WAO News and Notes - Medical Reviews
Volume 6, Issue 1 Reviews - January 2009
Announcing the WAO Web Site's new look at www.worldallergy.org
Medical Journal Reviews

Reviewed by Gary Hellerman, PhD, in collaboration with Richard F. Lockey, MD, WAO Web Chief Editor.

今月の医学雑誌レビューの担当はGary Hellerman 博士とRichard F. Lockey 博士による。

1. Cigarette smoke combined with Toll-like receptor 3 (TLR3) signaling triggers exaggerated epithelial RANTES (regulated upon activation, normal T-cell-expressed and -secreted)/CCL5 expression in chronic rhinosinusitis (CRS).
Patients with CRS often suffer acute bacterial infections suggesting that a defect in innate immunity might be associated with the disease. In this study, epithelial cells from middle turbinate biopsies of 9 healthy persons and 11 CRS patients were cultured. The cells were exposed to cigarette smoke extract (CSE) or medium then stimulated with lipoteichoic acid (TLR2 agonist), lipopolysaccharide (TLR4) or double-stranded RNA (TLR3), and analyzed for TLR-2, -3 and -4 expression. CSE alone stimulated RANTES production 35-fold in CRS patients but not in healthy controls. The greatest increase in RANTES (12,115-fold) was seen in nasal epithelial cells treated with CSE and double-stranded RNA (dsRNA) compared to a 1500-fold increase in cells from healthy controls. IL-1β, IL-6 and IL-8, TNF-α, HBD2 and MCP-2 were all synergistically increased by CSE plus dsRNA. Exacerbations of CRS may be more severe in smokers because of CSE-induced excess RANTES production. Editor's comment: Although the mechanism whereby RANTES might contribute to CRS in viral infection is unclear, the large increase in CSE-induced RANTES seen here merits further study in vivo. Yamin M, et al. J Allergy Clin Immunol 2008; 122:1145-1153.

慢性鼻副鼻腔炎患者の気道上皮では喫煙とToll 様受容体(TLR)3 刺激により相乗的にケモカインRANTES の分泌が増加した。つまり、このような患者がウイルスによる呼吸器感染をおこした際に喫煙をすると炎症がさらに増悪するという可能性を示している。

2. The asthma-mental health nexus in a population-based sample of the United States.
This study examines the likelihood of having current asthma in an adult cross-section of the U.S. population with perceived mental health problems. The Behavioral Risk Factor Surveillance System (BRFSS) survey was used to assess mental health and to place subjects into one of five categories from 0 days per month of poor mental health to 22 to 30 days per month. Asthma status was assigned by asking subjects if a physician had ever told them they have asthma and whether they have asthma now. Other factors considered included overall health status, urban environment, age, gender, smoking status, obesity, exercise, socioeconomic level, ethnicity and marital status. The entire BRFSS database of 355,710 subjects was screened using a multinomial logistic regression model to determine correlation between mental health and asthma. Women reported worse mental health than men, and any history of smoking correlated with a reduction in mental health, as also did poor overall health, lack of exercise, and obesity. The odds of having asthma showed a "dose response" as the number of days of poor mental health per month increased from 1.38 for ≤ 1 week of poor mental health to 2.75 for ≥ 3 weeks per month. Editor's comment: A relationship between asthma and mental health has been proposed for many years and this study adds significant information to the analysis, but the exact mechanism remains elusive. Chun TH, et al. Chest 2008; 134:1176-1182.

喘息と心理状態の関係について大規模調査が行われた。女性は男性よりも悪い心理状態である日数(一ヶ月中)が多く、彼らの喫煙歴はそのほかの健康状態の悪化、肥満などと関係していた。喘息罹患のオッズ比と心理状態の悪化日数は” 用量依存的” であった。

3. Relationship between gastroesophageal reflux disease (GERD) and COPD in UK primary care.
Patients with a first diagnosis of GERD or COPD were identified from the UK General Practice Database and the incidence of combined GERD/COPD in the diagnosed group over a five-year follow-up was compared with that in a matched healthy cohort. Medication use, comorbidities, demographics and lifestyle factors were also examined. The relative risk of COPD in GERD patients was 1.17 while the risk of GERD in COPD patients was 1.46. Older patients (≥ 70 years) with GERD were 3.7 times as likely as controls to be diagnosed with COPD. A prior diagnosis of asthma was also associated with increased risk of COPD in GERD patients (odds ratio, 10.9). Editor's comment: The complex interrelationship between GERD, asthma and COPD needs to be examined carefully when assessing a patient's diagnosis and medication requirements. García-Rodríguez LA, et al. Chest 2008; 134:1223-1230.

