Medical Journal Reviews
Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief, reviewed premier medical journal articles for practicing allergists.
1. SALMETEROL (S) AND FLUTICASONE PROPIONATE (FP) AND SURVIVAL IN CHRONIC OBSTRUCTIVE PLUMONARY DISEASE (COPD)
This is a randomized, double-blind trial comparing S 50 µg plus FP 500 µg in a single inhaler two times daily with placebo, S 50 µg alone, or FP 500 µg alone for 3 yrs to treat COPD. The primary outcome was death from any cause. Secondary outcomes included frequency of exacerbation, spirometric values and health status. 6,112 patients were included, and 875 died within 3 yrs, 12.6% in the combination–therapy group, 15.2% in the placebo group, 13.5% in the S group, and 16.0% in the FP group, corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5% (P=0.052). S alone or FP alone did not differ significantly from placebo. Compared with placebo, the combination regimen reduced annual exacerbation rates from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). Pneumonia as an adverse event was higher among patients receiving medications containing FP (19.6% in the combination-therapy group and 18.3% in the F group) vs. placebo (12.3%, P<0.001 for comparisons between these treatments and placebo). The reduction in deaths from all causes did not reach statistical significance; however, there are significant benefits in other outcomes with the combined therapy. Editor’s comment: Combination-therapy reduced annual exacerbation rates and improved health status and spirometric values (secondary outcomes) but had no statistical effect on mortality (primary outcome). Calverley PMA, et al. N Engl J Med 2007; 356: 775. Editorial, Rabe KF. N Engl J Med 2007; 356; 851.
2. VANCOMYCIN-INDUCED IMMUNE THROMBOCYTOPENIA
Vancomycin-dependent, platelet-reactive IgG or IgM antibodies were identified in 34 patients suspected of having vancomycin-induced thrombocytopenia. Clinical follow-up information on 29 patients revealed a mean nadir platelet count of 13,600 per mm3 and severe bleeding in 10 patients (34%). Platelet levels returned to baseline in all 26 surviving patients when vancomycin was stopped. Vancomycin-dependent antibodies were not found in 25 controls given vancomycin without thrombocytopenia. The authors conclude that severe bleeding occurs in vancomycin-induced immune thrombocytopenia and the diagnosis can be confirmed by the detection of vancomycin-dependent antiplatelet antibodies. Editor’s comment: Add vancomycin to the list of drug-induced thrombocytopenia. Von Drygalski A, et al. N Engl J Med 2007; 356: 904. Editorial, Warkentin TE. N Engl J Med 2007; 356: 891.
3. A BRIEF HISTORY OF TH17, THE FIRSTS MAJOR REVISION IN THE TH1/TH2 HYPOTHESIS OF T CELL-MEDIATED TISSUE DAMAGE
This author reviews the evolution of several hypotheses which dominated thinking in cell-to-cell regulation and interaction and the pathogenesis of disease. First was the concept of T-helper and T-suppressor cells which was replaced by the concept that cytokines produced by the TH1 cells could negatively regulate the function of TH2 cells and vice versa. The TH1/TH2 hypothesis is being replaced by newer data which indicate that a pathway named TH17 is now credited for causing and sustaining tissue damage in diverse situations such as organ-specific autoimmunity in the brain, heart, synovium and intestines, allergic disorders of the lung and skin, and microbial infections of the intestines and nervous system. It is likely to become established that no single cytokine can regulate a vital process like tissue damage and that it is a constellation of cytokines, tuned in concert, which ultimately produces a complex phenotype like “tissue damage” or “recovery from tissue damage”. Editor’s comment: This is a very lucid article summarizing the newest information on T-helper cell differentiation and regulation. Must reading for everyone. Steinman L. Nature Medicine 2007; 13: 139.
