Medical Journal Review
Posted: June 2008
Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief
1. Budesonide/formoterol (B/F) maintenance and reliever therapy: impact on airway inflammation in asthma
1,538 patients were randomized for six months to open-label B/F maintenance (160/4.5 µg twice daily) and B/F as needed reliever therapy. They were compared to guideline-based practices (GBP) as managed by individual investigators. There were no differences in time to severe exacerbation and severe asthma exacerbation rate. However, there were fewer ER visits and hospitalizations with B/F maintenance and reliever therapy (not statistically significant). Mean daily inhaled corticosteroid dose, reliever use, asthma medication costs and total annual costs per patient were all significantly lower with the B/F maintenance and reliever therapy vs. GBP. The authors conclude that B/F maintenance and reliever therapy vs. GBP achieves similar outcomes with significant lower costs. Editor's comment: More data demonstrating that B/F maintenance and reliever therapy is an effective means to control asthma. Sears MR, et al., Eur Respir J 2008; 31:982.
2. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome (HIES, 'Job's syndrome')
TH17 cells, a subset of helper T cells, are critical to clear fungal and extracellular bacterial infections. These authors show that interleukin (IL)-17 production ex vivo by T cells from HIES individuals fails to produce IL-17, but not IL-2, tumour-necrosis factor or interferon-γ, on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or streptokinase. Purified naïve T cells did not differentiate into IL-17 producing (TH17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-γt, consistent with a crucial role for STAT3 signaling in the generation of TH17 cells. Mutations in HIES patients have been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3), presumed to underlie HIES. These data suggest that a lack of TH17 cells in HIES is a mechanism for recurrent infections. Editor's Comment: Improving IL-17 production may help patients with HIES. Milner JD, et al., Nature 2008; 452:773.
3. Allergens are distributed into few protein families and possess a restricted number of biochemical functions
Allergen data from the Allergome database and protein family definitions from the Pfam database were merged into a databased, AllFam, accessible on the Internet at http://www.meduniwien.ac.at/allergens/allfam/. 707 allergens were classified by sequence into 134 AllFam families containing 184 Pfam domains or 2% of 9318 Pfam families. These data indicate a similarity in protein structure in all allergens. The small number of protein families that contain allergens, and the narrow functional distribution of most allergens, confirm the existence of yet unknown factors that render these proteins allergenic. Editor's comment: Brilliant research bringing together 2 databases to show that most allergenic structures are contained in relatively few protein families. Radauer C, et al., J Allergy Clin Immunol 2008; 121:847.
4. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc
The use of monomeric immunoglobulin G (IgG) confers anti-inflammatory activity for a variety of autoimmune diseases. This article demonstrates that the anti-inflammatory activity of IgG is dependent on sialylation of the N-linked glycan of the IgG Fc fragment. The authors identified the precise glycan requirements for this anti-inflammatory activity, allowing them to engineer an appropriate IgG1 Fc fragment, thus generating a fully recombinant, sialylated IgG1 Fc with greater enhanced potency, thereby precisely defining the biological active component of IVIG. They conclude that it may be possible to develop an IVIG replacement with improved activity and availability. Editor's comment: It would be ideal to capture the anti-inflammatory effect of IVIG without the need for human donors. Anthony RM, et al., Science 2008; 320:373.
5. Nonsurgical management of obesity (O) in adults
O is a major risk factor for asthma, particularly in women. This article reviews the strategies involved in the non-surgical management of O. Assessing co-existing conditions, such as hypertension, glucose intolerance, dyslipidemia, and obstructive sleep apnea is important, and a reduction as low as 5-10% of body weight may be sufficient to favorably modify a variety of outcomes for these diseases. Lifestyle approaches include low-fat diets, low-glycemic-index diets, high-protein diets, and specific commercialized diets. The most interesting section of the article discusses drugs prescribed for weight loss, none of which are extremely effective vs. placebo. These medications include diethylpropion, orlistat, phentermine, sibutramine, and rimonabant. Not only is weight reduction difficult, maintaining it is equally difficult. Eating a low-fat diet, frequent self-monitoring of weight and food intake, high levels of physical activity, long-term patient-physician contact, and the careful use of medications are essential measures for successful outcomes. Editor's comment: This is a wonderful discussion outlining the treatment of obesity, a risk factor for severe asthma. Eckel RH, N Engl J Med 2008; 358:1941.
6. Severe atopic dermatitis (AD) is associated with a high burden of environmental Staphylococcus aureus (S. aureus)
These authors quantified the S. aureus burden in homes of patients with AD of varying severities and normal subjects. Dust was collected from their bed, bedroom floor, and home vacuum cleaner bag and the DNA extracted and quantified for the S. aureus-specific femB gene using quantitative real-time PCR. In general, participants with severe AD had significantly more S. aureus DNA in their bed dust than those with moderate, mild or no AD. Similar patterns were observed for dust from the bedroom floors and vacuum bags. The authors conclude that the high levels of S. aureus could contribute to disease severity and persistence in AD patients. Editor's comment: Patients with AD are colonized with S. aureus. Higher levels of this same organism are found in homes of AD subjects and correlate with its severity. Leung AD, et al., Clin Exp Allergy 2008; 38:789.