英国において胃食道逆流症GERD と慢性閉塞性肺疾患COPD それぞれの患者について両者の合併に関する5年間の追跡調査が行われた。COPD 患者がGERD を獲得する相対リスクは1.17 で、GERD 患者がCOPD を合併する相対リスクは1.46 であった。70 歳以上のGERD 患者ではCOPD 罹患リスクは3.7 倍であった。また、喘息の既往のあるGERD 患者のCOPD 罹患リスクは10.9 倍であった。

4. Clinical and molecular profile of a new series of patients with immune dysregulation, poly endocrinopathy, enteropathy, and X-linked syndrome (IPEX): Inconsistent correlation between forkhead box protein 3 (FOXP3) expression and disease severity.
IPEX is a rare disease caused by mutations in the FOXP3 gene. It is characterized by a range of symptoms including diarrhea, chronic dermatitis, diabetes and thyroiditis. FOXP3 is principally expressed on regulatory T cells but also on effector T cells and FOXP3 deficiency compromises immune tolerance. Fourteen patients with early-onset IPEX were screened for FOXP3 mutations and expression level. Seven of the patients had previously identified FOXP3 gene mutations and the other seven had novel mutations. In five of eight IPEX patients tested, FOXP3 protein levels were not affected although FOXP3 mutations were present and IgE and eosinophils were elevated. Diagnosis of IPEX should be made based on genetic analysis for FOXP3 mutations rather than on measurement of FOXP3 protein. Editor's comment: Although IPEX is relatively rare, infants with enteropathy or diabetes and elevated IgE should be genotyped for FOXP3. Gambineri E, et al. J Allergy Clin Immunol 2008; 122:1105-1112.

制御性T 細胞の分化を決定する分子FOXP3 の遺伝子欠損で重篤なアレルギー症状や免疫異常を示すIPEX 症候群の14 例(独立した家族例)についての報告である。FOXP3 の遺伝子の変異部位はそれぞれの患者で異なり、重篤な症状を示しているのにも拘わらずFOXP3 蛋白質量が正常の患者も存在していた。

5. Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D2 (PGD2) production.
Mast cell activation disorder (MCAD) produces symptoms similar to those experienced by patients with systemic mastocytosis (SM)-flushing, palpitations, light-headedness, syncope, and chest pain among others. Exercise-induced or idiopathic anaphylaxis can also mimic MCAD. This retrospective review of four patients with excessive prostaglandin D2 (PGD2) release sought to determine if MCAD was the cause. None of the patients had evidence of SM in bone marrow biopsies and histamine was not released during exacerbations. Baseline levels of PGD2 were normal to slightly elevated but increased significantly during activation episodes. Symptoms were effectively reduced by aspirin treatment. Editor's comment: Whether MCAD is an entity separate from idiopathic anaphylaxis is still controversial, but the absence of histamine release in these MCAD patients may be distinctive. Butterfield JH and Weiler CR, Int Arch Allergy Immunol 2008; 147:338-43.

マスト細胞の活性化による疾患Mast cell activation disorder (MCAD) とはマスト細胞増殖性疾患であるsystemic mastocytosis (SM) のような発赤、頻脈、胸痛、あるいは運動誘発性アナフィラキシーなどの症状を呈する。著者らは(ヒト・マスト細胞株HMC-1 の樹立者として知られている)4 例の患者についてまとめ、特徴を記載している。SM と異なりMCAD では、症状増悪の際のヒスタミン遊離がみられないが、プロスタグランディンPGD2 の増加を認めた。

