Medical Journal Reviews
Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief, reviewed premier medical journal articles for practicing allergists.
1a. RESCUE USE OF BECLOMETHASONE (B) AND ALBUTEROL (A) IN A SINGLE INHALER FOR MILD ASTHMA
This is a 6-mo double-blind, double-dummy, randomized, parallel-group trial of 455 patients (18 to 65 yrs) with mild asthma [FEV1 of 2.96 liters (88.36% of the predicted value)]. After a 4-week run-in, patients were randomly assigned to one of four regimens: placebo (P) 2X/day plus B, 250 μg, and A, 100 μg, in a single inhaler prn; P 2X/day plus A, 100 μg, prn; B, 250 μg, 2X/day, and A, 100 μg, prn; or B, 250 μg, and A, 100 μg, in a single inhaler 2X/day plus A, 100 μg, prn. Morning PEF during the last two weeks of the 6-mo treatment was higher (P = 0.04) and the number of exacerbations during the 6-mo treatment lower (P = 0.002) in the as-needed combination therapy than in the prn A therapy group. However, the values in the prn combination therapy were not significantly different from regular B therapy or regular combination therapy. The authors conclude that the symptom driven use of prn inhaled B, 250 μg and A, 100 μg, in a single inhaler, is effective treatment and is associated with a lower 6-mo cumulation dose of inhaled corticosteroids. Papi A, et al. N Engl J Med 2007; 356: 2040.
1b. RANDOMIZED COMPARISON OF STRATEGIES FOR REDUCING TREATMENT IN MILD PERSISTENT ASTHMA
500 patients (six yrs or older) with mild asthma, well-controlled with inhaled fluticasone (F), 100 μg 2X/day, were randomly assigned to receive continued F, 100 μg 2X/day, montelukast (M), 5 or 10 mg each night, or F, 100 μg, plus salmeterol (S),50 μg, each night for 16 weeks in a DB study. Treatment failure was the primary outcome. 20% of patients assigned to receive F or F + S failed compared to 30.3% of those on M. The hazard ratio for both comparisons was 1.6 (95% CI, 1.1 to 2.6; P = 0.03). The % of asthma free days was similar across the three groups. The authors conclude that patients controlled with 2X/daily F can be switched to 1X/daily F + S without increased treatment failure. However, a switch to M results in an increased treatment failure and decreased asthma control, even though M treated patients remained free of symptoms on 78.7% of treatment days. Editor’s comment: Three physicians’ comments on various treatment options for mild, persistent asthma are included. One of the experts would use prn B and A in a combined inhaler, another, a leukotriene antagonist plus a prn rescue β-agonist, and the third, once daily inhaled corticosteroid plus a long-acting β-agonist in a single inhaler. William Osler, the Father of American Medicine, stated, “The practice of medicine is an art, based on science”. No single treatment may be absolutely correct to treat mild, persistent asthma. The American Lung Association Asthma Clinical Research Centers. N Engl J Med 2007; 356: 2027.
Clinical Decisions. Kraft M: 2096. Israel E: 2097. O’Connor GT: 2098.
