WAO News and Notes - Medical Reviews
Volume 5, Issue 11 Reviews - November 2008
Announcing the WAO Web Site's new look at www.worldallergy.org
Medical Journal Reviews

Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief reviewed premier medical journal articles for practicing allergists.

実地医家のための今月の医学雑誌レビュー

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

1. EFFECT OF PHARMACOTHERAPY ON RATE OF DECLINE OF LUNG FUNCTION IN COPD - RESULTS FROM THE TORCH STUDY
This study investigates the effects of combined salmeterol (S) 50 μg plus fluticasone propionate (F) 500 μg (SF), either S or F alone or placebo (P), on the rate of post-bronchodilator FEV1 decline in patients with moderate or severe COPD. 5,343 of 6,112 patients in the TORCH Study were included in the analysis of randomized, DBPC data. Spirometry was measured every 24 weeks for three years and there were 26,539 on-treatment observations. The adjusted rate of decline in FEV1 was 55 ml/year for P, 42 ml/year for S, 42 ml/year for F, and 39 ml/year for SF (95% confidence interval, 7-25; P <0.001). Rates of decline were similar among the active treatment arms. Decline rates were the greatest in current smokers and patients with a lower body mass index. Treatment with SF or S or F reduces the rate of decline in FEV1 in patients with moderate to severe COPD. Editor's comment: Treatment with S, F, or SF decreases the decline in FEV1 in COPD. Celli BR, et al., Am J Respir Crit Care Med 2008;178:332. (editorial: a Suissa, pp. 322)

5千人以上のCOPD患者を対象にサルメテロール、フルチカゾン、合剤の効果を対照比較盲検にて検討した。その結果、プラセボに比して、これらの薬剤投与は経時的な気管支拡張剤吸入後のFEV1の減少を抑制することが示された。

2. A 4-YEAR TRIAL OF TIOTROPIUM (T) IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
This randomized, DBPC trial compared four yrs of therapy with either T or placebo (P) in patients with COPD permitted to use all respiratory medications except inhaled anticholinergic agents. A total of 5993 patients (mean age, 65±8 yrs) with a mean FEV1 of 1.32±0.44 liters after bronchodilation (48% of predicted value) participated. 2987 were assigned to T and 3006 to P. Mean absolute improvements in FEV1 in the T group were maintained compared to P (P <0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV1 before and after bronchodilation were not significant. The mean absolute total score on the St. George's Respiratory Questionnaire (SGRQ) was lower in the T group at each time point throughout four yrs. At four yrs and 30 days, T was associated with a reduction in the risks of exacerbations, related hospitalizations and respiratory failure. The authors conclude that T is associated with improvements in lung function, quality-of-life (QOL), and exacerbations during a four yr period but does not reduce the rate of decline in FEV1. Editor's comment: T is an excellent medication to treat COPD. Tashkin DP, et al., N Engl J Med 2008;359:1543.

5千人以上の患者を対象として抗コリン薬tiotropiumのCOPDに対する効果を4年間観察した。その結果、投与後30日までは気管支拡張剤吸入後のFEV1値はプラセボと比して有意に優れていた。4年後の発作、入院、QOLは有意に優っていた。

3. ALLERGEN IMMUNOTHERAPY (AI): WHAT CAN AND CANNOT BE MIXED?
Grass pollen allergens are most susceptible to proteases. Fungal and insect allergenic extracts contain the highest levels of proteases and should be separated from pollen extracts, particularly grass extracts, unless otherwise indicated by the manufacturer. Grass allergens can be mixed with U.S. manufactured dust mite extracts at concentrations for optimal therapeutic outcomes. These mite extracts contain relatively low protease content since they are derived from 99% pure mite bodies as compared to European extracts which contain higher levels of protease because they are derived from spent cultures. An AAAAI committee investigated the stability of an extract containing standardized dust mite, cat hair, short ragweed pollen, and timothy grass pollen. The optimal concentration for immunotherapy retained potency for up to one year when stored at 2ºC to 8ºC. A figure is included indicating which extracts should or should not be mixed with others. Editor's comment: This is a short, easily understood treatise on allergen extracts and compatibility in a mixed vaccine. Esch RE, J Allergy Clin Immunol 2008;122:659.