6. Evidence of a causal role of winter virus infection during infancy in early childhood asthma.
Infant bronchiolitis has been linked to later onset of asthma and most commonly associated with viral respiratory tract infections, so it is not unreasonable to suppose that the season of birth may influence the risk of asthma. To test this hypothesis, the medical histories of a group of 95,310 children from birth to about 5 ½ years of age were examined for a correlation between age at time of first winter virus infection peak and development of high-risk asthma as defined by one or more hospitalizations or ER visits or a course of corticosteroids. Infants between the ages of 118 and 126 days at the time of winter virus peak had the highest risk of significant bronchiolitis, and those 118 to 131 days old at virus peak had the greatest likelihood of developing high-risk asthma-about 30% higher than infants who were one year old at peak. The timing of the age at highest risk shifted in synchrony with variation in the date of peak virus infections. Viral bronchiolitis at about 4 months of age could produce a chronic inflammation with long-lasting effects on lung development and immune maturation. Editor's comment: The significant correlation between age at time of winter virus peak and incidence of asthma suggests a strong potential for therapeutic intervention and avoidance of infection in this group of children. Wu P, et al. Am J Resp Crit Care Med 2008; 178:1123-1129.

生後118-131 日目つまり生後約4 ヶ月の頃に呼吸器ウイルス感染をおこすと、その後の喘息診断のリスクが30% 増加する。つまり、呼吸器ウイルスに感染しやすい冬季をむかえる晩夏から秋に生まれた子供もリスクが高くなるということが想像される。

7. Inhaled corticosteroids (ICS) in patients with stable chronic obstructive pulmonary disease (COPD).
COPD affects 10-15 million people in the U.S. and is the fourth leading cause of death. This meta-analysis of the existing literature on the use of ICS by stable COPD patients focused on 11 randomized controlled trials involving a total of 14,426 participants. ICS use did not decrease mortality during follow-up periods of up to three years and was associated with a 34% increase in the incidence of pneumonia. However, ICS did improve quality-of-life scores for COPD but did not increase the fracture rate. The analysis suffered from some limitations in that an unequivocal distinction between pneumonia and COPD exacerbation was not always made and there was considerable diversity in the type and dosage of ICS used. Thus, it is always necessary to weigh the risks in COPD of increased respiratory infection against the benefits of improved quality of life. Editor's comment: In spite of the limitations of this meta-analysis, the results raise important questions about the use of ICS to treat stable COPD. Drummond MB, et al. JAMA 2008; 300:2407-2416.

COPD に対する吸入ステロイド治療に関するメタ解析(最も強いエビデンスとなる)の論文。報告されているように吸入ステロイド薬はCOPD の死亡率を低下させることはないが、QOL の改善には有効であった。

8. Asthma and allergic symptoms in relation to house dust endotoxin: Phase Two of the International Study on Asthma and Allergies in Childhood (ISAAC II).
Six centers in five different countries supplied data on the incidence of asthma and atopy in 840 children, age 9 to 12 years, in relation to endotoxin levels in living room floor dust. Standardized questionnaires were used for demographics, wheezing, allergy and eczema, and atopy was defined as serum IgE reaction to one or more airborne allergens. Overall, there was an inverse relationship between exposure to dust endotoxin levels in this age group and both atopic and non-atopic asthma, but not hay fever. Editor's comment: The controversy over whether endotoxins protect against or exacerbate asthma continues, but this study provides substantial evidence of a protective effect among children in a wide range of settings. Gehring U et al. Clin Experimental Allergy 2008; 38:1911-1920.

寝室のエンドトキシン量と9-12 歳の喘息、アトピー感作、花粉症発症に関して大規模な調査が実施された。その結果、寝室のエンドトキシン量はIgE 依存性および非依存性の喘息と逆相関していたが、この年齢では花粉症との関連は見いだせなかった。

9. ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma.
Asthma is more common in males before puberty but in females afterwards suggesting a protective effect of androgens. Leukotrienes (LTs) are proinflammatory molecules synthesized by 5-lipoxygenase (5-LO) primarily by neutrophils (NPs). Isolated NPs from female blood produced more LT-B4 than those from male blood when stimulated. In female NPs, 5-LO was localized in the cytoplasm and moved to the nucleus upon stimulation. In male NPs, 5-LO was present in both cytoplasm and nucleus but the location did not change after stimulation. The nuclear localization of 5-LO is dependent on dihydrotestosterone (DHT) and DHT suppresses LT synthesis by female NPs. Extracellular-regulated kinases (ERK1/2) were more active in male NPs, and inhibition of ERKs caused 5-LO to become cytosolic and to migrate to the nucleus as in female NPs. Editor's comment: The suppressive effect of DHT on 5-LO suggests that treatment with LT antagonists such as montelukast may have to be optimized according to sex. Pergola C, et al. Proc Nat Acad Sci 2008; 105:19881-19886.