4. META-ANALYSIS: INTRAVENOUS IMMUNOGLOBULIN (IVIG) IN CRITICALLY ILL ADULT PATIENTS WITH SEPSIS
All randomized controlled trials of critically ill adults with sepsis, severe sepsis or septic shock who received IVIG or placebo or no intervention were reviewed. 20 trials (n=2621) met eligibility criteria and were analyzed. IVIG was associated with an overall survival benefit (RR, 0.74 [95% CI, 0.62 to 0.89) compared with placebo or no intervention. The authors suggest that a large randomized, controlled trial of IVIG therapy be performed because of the methodological limitations of the current literature review. Editor’s comment: IVIG seems to be helpful in adult patients with sepsis, but a large controlled trial is necessary. Turgeon AF, et al. Ann Intern Med 2007; 146: 193.
5. CLINICAL TRIAL OF LOW-DOSE THEOPHYLLINE (T) AND MONTELUKAST(M) IN PATIENTS WITH POORLY CONTROLLED ASTHMA (A)
This is a randomized, double-masked, placebo-controlled trial of 489 subjects with poorly controlled A randomly assigned to placebo, T (300 mg/d), or M (10 mg/d). Participants were monitored for 24 wk to measure rate of episodes of poor A control (EPACs) defined by decreased peak flow (PEF), increased β-agonist use, increased oral corticosteroid (CS) use, or unscheduled health care visits. Results show there was no significant difference in EPACs compared with placebo: low-dose T, 4.9 (95% CI, 3.6-6.7; not significant); M, 4.0 (95% CI, 3.0-5.4; not significant) and placebo, 4.9 (95% CI, 3.8-6.4). M and T caused small improvements in prebronchodilator FEV1 of borderline significance. Either treatment improved A symptoms or QOL. In subjects not receiving inhaled CS, additional T significantly (p<0.002) improved asthma control and symptoms as well as lung function. The authors conclude that neither M nor low-dose T lowered EPACs in patients with poorly controlled A despite improved lung function. For patients not using inhaled CS, low-dose T improves A symptom control more than M or placebo and provides a safe and low-cost alternative A treatment. Editor’s comment: T is still a good cost-effective drug to use for A. The American Lung Association Asthma Clinical Research Centers. Am J Respir Crit Care Med 2007; 175: 235.
6. COMBINATION THERAPY WITH A LONG-ACTING β-AGONIST AND A LEUKOTRIENE ANTAGONIST IN MODERATE ASTHMA
192 subjects (12 to 65 yr) with moderate asthma were enrolled in a randomized, placebo-controlled study comparing the clinical efficacy of treatment for 14 wks with montelukast (M) and salmeterol (S) compared to beclomethasone (B) and S. The primary outcome was time to treatment failure. M and S was inferior to B and S as judged by protection against asthma treatment failures (p =0.0008), lung function (26 L/min difference in A.M. PEF, P = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity. The authors conclude that M and S should not be substituted for inhaled corticosteroid (ICS) and LABA. Editor’s comment: ICS (with or without a long-acting β-agonist) remains the first treatment of choice for moderate asthma in this age group. Deykin A, et al. Am J Respir Crit Care Med 2007; 175: 228.
7. LIVE ATTENUATED (LAIV) VS. INACTIVATED INFLUENZA VACCINE (IIV) IN INFANTS AND YOUNG CHILDREN
Approximately, 8,000 children, 6 to 59 months of age, without a recent episode of wheezing illness or severe asthma, were randomly assigned in a 1:1 ratio to receive either cold-adapted trivalent IAIV intranasally or trivalent IIV in a double-blind manner. Influenza-like illness was monitored with cultures throughout the 2004-05 influenza season. There were 54.9% fewer cases of cultured-confirmed influenza in the group that received LAIV than in the group that received IIV (153 vs. 338 cases, P<0.001). Among previously unvaccinated children, wheezing within 42 days of the administration of dose 1 was more common with LAIV than IIV, primarily among children 6 to 11 months of age (P=0.076). Rates of hospitalization for any cause during the 180 days were higher among the LAIV recipients who were 6 to 11 months of age (6.1%) vs. the recipients of IIV in this age group (2.6%, P=0.002). The authors conclude that LAIV had significantly better efficacy than IIV and should be a highly effective, safe vaccine for children 12 to 59 months of age without a history of asthma or wheezing. Editor’s comment: LAIV is more effective than IIV but should not be used in children with asthma. Belshe RB, et al. N Engl J Med 2007; 356: 685. Editorial, Cox NJ, Bridges CB. N Engl J Med 2007; 356: 729.