アレルゲン特異的免疫療法のエキスの中には草本花粉のように蛋白分解酵素の影響を受けやすいものから真菌や昆虫のアレルゲンエキスのように蛋白分解酵素活性の強いまのまで様々である。この論文は米国アレルギー学会の委員会による総説で、混合してよいエキスとそうでないエキスについて解説している。

4. WHEEZING RHINOVIRUS (RV) ILLNESSES IN EARLY LIFE PREDICT ASTHMA (A) DEVELOPMENT IN HIGH-RISK CHILDREN
259 children (one parent was required to have a positive aeroallergen skin test and A) were followed prospectively from birth to six years of age during which time the etiology and timing of specific viral wheezing respiratory illnesses were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. Viral etiologies were identified in 90% of wheezing illnesses. From birth to age three yrs, respiratory syncytial virus (RSV) (OR, 2.6), RV (OR, 9.8), or both, (OR, 10) were associated with increased A risk at six yrs. In year one, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased A risk at age six yrs. By age three yrs, wheezing with RV (OR, 25.6) was more strongly associated with A at age six yrs than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in year three had A at six yrs of age. Wheezing in infancy and early childhood associated with RV infections are the most significant predictors of subsequent A at age six in a high-risk birth cohort. Editor's comment: RV infection in early life is associated with a risk for asthma. Jackson DJ, et al., Am J Respir Crit Care Med 2008;178:667.

ライノウイルスは学童期の喘鳴の大きな原因となっている。この研究では、家族歴があり、3歳以前に伴う喘鳴に伴いライノウイルス感染が証明された子どもは、その後、喘息と診断されるリスクがRSウイルス(オッズ2.6)などのウイルス感染と比べ高かった(オッズ9.8)ことがわかった。

5. BODY MASS AND GLUCOCORTICOID (GC) RESPONSE IN ASTHMA (A)
45 non-smoking adults, 33 with and 12 without A underwent characterization of lung function, BMI, and spirometric response to prednisone. Dexamethasone (DEX, 10-6 M) -induced mitogen-activated protein kinase phosphatase-1 (MKP-1) and baseline tumor necrosis factor (TNF)-α expression were evaluated by PCR in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage cells. DEX-induced PBMC MKP-1 expression was reduced in overweight/obese vs lean patients with A (P = 0.01). PBMC TNF-α; expression increased as BMI increased in A (P = 0.01). The PBMC log (TNF-α):DEX-induced MKP-1 ratio also increased as BMI increased in A (P =0.004). In bronchoalveolar lavage cells, DEX-induced MKP-1 expression was also reduced in overweight/obese versus lean patients with A (P = 0.05). Similar findings were not observed in control subjects. The authors conclude that in vitro biomarkers of GC insensitivity increase in both the lung and peripheral blood as body mass increases in A. Editor's comment: Obesity may lead to reduce efficacy of GC in A subjects. Sutherland ER, et al., Am J Respir Crit Care Med 2008;178:682.

肥満のある喘息患者ではそうでない喘息患者に比べ、末梢血単核細胞のデキサメタゾンに対する反応性の低下とTNFαの増加が認められた。

6. ARG 1 IS A NOVEL BRONCHODILATOR RESPONSE GENE
The authors genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma (A) Management Program. The association of these SNPs with acute response to inhaled β-agonists (bronchodilator response [BDR]) was screened using a novel technique. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts. Evidence for association from the four A cohorts was combined, and SNPs from ARG 1 were significantly associated with BDR. The authors conclude that ARG 1 is a novel gene for acute BDR in both children and adults with A. Editor's comment: The arginase 1 gene (ARG1) is a potential ?-agonist response gene. Litonjua AA, et al., Am J Respir Crit Care Med 2008;178:688.

呼気中一酸化窒素NOの測定は非侵襲的な喘息気道炎症の評価として最も優れていることが知られている。アルギニン分解酵素機能不全によりNO値は上昇する。筆者らはアルギニン分解酵素ARG1の遺伝子多型と喘息の発症が相関していることを示した。