吸入ステロイド薬フルチカゾン単独使用でコントロール良好な軽症持続型喘息患者500名を、フルチカゾン継続使用、フルチカゾン＋サルメテロール合剤への変更およびモンテルカストへの変更の３群に分けて、treatment failure（入院や救急外来受診として定義）などを指標として比較検討した。Treatment failureの割合は、他の２群が20%であったのに対し、モンテルカストへの変更群では30.3%であった。しかしながら、無発作の日数に関して３群とも同等であった。編集者注：様々なエビデンスが蓄積しているが最終的な選択は主治医である。Oslarは「医療行為は（普遍的な）科学に立脚した（個人的な）技法である」といっている。
2. REMODELING AND AIRWAY HYPERRESPONSIVENESS (AHR) BUT NOT CELLULAR INFLAMMATION PERSIST AFTER ALLERGEN CHALLENGE IN ASTHMA (A)
Fiberoptic bronchoscopy was performed at baseline, 24 hrs and seven days after allergen inhalational challenge of dual responders with mild-moderate asthma. At each time point, AHR, spirometry, and expression of tenascin (extracellular matrix protein), procollagen I, procollagen III, and heat shock protein (HSP)-47 (markers of collagen synthesis), and α-smooth muscle actin (myofibroblasts) were evaluated as markers of activation of airway remodeling. Likewise, numbers of mucosal major basic protein-positive eosinophils, CD68+ macrophages, CD3+, CD4+, CD8+ T cells, elastase-positive neutrophils, and tryptase-positive mast cells were assayed. AHR was increased from baseline at 24 hrs and seven days after allergen challenge. However, reticular basement membrane tenascin expression, elevated at 24 hrs, returned to baseline levels at seven days. Reticular basement membrane procollagen III expression was significantly elevated at seven days, and procollagen 1, HSP-47, and α-smooth muscle actin were all higher at seven days vs. 24 hrs. Eosinophil, macrophage, neutrophil, and CD3+ T cells increased at 24 hrs but returned to baseline by seven days. The authors conclude that the 24-hr increase after allergen challenge in dual responders with asthma in airway wall cellular inflammation resolves by seven days, whereas increases in AHR and markers of remodeling persist. Editor’s comment: AHR is associated with remodeling and not cellular inflammation. Kariyawasam HH, et al. Am J Respir Crit Care Med 2007; 175: 896.
3. A COMPREHENSIVE ANALYSIS OF ADVERSE OBSTETRIC AND PEDIATRIC COMPLICATIONS IN WOMEN WITH ASTHMA (A)
Outcomes for 37,585 pregnancies of women with A were compared to 243,434 without A. Risks of stillbirth and therapeutic abortion were similar; however, the risk of miscarriage was slightly higher (OR 1.10; 95% CI, 1.06 – 1.13). Risk of placental abruption, placental insufficiency, placenta previa, preeclampsia, hypertension, gestational diabetes, thyroid disorders in pregnancy, and assisted delivery were similar with the exception of increases in antepartum (OR, 1.20; 95% CI, 1.08-1.34) or postpartum (OR, 1.38; 95% CI, 1.21-1.57) hemorrhage, anemia (OR, 1.06; 95% CI, 1.01-1.12), depression (OR, 1.52; 95% CI, 1.36-1.69), and C-section (OR, 1.11; 95% CI, 1.07-1.16). Editor’s comment: Asthma is not a major risk factor in pregnancy. Tata LJ, et al. Am J Respir Crit Care Med 2007; 175: 991.
4. HERPESVIRUS LATENCY CONFERS SYMBIOTIC PROTECTION FROM BACTERIAL INFECTION
Reviewed by Gary Hellermann, PhD
Can herpesvirus infection be good for you? In this intriguing report, mice were infected with gamma herpesvirus (GHV) and the infection allowed to proceed to latency after which the animals were challenged with the intracellular pathogen, Listeria monocytogenes (L.m.). Mice without latent GHV suffered much greater susceptibility to L.m. infection than those previously infected with GHV. The mechanism for this enhanced antibacterial response may lie with subclinical reactivation of the virus producing sufficient viral antigen to maintain a prolonged increase in interferon gamma production. Editor’s comment: While this unusual type of latency-induced cross protection has not yet been shown in humans, this report demonstrates once again that in studying the immune system the rules are always subject to change. Barton ES, et al. Nature 2007; 447:326.
5. SMOKING AFFECTS RESPONSE TO INHALED CORTICOSTEROIDS OR LEUKOTRIENE RECEPTOR ANTAGONISTS IN ASTHMA (A)
44 nonsmokers and 39 light smokers with mild A were randomly assigned to treatment with inhaled beclomethasone (B) or once daily oral montelukast (M) in a multicenter, placebo-controlled, double-blind, double-dummy, crossover trial. The primary outcome was change in prebronchodilator FEV1 in smokers versus nonsmokers. Secondary outcomes include PF, PC20 methacholine, symptoms, QOL, and markers of airway inflammation. Subjects with A who smoked, had significantly more symptoms, worse QOL, and lower daily PF than nonsmokers. B significantly reduced sputum eosinophils and ECP in both smokers and nonsmokers but increased FEV1 (170 ml, P = 0.0003) only in nonsmokers. M significantly increased A.M. PF in smokers (12.6 L/min, P = 0.002) but not in nonsmokers. The authors conclude that in subjects with mild A who smoke, the response to B is attenuated and that M may be appropriate to treat smokers with A. They call for larger studies to confirm these data. Editor’s comment: Perhaps leukotrienne antagonists and not B will be more helpful for smokers than nonsmokers with A. Lazarus SC, et al. Am J Respir Crit Care Med 2007; 175:783.
