February 2006 World Medical Journal Review

Reviewed by Mark C. Glaum, M.D., Ph.D., WAO Guest Editor

1. SALMETEROL MULTICENTER ASTHMA RESEARCH TRIAL (SMART)
To compare the safety of adding salmeterol or placebo to "usual" asthma care, subjects (> 12 years old n=26,355) with physician-diagnosed asthma were randomized to receive salmeterol, 42 mcg twice daily via MDI or placebo MDI over 28 weeks in a double-blind observational study. Telephone follow-up was scheduled monthly. The study was terminated prior to completion due to safety findings. In the salmeterol group, there were small but statistically significant increases in respiratory-related deaths (24 vs 11; relative risk [RR]=2.16; 95% confidence interval [CI], 1.06-4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25-15.34) and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89). Differences occurred largely in African-American subpopulations. The study was not designed to control for adherence to other asthma medications, and follow-up was conducted only by phone interview every four weeks. Editor's comment: Studies specifically designed to assess safety of long-acting beta 2 agonists (LABA) in combination with inhaled corticosteroids are needed to stratify the potential risk of using LABA in subpopulations of asthmatic patients. Nelson HS, Weiss, ST, Bleeker ER, et al. Chest 2006; 129:15-26

2.) OMALIZUMAB PROTECTIVE FOR RUSH IMMUNOTHERAPY
Adults (mean age 33, n=159) with ragweed allergic rhinitis were enrolled in a randomized double-blind placebo-controlled study to receive 9 weeks of omalizumab (0.016 mg/kg/IgE/month) or placebo followed by one-day rush immunotherapy (RIT) with Amb a 1 (1.2-4 µg). After maintenance dose was achieved, omalizumab or placebo was continued for an additional 12 weeks along with maintenance immunotherapy. As expected, levels of ragweed-specific IgG increased with immunotherapy (>11 fold), while free IgE levels decreased in omalizumab-treated patients (>10 fold). Subjects receiving omalizumab experienced fewer adverse reactions (33%) during RIT than those receiving placebo (55%), and post-hoc blind analysis suggested an even greater reduction in serious adverse events (symptoms in >1 organ system) in the omalizumab group vs placebo (5.6% vs 25.6%) following RIT. Once maintenance was achieved, subjects receiving omalizumab plus immunotherapy also reported fewer symptoms in the ragweed season as compared to placebo. Editor's comment: Omalizumab may protect against systemic reactions from immunotherapy in allergic rhinitis patients. Casale TB, Busse WW, Kline LN, et al. J Allergy Clin Immunol 2006; 117:134-40

3.) ROLE OF TUMOR NECROSIS FACTOR ALPHA IN REFRACTORY ASTHMA
Subjects with refractory (severe persistent) asthma, mild to moderate asthma and non-asthmatic controls underwent peripheral blood draw to assess for TNF-alpha activity on mononuclear cells. Compared to non-asthmatic controls and mild to moderate asthmatics, subjects with severe persistent asthma demonstrated increased expression of membrane-bound TNF-alpha, TNF-alpha receptor 1, and TNF-alpha converting enzyme on peripheral blood mononuclear cells. Ten subjects (ages 25-59 years) with refractory asthma were then enrolled in a randomized, double-blind, placebo-controlled, crossover study to determine if TNF-alpha blockade would improve methacholine sensitivity, asthma quality of life scores and post-bronchodilator FEV1. Following ten weeks of treatment with the TNF-alpha receptor antagonist, etanercept, subjects in the treatment group were less sensitive to methacholine provocation and showed improvement in asthma quality of life scores and in post-bronchodilator FEV1. Editor's comment: This pilot study suggests that TNF blockade may improve symptoms and pulmonary function of severe asthmatics. Larger clinical trials are warranted to validate this association. Please note excellent accompanying editorial. Berry MA, Hargadon B Shelley M, et al. N Engl J Med 2006;354;7: 697-708, Erzurum SC;354;7: 754-58

4.) LEUKOTRIENE PATHWAY POLYMORPHISMS INFLUENCE MONTELUKAST RESPONSIVENESS IN ASTHMA
This is a pharmacogenetic ancillary study associated with a randomized double blind parallel-designed trial designed to compare the efficacy of placebo, theophylline or montelukast as add-on therapy in mild to moderate persistent asthma. DNA was collected from 252 participants who were randomized to receive montelukast or placebo. Asthmatic subjects receiving montelukast as add on therapy who demonstrated improvement in FEV1 or asthma exacerbation rate as compared to placebo, demonstrated unique genetic polymorphisms associated with the leukotriene pathway. In particular, examination of the gene encoding for membrane-bound 5 lipoxygenase (ALOX5) revealed several polymorphisms associated with improved clinical response to montelukast. Editor's note: Pharmacogenetic studies will allow clinicians to tailor therapeutic regimens for unique asthma phenotypes. Lima JJ, Zhang S, Grant A, et al. Am J Respir Crit Care Med 2006; 173:379-85