7. EFFECTS OF DOG OWNERSHIP IN EARLY CHILDHOOD ON IMMUNE DEVELOPMENT AND ATOPIC DISEASES
275 children at increased risk of developing allergic diseases were evaluated to age three yrs for pet ownership, blood cell cytokine responses, and atopy. Can f 1, Fel d 1, endotoxin, ergosterol, and muramic acid were measured in settled dust from 101 homes. Dog exposure at birth was associated with decreased atopic dermatitis (AD) (P = 0.004) and wheezing (W) (P = 0.005) in year three. The rates of AD and W in year three were relatively high in children who acquired dogs after birth. The prevalence of dog sensitization between the two groups did not vary according to dog exposure. Can f 1 levels in bedroom dust were positively associated with IL-10 (P =0.01), IL-5 (P< 0.001), and IL-13 (P =0.0004) responses at age one and IL-5 (P=0.022) and IL-13 (P=0.015) responses at age three. Endotoxin was associated with IFN-γ (P=0.002) and IL-13 (P=0.01) responses at age three but not at age one, and similar relationships were found for muramic acid. Exposure to dogs in infancy, and especially around the time of birth, is associated with changes in immune development. Reductions in W and atopy are not explained by exposure to endotoxin, ergosterol, or muramic acid. Editor's comment: The means by which dog ownership at birth may prevent atopic disease remains an enigma. Bufford JD, et al., Clin Exp Allergy 2008;38:1635.

子どもが1歳になるまでの家庭での犬の飼育は、その後の喘鳴やアトピー性皮膚炎のリスクを有意に低下させた。この効果はエンドトキシンレベルとは関係しなかった。

8. SUBLINGUAL IMMUNOTHERAPY (SLIT) IN YOUNGSTERS: ADHERENCE IN A RANDOMIZED CLINICAL TRIAL
204 youngsters (6-18 yrs) with hayfever participated in a SLIT randomized controlled trial with grass pollen extract or placebo for two yrs. The primary outcome, i.e., change in mean daily total rhinoconjunctivitis symptom score in the second grass pollen season was negative. Adherence to medication intake was assessed by weighing the study medication. Participants who completed the follow-up and used ≥80% of the prescribed medication were considered adherent. 154 youngsters completed the study. The number and reasons for drop-outs did not differ between treatment groups. Drop-out was affected by age, evaluation of the treatment effect and medication instructions. Non-adherence to medication intake was influenced by the severity of the disease before the trial. However, the ineffectiveness of SLIT could not be explained by non-adherence. Editor's comment: Non-adherence to the study protocol did not explain the outcome in this negative SLIT study. Röder E, et al., Clin Exp Allergy 2008;38:1659.

6-18歳における草本花粉エキスによる舌下免疫療法を対照比較において実施した。その結果、有意な結果が得られなかったが、著者らは、ドロップアウトの率が他の年齢に比して高いなど、患者のアドヒアランスが低いためとしている。

9. ARE FISH OIL SUPPLEMENTS SAFE IN FINNED FISH (FF)-ALLERGIC PATIENTS?
Many manufacturers label fish oil supplements with the warning "avoid this product if you are allergic to fish". Six FF-sensitive subjects, as determined by a positive history and skin tests, were selected. They were skin tested with two different fish oil supplements and given an oral challenge of each supplement one hour apart. All patients with positive skin tests to at least one FF had negative skin tests to both fish oil supplements. All tolerated the fish oil challenge. This pilot study indicates that FF-sensitive patients tolerate fish oil supplements. Editor's comment: These data indicate that food labeling for FF-allergic subjects is not necessarily accurate. Mark BJ, et al., Allergy and Asthma Proc 2008:29:528.

フィンランドにおいて、魚アレルギー患者に対する魚油の効果について検討した。その結果、魚油でアレルギー症状を示す患者はいなかった。

10. GOOD PROGNOSIS, CLINICAL FEATURES, AND CIRCUMSTANCES OF PEANUT AND TREE NUT REACTIONS (PTNR) IN CHILDREN TREATED BY A SPECIALIST ALLERGY CENTER
785 children were followed for 3640 patient-years for PTNR. The prognosis for children with PTNR is good with a low frequency and severity of subsequent reactions and need for epinephrine (E). School age children are at highest risk for a recurrent reaction, which occurs most commonly at home. The fact that few reactions occur in school is attributed to informed school training by professionals with expertise in food allergy. Contact PTNR were always mild. A three-fold reduction in the use of E in subsequent vs the index reaction is reported. Index reactions were mild in 66% (516), moderate in 29% (224) and severe in 5% (45). Ninety percent had the same/reduced severity grade on follow-up reactions. Editor's comment: Education is the primary means to control PTNR. By doing so, accidental reactions are uncommon and when they do occur, they are usually mild requiring little or no treatment. Clark AT, et al., J Allergy Clin Immunol 2008;122:286.

