt to describe the complex immune system in great details, there are few, if any, that focus on one of the key roles of immune system - immunity from infection. Immunology, infection, and immunity deals with this ongoing struggle between infectious agents and host defence system. It approaches this topic mainly from an immunology point of view without neglecting components of infection. As a standalone textbook in immunology, it faithfully explains various components of immune system in depth like many others. While it provides a solid description of immune system's interaction with pathogens, it is weaker on the specific details of infectious agents themselves. Then again, this is not a microbiology textbook. As an immunology textbook, it has chapters on immune system dysfunction. They are not heavy in details but they do provide a concrete description of these complex subjects.

Purpose
The purpose is to provide the reader with a detailed description of the immune system, its role in maintaining immunity and its dysfunction in terms of infection and other immunological conditions.

Audience
The textbook is suitable for clinicians and researchers with a special interest in the discipline of immunology and microbiology. Medical students may find it too heavy but the texts are quite a good reading and the illustrations are excellent. This book will be a useful adjunct to a library. Certain sections of the book will provide useful materials for in-depth reading at both undergraduate and graduate level curriculum..

Features
The first half of the book is devoted to the description of various components of immune system. It is well written, sufficiently detailed, great in illustrations and exceptional in tying the immune system with infection, especially at molecular level. The second half of the book describes the ongoing struggle between host defence mechanism and various pathogens. It provides a good overview and principles of immunity but lacks in details of specific pathogens. The last section of the book provides a brief but solid review of immune dysfunctions in terms of immunodeficiency, cancer immunology, immune overactivity and transplantation. Its strength is in explaining the role of immunology in the pathogenesis of diseases but it is lacking in clinical description and management.

Assessment
While Immunology, infection, and immunity is not the most comprehensive immunology textbook in either breadth or depth, it provides an excellent explanation of the immune system in its role in maintaining immunity and the mechanisms by which infectious agents overcome this immunity. As a stand alone immunology textbook, it is not lacking in any way. However, it is certainly not a clinical textbook but rather describes the connection between the discipline of immunology and microbiology from an immunological perspective.

Find more allergy book reviews on the WAO Website here.

WAO JournalDecember 2008

Editorial
One Year with WAO Journal
Johannes Ring; Lanny Rosenwasser

Original Study
Delayed-type heparin allergy: diagnostic procedures and treatment alternatives. A case series including 15 patients
Claudia Pföhler, M.D.; Cornelia S Müller, MD; Gerhard Pindur, MD; Hermann Eichler, MD; Hans-Joachim Schäfers, MD; Ulrich Grundmann, MD; Wolfgang Tilgen, MD

Original Study
Asthma in a Primary Health Care Center serving a poor population. A descriptive and interventional study.
Eloisa Malbrán, Student; Graciela L Rey, MD; Alejandro Malbrán, MD PhD

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