8. DETECTION OF AN ALERGEN IN DOG DANDER THAT CROSS-REACTS WITH THE MAJOR CAT ALLERGEN, Fel d 1
These authors took a recombinant (rFel d 1) with the same immunologic properties as natural Fel d 1 and used it for quantitative (CAP) IgE competition experiments performed with sera obtained from 36 cat-allergic patients. They found that a Fel d 1 cross-reactive dog allergen was characterized by one- and two-dimensional immunoblotting using rFel d1 for IgE inhibition experiments and with monospecific, polyclonal rabbit anti-recombinant Fel d 1 antibodies. In 25% of Fel d 1-reactive cat-allergic patients, more than 50% inhibition of IgE reactivity to dog allergens was achieved with rFel d 1. A Fel d 1 cross-reactive 20 kDa allergen with a pI of approximately 3.4 was detected in dander extracts of several different dog breeds. They conclude that a Fel d 1-like allergen in dog dander extracts exist and may be responsible for double positivity to cat and dog in serology, and provide evidence that dog and cat dander, besides Can f 3/Fel d 2 (albumin) and perhaps Fel d 4 (lipocalin), contain other cross-reactive antigens. Editor’s comment: This is additional evidence that cat and dog allergens cross-react. Reininger R, et al. Clin Exp Allergy 2007; 37: 116.
9. A HUMAN INTERLEUKIN-12/23 MONOCLONAL ANTIBODY (MA) FOR THE TREATMENT OF PSORIASIS
320 patients (age > 18 yr) with moderate-to-severe plaque psoriasis underwent randomization in this double-blind placebo-controlled trial for treatment with the MA or placebo. 64 patients were randomly assigned to each group. There was at least 75% improvement in the psoriasis area-and-severity index at wk 12 (the primary end point) in 53% of patients who received 45 mg of the MA vs. placebo. Higher doses achieved even better results (P < 0.001). There was no statistical difference in adverse or serious adverse events. The authors conclude that this study demonstrates the therapeutic efficacy of a MA for psoriasis and provides further evidence of a role of the interleukin-12/23 p40 cytokines in the pathophysiology of this disease. Editor’s comment: Aberrant type I immune responses are linked to the pathogenesis of psoriasis and interleukin-12 and IL-23 seem to be the appropriate therapeutic targets. Krueger GG, et al. N Engl J Med 2007; 356: 580.
10. NFkB IN BREAST CANCER (BC) CELLS PROMOTES OSTEOLYTIC BONE METASTASIS BY INDUCING OSTEOCLASTOGENESIS VIA GMCSF
Reviewed by Gary Hellermann, Ph.D.
Persons with BC have a high incidence of bone metastases because BC cells have an affinity for bone but also because they secrete factors that stimulate osteoclasts which are responsible for bone resorption. These authors reasoned that since the transcription factor NF-kappaB (nuclear factor-kappa B) regulates genes involved in tumor invasion and metastasis, it may also be involved in the osteolytic bone metastases seen in some BC patients. They found that a cancer cell line highly metastatic for bone had significantly higher NF-kappaB activity than one that was weakly metastatic. Using mice as a model they showed that blocking NF-kappaB reduced the size and number of osteolytic lesions, in some cases preventing them completely. A potential connection with NF-kappaB was made when it was discovered that the increased activity of NF-kappaB correlated with an increase in GM-CSF (granulocyte macrophage-colony stimulating factor) which stimulates osteoclast differentiation. Editor’s comment: NF-kappaB is a ubiquitous proinflammatory factor and this study demonstrates that anti-NF-kappaB treatment may prove to be effective in preventing cancer metastasis. Park et al. Nature Med 2007; 13: 62.