男性と女性の好中球からのロイコトリエンB4 の産生を比較したところ、女性の好中球からより多く産生された。それはアンドロゲンの作用によりExtracellular-regulated kinases (ERK1/2) が活性化され、ERK はロイコトリエン合成酵素5-lipoxygenase (5-LO) の核内移行を阻害するためであった。

10. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease (COPD) exacerbations.
Frequent exacerbations in COPD patients cause rapid disease progression and poor prognosis. This randomized, double-blind, placebo-controlled trial tested long-term use of erythromycin (EM) to reduce COPD excacerbations. COPD patients (n = 115) with FEV1 30% to 70 % of predicted received either placebo or 250 mg EM twice a day for one year. Most patients were using corticosteroids at the time of the study and were allowed to continue with them. Blood and sputum samples were taken for analysis of IL-6, IL-8, C reactive protein and myeloperoxidase and spirometry was done at each visit. Subjects kept a symptom diary and reported exacerbations as soon as they occurred. One year EM treatment reduced exacerbation frequency, duration and symptom severity and caused no adverse side effects. No change in FEV1, sputum inflammatory markers or bacterial colonization was seen. Editor's comment: The use of macrolide therapy seems to be indicated as a well-tolerated way to reduce COPD exacerbations. Seemungal TAR, et al. Am J Resp Crit Care Med 2008; 178:1139-1147.

長期間のエリスロマイシン療法はCOPD 増悪に対して有効であった(訳者注:日本で開発された治療法であるが、大規模治験を実施しやすい海外で実施されると、一流雑誌に掲載されるようだ)

11. Increased gastrointestinal permeability and gut inflammation in children with functional abdominal pain and irritable bowel syndrome (FAP/IBS).
In this study, children aged 7 to 10 years with FAP/IBS were studied to determine if symptom severity could be correlated with GI permeability and inflammation. The Pediatric Rome II criteria for FAP and IBS were used to rate the pain frequency and intensity. Gut inflammation was measured as fecal calprotectin levels and stooling patterns were recorded by diary. The subjects included 109 children with FAP/IBS and 66 controls. Calprotectin was higher in FAP/IBS patients indicative of greater gut inflammation than healthy controls. Permeability of the proximal GI and colon as measured by sugar recovery was greater in FAP/IBS subjects. No correlation was found between GI permeability and pain levels, and increased GI inflammation was associated only with increased pain-related interference with activity. Editor's comment: The results of this study suggest that the relationship between GI permeability, inflammation and abdominal pain in children is complex. Shulman RJ, et al. J Pediatr 2008; 153:646-650.


12. Effects of average childhood dairy intake on adolescent bone health.
Supplementary calcium increases bone mineral content (BMC) in children during the bone-building phase but there have been fewer studies on the effects of dairy intake on BMC. This report examined the Framingham Children's Study data in terms of dairy intake during childhood compared to BMC, area and density measured when the children were 15 to 17 years old. BMC was determined by scan over the entire body and was used rather than BMD which is subject to error in children with larger bones. Children who ate more than two servings of dairy products a day had higher BMC and bone area than those eating less. Children who ate more dairy and had more than 4 servings per day of meat or other protein had the highest BMC and area. Editor's comment: This longitudinal study of the Framingham data reiterates the importance of adequate protein (meat) and dairy products on adolescent bone health. Moore LL, et al. J Pediatr 2008; 153:667-673.


13. Clinical and immunologic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy (BVIT).
Patients undergoing BVIT are commonly given antihistamine treatment to reduce the risk of systemic allergic side effects. In this study, the effectiveness of BVIT in the presence of the histamine receptor-1 (HR1) blocker, levocetirizine (LC), was compared to placebo. BVIT patients (n = 54) were given LC from two days before BVIT to day 21 and examined for systemic allergic reactions (SARS) and allergen-specific immunity by skin test, serum Abs and cultured T cell activity. SARS were observed significantly more frequently in the placebo group with a higher use of rescue medications. The efficacy of BVIT was not altered by LC administration. Editor's comment: The potential contribution of antihistamine treatment to development of allergen tolerance needs to be better defined. Muller UR, et al. J Allergy Clin Immunol 2008; 122:1001-1007.