6. OSTEOPONTIN HAS A CRUCIAL ROLE IN ALLERGIC AIRWAY DISEASE THROUGH REGULATION OF DENDRITIC CELL SUBSETS
Reviewed by Gary Hellermann, PhD
Osteopontin (Opn), also known as early T lymphocyte activation-1 (Eta-1) factor, is a cytokine that wears many hats. Bone researchers found that it assists osteoclasts in localizing to bone matrix while cancer researchers reported Opn is involved in tumor suppression. Opn-1 is produced in abundance by activated T lymphocytes and binds to the cell adhesion receptor, CD44, affecting homing and attachment of lymphocytes and other immune system cells. New research now implicates the secreted form of the cytokine, Opn-s, in differential regulation of the allergic immune response through actions on dendritic cells. In this report on a mouse model, Opn-s proved to be pro-inflammatory during allergen sensitization, but anti-inflammatory during challenge. Editor’s comment: The demonstration of both pro- and anti-inflammatory activities in the same molecule emphasizes the need for great care in the design and evaluation of clinical trials of cytokines such as Opn. Xanthou G, et al. Nature Medicine 2007, 13:570.
7. A WEB-BASED, TAILORED ASTHMA (A) MANAGEMENT PROGRAM FOR URBAN AFRICAN-AMERICAN HIGH SCHOOL STUDENTS
This study was developed and evaluated as a multimedia, web-based A management program which specifically targeted urban high school students in an attempt to alter their behavior as it related to A outcome. High school students were randomized to receive the treatment website vs a sham website on school computers. At 12 mo, treatment students reported fewer symptom-days, symptom-nights, school days missed, restricted activity days, and hospitalizations for asthma when compared to controls (RR and 95% CIs all significant). Editor’s comment: Education, which leads to compliance, is a key to improved asthma outcomes in all populations. Joseph CLM, et al. Am J Respir Crit Care Med 2007; 175: 888.
8. ADENOTONSILLECTOMY (AT) IMPROVES SLEEP, BREATHING, AND QUALITY OF LIFE (QOL) BUT NOT BEHAVIOR
This retrospective cohort study was designed to obtain parental perspectives on changes in sleep, breathing, QOL, and neurobehavioral outcomes after AT was performed for obstructive sleep apnea syndrome (OSAS) from 1993 to 2001. Children who underwent AT were compared to children who did not. 138 of the 166 questionnaires returned (35%) from parents of 473 children were complete. Compared to controls, parents of children who had AT reported improvements in sleep, breathing and QOL but not in concentration, school performance, and intellectual or developmental progress. Both short and long term, there were no significant effects of AT on any of the Conners’ Parent Rating Scale-Revised behavior subscales. The authors conclude that AT improves sleep, breathing, and QOL but not neurobehavioral outcomes. Editor’s Comment: Neurobehavioral outcomes did not improve in this study following AT for sleep apnea in children. More data are necessary. Constantin E, et al. J Peds 2007; 150: 540.
9. BASAL SERUM TRYPTASE (T) LEVEL CORRELATES WITH SEVERITY OF HYMENOPTERA STING AND AGE
109 patients, 63 wasp venom and 46 honey bee venom-allergic, had basal serum T levels measured. T levels were elevated in 12 (11%) and increased from a mean of 5.14 to 6.98 μg/L for patients with sting reactions from grades I through IV, (Mueller classification). Serum T levels correlated significantly with the sting reaction severity (r = 0.2752; P = .004) and with age (r = 0.2906; P = .002). Sting reaction severity also correlated with age (r = 0.3654; P = .001). The authors conclude that serum T levels correlate with both sting severity and age. Editor’s comment: This is another paper which indicates that basal levels of serum T probably influence outcomes of sting induced anaphylaxis. Kucharewicz I, et al. J Investig Allergol Clin Immunol 2007; 17: 65.