WAO Now: What's New in the World of WAO
May 2007 Seminars & Conferences Placement
6th Colombian Congress of Allergy, Asthma and Immunology
May 24 - 27, 2007
WAO Invited Lecturer:
Spanish Version of Anaphylaxis Now Available!
WAO extends its sincere gratitude to Dr. Mario Sanchez Borges for translating into Spanish the GLORIA module on Anaphylaxis. For the Spanish Anaphylaxis module, click here.
2007 May GLORIA Placements
Finger Lakes Allergy Society
May 5, 2007
W. Henrietta, NY, USA
US GLORIA Faculty:
Module 2: Allergic Conjunctivitis
Module 4: Immunotherapy
Long Island Allergy & Asthma Society
May 8, 2007
Woodbury, NY, USA
US GLORIA Faculty:
Module 2: Allergic Conjunctivitis
African International Conference on Immunity
26 -30 May 2007
Victoria Falls, Zimbabwe
International GLORIA Faculty:
Module 3: Allergic Emergencies
Module 6: Food Allergy
GLORIA is supported through unrestricted educational grants from:
WAF Materials Available
"A Global Perspective on Genetics, the Environment and Allergy”
WAF presenter materials and audio recordings from the recent AAAAI Annual Meeting are now available for download on the WAF web page.
You Are Invited to Attend
WAF Symposium: Immune Tolerance
XXVI EAACI Congress
Tuesday, 12 June 2007, 8:30 - 10:00
Göteborg Convention Centre, Room K2-K3
Michael A. Kaliner, United States
Anthony J. Frew, United Kingdom
Concepts in tolerance induction
Dale Umetsu, United States
Modulation of IgE-related diseases in children
Patrick Holt, Australia
Can omalizumab synergize immunotherapy?
Thomas Casale, United States
World Allergy Forum is supported through an unrestricted educational grant from
Two new interviews with experts are now available on the Web site. To listen to Dr. Bill Solomon speak on "Pollen and Mold Aerobiology" and Dr. Gerald Gleich share his knowledge on "Hypereosinophilia and Eosinophilia Disease," click here.
Call for Applications
- WAO Short-Term Research Fellowship 2007 Applications
The World Allergy Organization (WAO) offers three Short-Term Research Fellowships, to commence in the latter half of 2007, to support junior allergists to visit a center of their choice to learn a research technique. The expected duration of each attachment is 2-3 weeks. WAO will contribute up to a maximum of $2,500 USD, to include travel and accommodations, for each Short-Term Fellowship.
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 to an academic department or clinical institute. Applicants must be current members of a WAO member society.
The Short-Term Fellowships 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 may be downloaded here
Applications must be received by WAO head office not later than 31 May 2007
- The WAO Henning Løwenstein Research Award 2007
The WAO Henning Løwenstein Research Award is a biennial award given to a young scientist who has shown excellence within the field of allergy. WAO and ALK-Abelló will present the award at the World Allergy Congress in Bangkok, 2-6 December 2007.
The winner will receive EURO 20,000 together with a travel grant to attend the World Allergy Congress.
For application guidelines, visit www.alk.abello.com and click on "The WAO Henning Løwenstein Research Award."
Deadline: 30 June 2007
Short-Term Research Fellowship 2006 Report
This month we post the report from the WAO 2006 Short-Term Research Fellowship awarded to Dr. Daniel Potaczek from the Jagiellonian University School of Medicine, Cracow, Poland. Dr. Potaczek visited the Atopy (Allergy) Research Center, Juntendo University School of Medicine, Japan to learn new research techniques for his study "The Genetic variability of alpha chain of high-affinity IgE receptor gene and its expression". To read a report of the Fellowship, click here.