7. Safety of long-acting β-agonists in stable COPD (A systematic review)
This meta-analysis of 27 randomized clinical trials (≥ one month in duration) compares LABAs with placebo (P) or anticholinergics in stable, poorly reversible, and reversible COPD. LABAs reduced severe exacerbations vs. placebo (RR, 0.78; 95% confidence interval [CI], 0.67 to 0.91). There was no significant difference between LABA and P groups for respiratory deaths. LABAs used with inhaled corticosteroids (ICS) reduced the risk of respiratory deaths compared to LABAs alone (RR, 0.35; 95% CI, 0.14 to 0.93) and significantly improved airflow limitation measures, health-related quality-of-life and decreased the use of rescue medication. Tiotropium bromide vs. LABAs decreased the incidence of severe COPD exacerbations (RR, 0.52; 95% CI, 0.31 to 0.87). There is no increased risk of respiratory deaths associated with the use of LABAs. Editor's comment: Tiotropium bromide is first-line therapy for stable COPD followed by a LABA preferably used with an ICS. Rodrigo GJ, et al., Chest 2008; 133:1079. (editorial: Sears, p. 1057).
8. Issues in the diagnosis of α1-antitrypsin deficiency (AATD)
This is a thorough review of AATD, an under-recognized and underdiagnosed worldwide problem. The authors outline the diagnostic challenges, guidelines to confirm the diagnosis, and a call to physicians to have a high index of suspicion for this deficiency. Those at highest risk are those who have early signs or symptoms of emphysema, unexplained liver disease, necrotizing panniculitis, anti-proteinase 3-positive vasculitis, bronchiectasis, or a family history of any of these diseases. The method to diagnose this disease is outlined in an algorithm. The authors conclude with treatment options which include α1 proteinase inhibitor therapy. Editor's comment: AATD is a common problem, with a similar prevalence to cystic fibrosis, but remains greatly underdiagnosed and treated. Rachelefsky G, Hogarth K, J Allergy Clin Immunol 2008; 121: 833.
9. Nasal and sinus endoscopy for medical management of resistant rhinosinusitis, including postsurgical patients
This paper outlines the utility of performing nasal endoscopy, practiced by some allergists since 1980. However, for reasons unexplained, allergists, in general, have not embraced its use. It discusses the history of nasal endoscopy and outlines the advantages of flexible vs. the rigid endoscope. There are few safety issues for its routine use. The article explains how endoscopy can assist the physician to understand and follow patients with a variety of nasal problems, particularly, chronic rhinosinusitis. Editor's comment: Nasal endoscopy is not only used to diagnose and assess nasal pharyngeal problems but also oral and laryngeal problems. It should be utilized by allergists throughout the world. Tichenor WS, et al., J Allergy Clin Immunol 2008; 121:917.
10. Irritable Bowel Syndrome (IBS)
IBS has a worldwide prevalence of 10 - 15%. It is always included in differential diagnosis of most chronic GI problems, and, in particular, in the differential diagnosis by many physicians and patients of food allergy. This is an excellent review of IBS and its differential diagnosis, which includes celiac sprue, microscopic and collagenous colitis and atypical Crohn's disease, and chronic constipation. An algorithm of the differential diagnosis is included as well as an extensive list of medications to treat IBS. Editor's Comment: Patients with IBS frequently present to the allergist because they wonder whether or not they are allergic to certain foods. IBS is always in the differential. Mayer EA, N Engl J Med 2008; 358:1692.
11. Screening for osteoporosis in men: A systematic review for an American College of Physicians guideline
This study identifies men at risk for low bone mineral density (BMD) and fracture. The most important risk factors for low BMD-mediated osteoporotic fracture in men without a known diagnosis of osteoporosis or fracture are increased age (>70 years) and low body weight (body mass index <20 to 25 kg/m2) or weight < approximately 70 kg. Additional risk factors include a variety of health conditions and medications, particularly, weight loss, physical inactivity, prolonged corticosteroid use, previous osteoporotic fracture and androgen deprivation therapy. Cigarette smoking is associated with lower BMD, but there is less evidence in men to determine its association with fracture. Editor's comment: Osteoporosis is a risk factor for patients with chronic obstructive lung disease (COPD) as well as those treated with glucocorticosteroids. Appropriate screening of men is as equally important as is screening of women for this disease. Liu H, et al., Annals Int Med 2008;148:685.