アレルギー専門医の診察下におけるピーナッツや木の実による小児アレルギー患者の予後は良好である。

11. REVIEW ARTICLES ON EXERCISE-INDUCED ASTHMA (EIA)
The August J Allergy Clin Immunol contains five articles on EIA, "Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes" (Anderson SD, et al., p225); "Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes" (Rundell KW, et al., p238); "The elite athlete: Yes, with allergy we can" (Bonini S, et al., p249); "Long-acting β-agonists and exercise" (Weinberger M, p251); "Asthma and the elite athlete: Summary of the International Olympic Committee's Consensus Conference, Lausanne, Switzerland, January 22-24, 2008" (Fitch KD, et al., p254). EIA is caused by evaporative water loss resulting in cooling and dehydration of the airway surface. The release of mediators is also implicated. These reviews outline the pathophysiology of EIB and how to diagnose and treat it even in elite athletes compelled to follow international guidelines required by the World Anti-Doping Agency. Editor's comment: Great review articles on EIA. J Allergy Clin Immunol 2008;122. Anderson; Rundell; Bonini; Weinberger; Fitch

運動誘発喘息に関する優れた総説である。

12. NEURO-MEDIATORS AS PREDICTORS OF PAEDIATRIC ATOPIC DERMATITIS (AD)
40 AD cases were matched with 80 unaffected controls from the prospective Taiwan birth panel cohort study. Concentrations of IgE, nerve growth factor (NGF), and vaso-active intestinal peptide (VIP) in cord and maternal plasma were performed by ELISA. The NGF levels were significantly higher in AD patients vs controls (mean ± SD: 65.47 ± 44.45 vs 49.21 ± 12.18 pg/mL for cord plasma and 89.68 ± 41.04 vs 66.96 ± 23.05 pg/mL for maternal plasma) (P < 0.05). Comparative VIP levels were not significantly different from controls. NGF was a better biomarker than IgE to detect both intrinsic and extrinsic pediatric AD. The authors conclude that NGF is a good alternative biomarker to predict childhood AD. Editor's comment: NGF should be investigated as a biomarker for other atopic diseases. Wang IJ, et al., Clin Exp Allergy 2008;38:1302.

臍帯血のnerve growth factor (NGF)測定はIgEの測定よりもアトピー性皮膚炎の発症予測に有用であった。

13. WHEEZING (W) IN CHILDHOOD: INCIDENCE, LONGITUDINAL PATTERNS AND FACTORS PREDICTING PERSISTENCE
This study investigates the incidence and natural course of W over the first 13 yrs of life and risk factors which predict W at 11-13 yrs. The Multicentre Allergy Study, a German birth cohort, recruited 1,314 children in 1990. History and physical examinations, immunoglobulin(Ig) E, and lung function tests were performed up to 13 yrs of age. Complete data on 441 children indicate that W declined with age. The first W episode was reported by 29%, 9% and 9% of participants at <3 yrs (early W), 3-6 yrs (late W), and >6 yrs (very late W) of age, respectively. W at age 13 was associated with parental atopy, with positive in vitro IgE tests, elevated IgE, and exposure to high levels of indoor allergens in early life. All associations were stronger among early W vs nonwheezers. The authors conclude that the early expression of atopy as a predictor of W at age 13 declines with increasing age of W onset. Editor's comment: Parental atopy, positive in vitro IgE tests, elevated IgE, and high levels of indoor allergens in early life are associated with higher incidence of W at age 13 in children. Matricardi PM, et al., Eur Respir J 2008;32:585.

1990年に開始された出生コホート調査の結果、13歳における喘息の存在を早期に予測する因子は両親のアトピー歴、IgE抗体、室内アレルゲンの= 9640;値であった。予想通りの結果であった。

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WAOJ TABLE OF CONTENTS
November 2008, Volume 1, Issue 11

Original Article
Eight Years of Severe Allergic Reactions in Finland: A Register-Based Report
Soili Mäkinen-Kiljunen; Tari Haahtela

Original Article
An Unusual Cause of Subarachnoid Hemorrhage
Yuen Su; Constance Katelaris

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

Journal Issue Review

Eosinophilic Esophagitis
Gastrointestinal Endoscopy Clinics of North America
Volume 18, Issue 1, Pages 1-224 (January 2008)
Guest Editor: Furuta, G.T.
Consulting Editor: Lightdale, C.D.
ISSN: 1052-5157

今月の紹介書籍は好酸球性食道炎に関するものである。近年増加し、難治性である好酸球性食道炎は消化器専門医のみならず多くの分野の医師が関わるはずの疾患であり、この本は推奨される。