Emerging Societies Meeting - Cancun, Mexico
WAO's first Emerging Societies Meeting (ESM) of 2007 will take place during the LXI National Congress of Clinical Immunology and Allergy, 27-30 June 2007 in Cancun, Mexico. The ESM is intended as a follow-up to the ESM that was held in Latin America in 2006 and will include representatives from Honduras, Guatemala, Cuba, El Salvador, Nicaragua and Martinique. This meeting is jointly funded by the American College of Allergy, Asthma and Immunology, the Mexican College of Allergy, Asthma and Clinical Immunology and the World Allergy Organization.
For more information on the Mexican College of Allergy, Asthma and Clinical Immunology’s meeting 27-30 June 2007, click here.
Sign up for Online Journal Subscription -
WAO and Hogrefe & Huber Publishers are offering a limited number of free online subscriptions to Allergy & Clinical Immunology International - Journal of the World Allergy Organization for members in developing countries. If you are interested in receiving a complimentary, online subscription, please send an e-mail to firstname.lastname@example.org, noting "Free Journal Subscription" in the subject line, with the following details:
Last (Family) name
City, State/Province and postal code
Name of Member Society
And In Other News
Urticaria Guideline Published
The British Society for Allergy & Clinical Immunology’s (BSACI) Urticaria Guideline was recently published by Blackwell Publishing in Clinical & Experimental Allergy. To read the full text, click here.
Dr. Allan Kaplan, WAO Guest Editor, reviewed the BSACI’s Urticaria Guidelines and made the following comments:
The published guidelines for the manuscript of chronic urticaria and angioedema by The British Society of Allergy and Clinical Immunology (BSACI) are excellent. The guidelines are evidence based, where possible, and offer an informative and practical approach to the disorder.
The areas that I would offer some caution in interpretation are as follows:
P. 6 – The guidelines acknowledge that urticaria and angioedema cause stress and also indicate that the reverse is recognized i.e. that psychologic stress can trigger or aggravate urticaria. One article regarding a possible mechanism with upregulation of corticotrophin-releasing hormone is offered. Nevertheless stress as a trigger of urticaria is more likely to be a myth and a higher steroid receptor level in the skin should improve urticaria.
P. 8 – Two studies assert that 20% of chronic urticaria patients remain symptomatic after 10 years. Assessment of the last 2000 such patients by Dr. Allen Kaplan suggests a figure closer to 2%.
P. 12 – Studies of sedation with first generation antihistaminics have never been done with urticaria/angioedema patients. Thus the subjects have no hives, no swelling, and no itch. Sedation and performance in chronic urticaria patients may not be normal to start with; round-the-clock doses of first generation antihistaminics are often effective, and if employment of these agents (e.g. Hydroxazine or Diphenhydramine) are steroid sparing or obviate the need for cyclosporine, their use may in-fact be an important step between giving up on antihistaminics and employment of more toxic agents.
P. 12 – Tranexamic acid may have some efficacy for angioedema (other than HAE where it is documented to be an effect approach), but inhibiting the conversion of plasminogen to plasmin does not affect production of bradykinin.
Two Allergy Book Reviews
Title: Problem-based immunology
Reginald M. Gorczynski and Jacqueline Stanley
List price: $34.95 USD
Available from: Elsevier
Dr Jane Peake MBBS, FRACP, DTM&H
University of Queensland, Herston, Queensland, Australia
In few areas of medicine has the scientific understanding of underlying pathological processes expanded as quickly as it has in the area of immunology. This makes it difficult for medical students and clinicians to keep abreast of these findings and in particular to grasp their clinical relevance. This textbook is designed to provide "up-to-date" understanding in immunology, both the basic concepts and clinical applications. Case scenarios are used to provide relevance and to increase interest and illustrate the broad spectrum of clinical immunology disorders.
The purpose of this textbook is to cover the basic science of immunology and using the problem-based approach provides the bridge with clinical medicine. Each section presents clinical case studies to demonstrate the practical relevance of immunology knowledge in diagnosing a variety of complex clinical disorders.
This book is designed for medical students and postgraduate students wanting to learn more about clinical immunology. It may also be of interest to those teaching these students as it provides problems and suggested group discussion topics, which can be used to stimulate teaching.