H1 ヒスタミン受容体拮抗薬をハチ毒の抗原特異的免疫療法の際に前投与しておくと全身性のアレルギー反応のリスクが有意に低下した。

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


Abstract Submission: 11 May 2009
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Medical Book Review

Janeway's Immunobiology, Seventh Edition
2007 Garland Science / Taylor & Francis Group
Edited by Kenneth Murphy, Paul Travers and Mark Walport
ISBN: 978-0-8153-4123-9

Immunobiology の第 7 版の紹介である。この教科書の最初の編集をおこなったCharles A. Janeway の思い出のために Janeway's Immunobiology >と改名されている。下の記事にも 美しいイラストのパワーポイントの付録で知られており、実際、訳者も学生への講義にこれらのイラストを最も頻繁に使用している。

Available from: Garland Science
$95.95 USD for Book and CD-ROM

Dr Sandhya Limaye, MBBS FRACP FRCPA
Department of Immunology
Liverpool Hospital
Liverpool, New South Wales

Retitled Janeway's Immunobiology in memory of Charles A. Janeway who originated this classic textbook series, the seventh edition of Janeway's Immunobiology provides a comprehensive introduction to, and overview of all aspects of the immune system in both health and disease. All chapters have been revised for the seventh edition, with the inclusion of updates on areas such as NK cells, Toll-like receptors, the role of AID in antibody diversity, antigen cross-presentation and celiac disease to highlight just a few.

The textbook is designed to increase the reader's understanding of the complexities of the immune system presented from the perspective of its basic protective function in mediating interactions between host and environment. This allows for a consistent approach to the discussion of diverse aspects of immunology such as allergy, graft rejection and tumour immunology which are introduced as variations in the presented antigen.

The book is aimed as an introductory text to a target audience of medical students, undergraduate and graduate biology students and other scientists. However its extensive coverage of innate and adaptive immunobiology, an overview of in vivo and in vitro diagnostic immunoassays, and updated clinical chapters ensures its appeal to a much broader readership, including clinical immunologists and others with expertise in the field.

The breadth of information required of an introductory immunology textbook is covered well, with the organization of the text into clearly divided parts and chapters. The writing style is simple and easy to understand, and well-complemented by numerous colour diagrams and tables on almost every page. Extensive and up-to-date reference lists at the conclusion of each chapter are also helpfully subdivided into chapter sections, and direct the interested reader to both current and topical research findings as well as comprehensive published reviews. Five appendices in mostly tabulated format allow for the inclusion of detailed but readily accessible information on topics such as CD antigens and an extensive list of cytokines.

The highly acclaimed accompanying CD-ROM, Immunobiology Interactive, from previous editions is once again a standout feature. It includes all figures and tables from the book pre-loaded into Powerpoint® slide format, thus providing an invaluable resource to anyone delivering educational lectures or multi-media presentations. Of even greater visual appeal on the disc however, are the updated and enhanced immunological animations and videos with voice-over narration.

This is an outstanding textbook of immunology that thoroughly deserves its reputation as an authoritative, accurate and up-to-date standard. It is highly recommended as either an initial introduction to immunology, as well as to those wishing to further their knowledge and develop a deeper understanding of the subject.

Find more allergy book reviews on the WAO Website here.

WAO JournalWorld Allergy Organization Journal
January 2009

The State of SLIT
Lanny J. Rosenwasser, Johannes Ring

Original Study
Monitoring and management of childhood asthma in Asian countries: a questionnaire study
Belle Wong, Colin Tan, Bee Wah Lee, Hugo Van Bever, and the APAPARI Study Group

Original Study
Immediate hypersensitivity to common food allergens - An investigation on food sensitization in respiratory allergic patients of Calcutta, India
Jyotshna Mandal, Mahasweta Das, Indrani Roy, Soma Chatterjee, Minai Chandra Barui, and Swati Gupta-Bhattacharya

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