Available from: Saunders/Elsevier

Reviewer:
Alyson Kakakios MB BS, FRACP
Department of Allergy and Immunology
The Children's Hospital at Westmead
Westmead, Sydney, New South Wales
Australia

Description
This issue of "Gastrointestinal Endoscopy Clinics of North America" is very timely since it marks the transition of eosinophilic esophagitis (EE) from an emerging disease to an established disorder whose importance has led to two international conferences and the publication of consensus recommendations for diagnosis and treatment (Gastroenterology 2007; 133:1342-1363). This state-of-the-art issue on eosinophilic esophagitis makes several things clear:

  • Eosinophilic esophagitis is a complex disorder with a truly multidisciplinary nature involving gastroenterologists, adult and paediatric specialist physicians, pathologists, allergists, surgeons, dietitians and scientists.
  • EE is an important disease which causes considerable morbidity in those affected.
  • EE is a chronic disease with few patients "outgrowing" their illness, indeed, EE may be the paradigm for a disease that begins in childhood and extends into adult life.
  • EE is increasing in incidence and prevalence with approximately a three-fold increase in incidence over the past two decades.
  • Although there is still much to be learned about many aspects of EE this issue on EE goes a long way towards an understanding of the natural history, pathogenesis, biomarkers and therapeutic approaches which will be of great importance in developing new diagnostic tools and therapeutic options for this disease.

Purpose
The purpose of this issue is to provide the latest update on EE. This has been achieved by assembling an extraordinary group of authors of individual chapters each of whom brings to the topic their unique perspectives of the disease arising from their particular area of specialization and research.

Audience
The issue is targeted not only at gastroenterologists performing endoscopies, although this is clearly a major audience, but also at paediatricians, allergists and pathologists. As a reviewer who is a paediatric immunologist actively involved in treating infants, children and adolescents with this disorder, my hope is that the issue will reach a much wider audience than might usually be the case with this series.

Features
As usual with the "Clinics of North America" format, each of the chapters is contributed by one or two authors from the viewpoint of their particular interest in the disorder, whether that be clinical, pathology, pathogenesis, treatment, diagnosis, paediatric or adult, allergy or gastroenterology. Given the nature of this "bringing together of the experts" there is considerable repetition of facts and information but there are also unique contributions derived from each of the authors' individual expertise.

Given that this is the "Gastrointestinal Endoscopy Clinics" it is not surprising that there are some beautiful pictures of the superficial appearance of the oesophagus in this disorder. This is of great importance for the non-gastroenterologist to be able to visualize the changes to the oesophagus, such as the linear furrowing, exudate, stenotic rings and strictures and to relate these to the clinical picture. For example, on page 55 there is a particularly interesting endoscopic view of meat impacted in the distal oesophagus of a previously asymptomatic adolescent boy which clearly shows the linear furrowing and exudate consistent with EE. Also of particular interest were the chapters relating to basic pathogenesis, ENT manifestations (new to me) and the possible relationship of oesophageal dysmotility syndromes (including achalasia) to EE. The importance of taking biopsies (5 from different places in the oesophagus) and of reviewing these biopsies with the pathologists is emphasized. The final chapter provides an integrated approach to treatment of children and adults with eosinophilic esophagitis. In this article, a paediatric gastroenterologist, an adult gastroenterologist and a paediatric allergist combine their efforts to provide a clear, practical approach to the evaluation and treatment of patients with EE.

Assessment
This issue of Gastrointestinal Endoscopy Clinics of North America brings together experts in the field of Eosinophilic Esophagitis in a way which to my knowledge has not been done before for this entity and which provides a state-of-the-art summary of all the major areas of the disorder. As expected for "the Clinics" it is very oriented towards North America with only one author, Alex Straumann, from outside the USA. However, each chapter is well-referenced and interestingly enough the Guest Editor Glenn Furuta, an acknowledged expert in EE himself, states that "the English language-centric medical community could have been light years ahead in its identification of this disease if it had recognized one of the first descriptions published by a private practice gastroenterologist from Olten County, Switzerland (Alex Straumann) in 1994." My own perspective as a Paediatric Immunologist working in a large public children's hospital, is one of considerable respect mixed with a degree of envy for the way in which our North American colleagues have embraced the idea of a multidisciplinary approach to this complex, fascinating, important and increasingly common disease and I can only hope that this particular issue is read with as much interest worldwide, particularly in Australia, as it truly deserves. I think this is a "must-have" for all clinicians involved with diagnosing, treating and understanding this disorder.

Find more allergy book reviews on the WAO Website here.

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