There is a section on each major area in the field of clinical immunology – immunodeficiency, hypersensitivity, autoimmunity, tumour immunology, transplantation and immunisation. In each section there is an overview of the main concepts and then a number of relevant case studies. Each of the case studies starts with a clinical vignette and then poses a number of questions for group discussion. The case is then further explored with analysis of the family history, laboratory investigations, differential diagnosis and, as relevant, there may be further explanation regarding investigations, laboratory result interpretation, therapy or underlying disease process and aetiology. An interesting and unique addition to this book is the final section on psychoneuroimmunobiology, which explores the concept that the immune system is influenced by non-immunological physiological systems and the interplay between “mind” and “body”.
Problem-based immunology provides an excellent basic textbook for medical students and postgraduate students in clinical immunology. Students often have difficulty understanding both the complex science that underpins immunology and the clinical relevance of what they are learning. The design of the book stimulates the student into thinking about the scientific concepts and the cases provide clinical relevance and interest. If used as designed, by starting with the initial discussion questions before proceeding with the case, the student will be engaged in a way that they will want to continue to read more. In the developed world allergic disease is becoming an increasing problem with rapid increases in the incidence of food allergy, allergic rhinitis and eczema. The hypersensitivity section would have benefited from having cases that explored these important topics. A further reading section at the end of each case or section would have provided resources for students whose interest has been piqued and was unfortunately only available for the psychoneuroimmunobiology section.
Title: Kendig’s Disorders of the Respiratory Tract in Children
Editors: Chernick, Boat and Wilmott, Bush
List Price: $249.00 USD
Available from: Elsevier
Peter van Asperen MD FRACP
Head, Department of Respiratory Medicine, The Children’s Hospital at Westmead &
Macintosh Professor of Paediatric Respiratory Medicine, University of Sydney, Australia.
The 7th Edition of this internationally respected "bible of pediatric pulmonology", first published in 1967, has been dedicated to the memory of Dr Edwin Kendig, the founding editor who was also involved in all previous editions. It covers this broad subject in a logical sequence commencing with a section on "General Considerations" (including chapters on normal lung development and physiology as well as clinical assessment) and proceeds through various infectious and non-infectious disorders of the respiratory tract as well as diseases with a prominent respiratory component including immune mediated and immune deficient disorders. This is the first edition to contain a separate section on "Asthma" including chapters on the epidemiology and immunopathogenesis of asthma, asthma in the pre-school years and in older children, and the influence of upper airway disease on the lower airway. This section is complemented by other chapters in the “General Considerations” section including the biology and assessment of airway inflammation, and drug administration by aerosol in children.
The book is designed to provide a comprehensive reference text on both common and rarer paediatric respiratory diseases as well a scientific understanding of normal pulmonary function and how it might be affected by these diseases.
Although primarily designed as a textbook for practising paediatric respiratory physicians and intensivists as well as trainees in these paediatric subspecialties, it also serves as a useful resource for all paediatricians and trainees, including paediatric allergists.
This latest edition has been extensively revised to incorporate the large body of new knowledge that has become available since the last edition in 1998. The authors have been carefully chosen as experts in their subject and represent views from both sides of the Atlantic as well as the Asia-Pacific. All the chapters are well set out and illustrated, are easy to read and contain a mixture of scientific and practical information with either up-to-date references or a suggested reading list. This edition also contains a series of colour plates which appear at the beginning of the book but are clearly referenced to individual chapters.
This has been and remains one of the relatively few comprehensive textbooks on paediatric respiratory disorders and with its updated material will continue to serve as an important resource for its intended audience. Like all textbooks some of the information will rapidly date but much of it will continue to be relevant until the next revision. In the section on Asthma, the information provided is generally consistent with current understanding and management approaches in paediatric asthma although the latter predominantly reflects North American management, which is not surprising given the authorship of these chapters. I would recommend this book to anyone seeking information on respiratory issues in children.
Find more allergy book reviews on the WAO Website here.