5.) EXPOSURE TO INDOOR NITROGEN DIOXIDE (NO2) AND CHILDHOOD ASTHMA
This cohort study evaluated 728 asthmatic children (age<12) to examine the association of respiratory symptoms with NO2 levels in the home. The frequency of asthma-related symptoms was recorded by a parent one month prior to measurement of NO2 in the subject's home. Mean (SD) levels of NO2 were 8.6 (9.1) ppb in homes with electric stoves vs 25.9 (18.1) ppb in homes with gas stoves. Both of these numbers are well below the USA Environmental Protection Agency (53 ppb) outdoor standard. When controlling for age, ethnicity, medication use and season, children living in homes with elevated NO2 and gas stoves had significantly increased likelihood of wheeze, shortness of breath and chest tightness. Editor's comment: Indoor pollutants may contribute to worsened asthma symptoms. Belanger K, Gent J, Triche EW, et al. Amer J Respir Crit Care Med 2006;173: 297-303

6.) T-CELL-MEDIATED HYPERSENSITIVITY TO QUINOLONES
Many drug-related exanthemas are non-IgE-mediated, and methods available to reliably test for drug hypersensitivities are limited. Six patients with cutaneous eruptions associated with quinolone antibiotics were investigated by in vivo and in vitro methods to determine the nature of drug-T cell interactions and to evaluate for any cross-reactivity among quinolones. Patch tests against suspect parent drugs were positive in three of six patients. Lymphocyte proliferation studies demonstrated enhanced tritiated thymidine uptake upon exposure to suspected quinolone drugs in all six subjects, while no increase in uptake was reported for drug-exposed and naïve control subjects. Cross-reactivity among quinolone drugs was observed. Editor's comment: New methodologies may aid in the evaluation of non-IgE-mediated drug reactions. Schmid DA, Depta JPH, Pichler WJ, et al. Clin Exper Allergy 2006; 36:59-69

7.) ACE INHIBITORS AND OBSTRUCTIVE SLEEP APNEA
Based on an observation of a patient with ACE-induced cough and obstructive sleep apnea (OSA) who had improvement in both conditions following discontinuation of the ACE inhibitor, 8 subjects with OSA on an ACE inhibitor for hypertension were enrolled in a prospective study. Four subjects experienced cough after initiation of ACE inhibitor treatment, and the other four did not. Subjects underwent arterial blood gas sampling, measurement of exhaled nitric oxide (NO) and ambulatory polysomnography during ACE inhibitor treatment and one month after substitution of the ACE inhibitor with diuretic therapy. Subjects with cough on the ACE inhibitor demonstrated an increased apnea-hypopnea index, increased exhaled NO and lower mean oxygen saturation than subjects without cough. Each of these parameters improved with substitution of the ACE inhibitor in subjects with cough. Editor's comment: ACE inhibitors are known to trigger symptoms of cough and may also worsen OSA. Cicolin A, Mangiardi L, Mutani R, et al. Mayo Clin Proc 2006;81(1): 53-55

8.) DIAGNOSIS AND MANAGEMENT OF COUGH: ACCP EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES
This is an updated version of the original evidence-based consensus panel report on "Managing Cough as a Defense Mechanism and as a Symptom" originally published in a 1998 edition of Chest. This updated edition attempts to focus guidelines on evidence supporting the diagnosis and management of cough in adult and pediatric populations. This 292-page supplement separates discussion of the etiology of cough into more than 20 separate chapters dealing with associated clinical conditions including: rhinosinusitis, asthma, the common cold, gastroesophageal reflux, acute bronchitis, lung tumors, aspiration, habit, hemodialysis and others. In addition to providing clinical practice guidelines and algorithms, this edition centralizes a vast body of literature studying the etiology of cough. Editor's comment: Chronic cough is a common complaint, and it is often a difficult condition to diagnose and treat. Irwin RS, Baumann MH, Bolser DC, et al. Chest 2006; 129:supplement

9.) REVIEW OF ANTIBIOTIC ALLERGY
This clinical case vignette and review highlights a common reason for allergy consultation. Evidence supporting the role for limited antibiotic skin testing is presented and current guidelines, when applicable, are discussed. The review concludes with clinical recommendations from the authors who are recognized experts in the field. Editor's comment: This is a "must read" for consultants who see patients with antibiotic drug allergy and for primary care physicians who commonly encounter cutaneous drug eruptions. Gruchalla RS, Pirmohamed M N Engl J Med 2006;354;6: 601-09

10.) PHARMACOTHERAPY FOR PEDIATRIC ASTHMA
This is a concise review of asthma treatment strategies in pediatric populations. There are several useful charts that summarize relative inhaled corticosteroid dose equivalencies, short-acting therapeutic strategies, and asthma controller medication treatment guidelines adapted for pediatric practice. Editor's comment: This review summarizes pediatric asthma therapeutics in an easily accessible format. Ostrom NK, J Pediatrics 2006;148: 108-14

No abstract is available for this article.