10. THE VARIABILITY OF REGIONAL AIRFLOW OBSTRUCTION WITHIN THE LUNGS OF PATIENTS WITH ASTHMA: ASSESSMENT WITH HYPERPOLARIZED HELIUM-3 MAGNETIC RESONANCE (H3HeMR) IMAGING
Using hyperpolarized helium-3 magnetic resonance (H3HeMR) imaging, airspaces are depicted and focal areas of airflow obstruction are shown as “ventilation defects”. The authors investigate the regional changes in airflow obstruction with time and repeated bronchoconstriction. H3HeMR and spirometry were performed before and immediately after methacholine challenge in 10 patients (18-35 yrs) with asthma on two days that were 7-476 days (mean, 185.3 ± 37.2 days) apart. Pair-wise image comparisons demonstrate that 41% ± 10% and 69% ± 5% (P = .017) of defects , respectively, were in the same location, and of those, 69% ± 12% and 43% ± 5% (P = .022), respectively, did not change size. Comparing premethacholine vs. postmethacholine images, 58% ± 9% of defects were in the same location on day one and 73% ± 7% (P = .088) on day two. The authors conclude that ventilation defects persist or recur in the same locations in asthmatics and suggest that regional changes of the airflow obstruction are relatively fixed. Editor’s comment: There is tremendous variability in asthma, even in different areas of the lung of the same subject. deLange EE, et al. JACI 2007; 119:1072.
11. STRUCTURAL INSIGHT INTO PRE-B CELL RECEPTOR FUNCTION
Reviewed by Gary Hellermann, PhD
B cells, like T lymphocytes, undergo constant scrutiny by regulatory cells to ensure that self-tolerance is maintained. One checkpoint is at the stage where the pre-B cell receptor contains an intermediate known as the surrogate light chain (SLC). Only those B cells in which the SLC can pair with the newly expressed heavy chain are allowed to go on to clonal expansion. In this report, the human pre-B cell receptor was crystallized and the structure of the SLC examined. Editor’s comment: Structural analysis at the submolecular level reveals significant new information about the interaction of the SLC with the heavy chain and suggests how this binding affects the yea or nay decision on B cell survival. Bankovich, AJ et al. Science 2007; 316:291.
免疫グロブリンsurrogate light chain (SLC)とheavy chainの会合はB細胞の増殖に必須である。筆者らはSLCの立体構造をあきらかにした。
12. ONCE-YEARLY ZOLEDRONIC ACID (ZA) FOR TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS (O)
This is a 3-year DBPC trial of 3889 patients (mean age, 73 yrs) randomly assigned to receive a single 15-minute infusion of ZA, 5 mg, or 3876 placebo (P) at baseline, 12 mo, and 24 mo. They were followed until 36 mo. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (all patients). Secondary end points included bone mineral density (BMD), bone turnover markers, and safety outcomes. Treatment with ZA reduced the risk of vertebral fracture by 70% compared to P (3.3% in ZA vs 10.9% in P, relative risk, 0.30; 95% CI, 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in ZA vs 2.5% in P; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Non-vertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). ZA was associated with improvement in BMD and bone metabolism markers. Atrial fibrillation occurred more frequently in the ZA group (50 vs 20 patients, P<0.001), without serious consequences. Once a year infusion of ZA significantly reduces the risk of vertebral, hip, and other fractures. Editor’s comment: Once a year treatment for osteoporosis is on its way. Black DM, et al. N Engl J Med 2007; 356: 1809. Editorial, Compston J: 1878.
13. EXERCISE-INDUCED BRONCHOSPASM (EIB): DIAGNOSIS AND TREATMENT
This CME article is an excellent review of the subject of EIB asthma (A). EIB is usually suspected from the clinical history; a methacholine, exercise, or eucapnic voluntary hyperventilation challenge can be helpful in its diagnosis. First-line pharmacologic treatment is a short-acting β-agonist. However, regularly used inhaled corticosteroids, leukotriene inhibitors, long-acting β-agonists and mast cell stabilizers are all effective treatments. Editor’s comment: EIB often goes unrecognized, untreated, and interferes with exercise. Bruns AS and Parsons JP. JCOM 2007; 14: 211.
WAO Now: What's New in the World of WAO
World Allergy Congress (WAC) 2007 – Bangkok, Thailand
Immunotherapy and Food Allergy Symposiums
Immunotherapy and Food Allergy are two major concerns for the practicing Allergist. To address these important topics in depth, World Allergy Congress in Bangkokwill start, 2 December 2007, with a full day symposium on Immunotherapy, co-sponsored by ALK, Dynavax (in partnership with UCB Pharma), Greer and Stallergens and the final day, 6 December 2007, will be a full day symposium on Food Allergy co-sponsored by Dey LP and Heinz. Our faculty will comprise world experts on each topic, bringing exciting updates on latest developments and debating new therapies. To see the programs for the symposia click here (Immunotherapy) or here (Food Allergy).
WAO – Nycomed International Fellows for 2007-2008
WAO, in partnership with Nycomed, is sponsoring 9 international fellows in order to identify and support up-coming key opinion leaders in asthma and/ or allergic rhinitis. WAO is delighted to announce the nine winners of the WAO-Nycomed International Short-Term Fellowship for 2007-2008. Each fellowship includes a 2-week stay at a research host center, as well as inclusion in the World Allergy Congress (WAC) in Bangkok, Thailand where fellows will have a chance to present posters on their research project at the Fellowship Luncheon. Please join us in congratulating:
Zuzana Rennerová, Slovakia
Damian Tworek, Poland
Mirjana Turkalj, Croatia
Corina Ureche, Romania
Mariana Malucelli, Brazil
Anne Ellis, Canada
Katja Adamic, Slovenia
Paraskevi Xepapadaki, Greece
Thaneshvari Moodley, South Africa
New Educational Postings on the WAO Website
We have the pleasure of announcing a new interview with the President of WAO, Michael Kaliner, MD. Please take a moment to listen to Dr. Kaliner share his extensive knowledge in the 2007 Annual WAO Update.
Ask the Expert – Exclusive Benefit to WAO Members
Ask the Expert is a new online tool available exclusively to WAO Members. Directed by Professors Cassim Motala and Ruby Pawankar, this online service provides the opportunity to pose educational, scientific and medical questions about allergy, asthma, and clinical immunology to one of the many WAO volunteer experts located throughout the world. We invite all WAO Members to become a part of this online service. To Ask the Expert, click here.
New Interactive Case Review
Take a moment to test your knowledge with the new Interactive Case Review based on a Clinical Case Report – Acute Parotitis by Dr. Andrew Bagg.
Interactive Case Reviews give you the chance to test your knowledge and make a diagnosis on an unusual case history. The case study is pictorially presented, along with questions and possible diagnoses. Once you select your diagnosis, you immediately learn whether or not your diagnosis corresponds to that of the experts who posted the case, and are able to read the rationale for the diagnosis and suggested treatment provided by the expert.
WAF Materials Available
WAF presenter materials from the recent XXVI Congress of the EAACI are now available for download on the WAF web page.
World Allergy Forum is supported through an unrestricted educational grant from
Call for Applications
Long-Term Research Fellowship
The World Allergy Organization (WAO) offers one Long-Term Research Fellowship, to commence in 2008. The Fellowship will support a junior allergist following an approved research program at a WAO proposed host center for up to two years. WAO will contribute a monthly stipend of $1,700 US and once-yearly travel expenses between the home country and the host center.
Priority will be given to junior clinicians within five years of award of the most recent professional degree, who are specializing in allergy and who are affiliated with an academic department or clinical institute. Applicants must be active members of a WAO member society.
The Long-Term Fellowship will be applied to a project which meets one of the WAO Research Priorities:
- Genetic factors involved in the development of allergic disease and response to treatment
- Allergen characterization and standardization
- Clinical and basic studies in allergy and asthma
Application forms including a list of host centers may be downloaded here
Applications must be received by WAO Secretariat no later than 30 September 2007
Upcoming Allergy Meetings
US GLORIA Placement
Alabama Society of Allergy, Asthma and Immunology
August 10-12, 2007
US GLORIA Faculty:
Module 5: Treatment of Severe Asthma
Module 10: Chronic Rhinosinusitis and Nasal Polyposis
GLORIA is supported through unrestricted educational grants from:
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And In Other News
Allergy Book Reviews
Handbook of Atopic Eczema: 2nd edition.
Editors: J Ring, B Przybilla, T Ruzicka
List price: $169.00 USD
Available from: Springer-Verlag
Dr Janet Rimmer, MBBS, MD (UNSW), FRACP
St. Vincent Clinic
Darlinghurst, NSW, Australia
The first edition of this book was printed 15 years ago and this 2nd edition has been extensively revised with the addition of new topics. As atopic eczema affects up to 25% of the population in many countries it is appropriate to have an up to date, in depth textbook on this topic. The title is somewhat misleading in that it provides a very comprehensive review of the topic rather than acting as a “handbook”.
The purpose of the book is to provide an in depth approach to atopic eczema.
Both the usual aspects of atopic eczema are covered as well as some very interesting sections such as ‘Complications and diseases associated with atopic eczema’ as well as ‘diseases rarely associated with eczema’; there is a comprehensive coverage of different therapy approaches eg. music therapy, eczema schools and alternative therapies.
This textbook is targeted primarily to clinicians who have a special interest in this condition, i.e., dermatologist and allergists. While there is a paediatric chapter in the clinical aspect section, this is not repeated in the management section which is an omission as it is an important disease in childhood and there are always specific treatment considerations for this age group.
The format is divided into 3 sections: clinical aspects, pathophysiology and management. There is a synopsis at the end of each section. There are 107 contributors most of whom are based in Europe, with only 3 contributors from the USA. The book is 613 pages and there are 66 chapters divided evenly between the 3 sections. Each chapter is divided into sections, which allows for clear organization of the material, there are reasonable numbers of illustrations and copious references.
This book provides a comprehensive review of a common disease. It brings together many aspects of this disease into one compact source. It is highly recommended for any clinician who has an interest in or treats this condition.
Current Problems in Dermatology, Vol. 33: Biofunctional Textiles and the Skin
Series Editor: G. Burg
Volume Editors: U.-C. Hipler, P. Elsner
List Price: $180.00 USD
Available From: Karger Publishers
James Young Joon Choi, MBBS FRACP
Allergist and Clinical Immunologist
Westmead Hospital Dermatology Registrar
Biofunctional textiles are a new and exciting scientific field established to create fabrics which have the potential to treat or prevent diseases. Much of this update focuses on the area of antimicrobial silver textiles – the biological properties of silver, the new methods of incorporating it into resilient seaweed based fibers, and its anticipated uses in the medical field – from preventing nosocomial infections to treating atopic dermatitis.
This book effectively combines and presents the current state of knowledge on silver antimicrobial fabrics from the perspectives of three disciplines – the microbiologist, the textile engineer, and the dermatologist.
Researchers and clinicians interested in infection control, atopic dermatitis, chronic wounds and burns will find this book a very useful introduction and summary of what is currently possible in antimicrobial textiles.
Each chapter begins with a succinct abstract. Although most figures are in black and white, they are of high quality. Charts and tables are well designed and clearly presented. All chapters conclude with a list of references. The index is detailed and useful. Overall, I felt that although the book could be read from front to cover, each chapter was in its own right self contained and could be read alone or out of order.
This book is an exciting introduction into the rapidly evolving science of antimicrobial textiles. It is a very useful and up-to-date synopsis for any practitioner dealing with atopic dermatitis, and emphasizes what can be possible when there is collaboration between a medical discipline (Clinic for Dermatology and Dermatological Allergology at the Clinic of the Friedrich Schiller University at Jena) and a non-medical industry (the German Textile Research Centre North-West, Krefeld).
Find more allergy book reviews on the WAO Website here.