Medical Journal Review
Posted: September 2008
Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief, and Guest Editor Mark Glaum MD PhD
1. DEFECTIVE KILLING OF STAPHYLOCOCCUS AUREUS IN ATOPIC DERMATITIS IS ASSOCIATED WITH REDUCED MOBILIZATION OF HUMAN B-DEFENSIN-3 (HBD-3)
Synthesis and mobilization are necessary for the rapid elimination of S aureus. In this study, keratinocytes from skin biopsies from subjects with AD vs normals were compared. AD vs normal individual keratinocytes were defective in killing S aureus (P < .001). The constitutive levels of HBD-3 in the epidermal keratinocytes were similar in the 2 groups. However, AD cells were unable to mobilize HBD-3 efficiently to kill S aureus. HBD-3 mobilization and the ability to kill S aureus were significantly inhibited by IL-4 and IL-13 (P < .05). Antagonism of IL-4/10/13 with antibodies significantly improved mobilization of HBD-3 onto the surface of S aureus by skin from patients with AD (P < .01). The authors conclude that AD subjects have problems with S aureus skin infections as a result of increased levels of TH2 cytokines, which inhibit keratinocyte mobilization of HBD-3. Editor's comment: The vexing problem of atopic dermatitis becomes more complex. Perhaps methods to interfere with IL-4 and IL-13 would be beneficial for patients with this disease. Kisich KO, et al., JACI 2008; 122:62.
2. RITUXIMAB (R) AND INTRAVENOUS IMMUNE GLOBULIN (IVIG) FOR DESENSITIZATION DURING RENAL TRANSPLANTATION
20 highly sensitized (high HLA antibody titers or with donor-specific antibodies) received RX with IVIG and R (a chimeric anti-CD20 monoclonal antibody that reduces B cell and antibody levels). The mean panel-reactive antibody level was 44±30% after the second infusion of IVIG vs a 77±19% pretreatment level (P < 0.001). 16 of the 20 patients (80%) received a transplant, and at 12 months, the mean creatinine level was 1.5±1.1 mg per deciliter and the mean survival rates of patients and grafts were 100% and 94%, respectively. At study entry, the mean dialysis time for recipients to receive a transplant from a deceased donor was decreased from 144±89 months to 5±6 months. There were no serious adverse events, infections, or neurologic problems. This approach may represent a breakthrough in the care of sensitized persons awaiting transplantation who are currently on a much longer waiting list than non-sensitized patients and who often die because of this problem. Editor's comment: This appears to be a major breakthrough for patients who until now have been the least likely to receive renal transplants. Vo AA, et al., N Engl J Med 2008; 359:242. (editorial: Shapiro, pp. 305).
3. MAST CELL (MC) ACTIVATORS: A NEW CLASS OF HIGHLY EFFECTIVE VACCINE ADJUVANTS
Reviewed by Mark C. Glaum, MD, PhD
MCs have emerged as prominent effectors of lymphocyte activation and immune cell migration to draining lymph nodes. To explore the role of MC in the development of humoral immune responses, investigators combined small-molecule MC activators with vaccine antigens and measured changes in antigen-specific immunoglobulin responses. Subcutaneous and intranasal administration of these combined formulations induces large antigen-specific immunoglobulin G and A responses in vaccinated animals, and this effect appears to depend on MC-dendritic cell interaction and tumor necrosis factor (TNF). Intranasal administration of these formulations provides protection against anthrax lethal toxin challenge in vitro and against vaccinia virus challenge in vivo. Editor's comment: MC activators may function as vaccine adjuvants by promoting MC-dendritic cell interaction thus boosting protective antigen-specific antibody responses. McLachlan JB, et al., Nat Med 2008;14:536.
4. EPINEPHRINE: THE DRUG OF CHOICE FOR ANAPHYLAXIS - A STATEMENT OF THE WORLD ALLERGY ORGANIZATION (WAO)
WAO has targeted anaphylaxis as a disease which is inappropriately and under treated. This statement discusses the definition of anaphylaxis, following WAO nomenclature, and emphasizes the absolute need for epinephrine to treat this acute allergic emergency. There is some disagreement among the panel members who contributed to this paper about when epinephrine should be given in the course of progressive anaphylaxis. The majority of authors thought it should be given at the earliest sign or symptom of anaphylaxis, particularly, when associated with SCIT, while others felt that such treatment could be delayed until more definitive signs of anaphylaxis are present. Editor's comment: This article will help each physician understand the pharmacology of epinephrine, why it is essential for the successful treatment of anaphylaxis, and when it should be administered. Kemp SF, et al., WAO Journal 2008; Suppl 2: S18. Conflict: the Editor is one of the senior authors.
5. COMBINATION FLUTICASONE AND SALMETEROL (FP/SAL) VERSUS FIXED DOSE COMBINATION BUDESONIDE AND FORMOTEROL (BUD/F) FOR CHRONIC ASTHMA IN ADULTS AND CHILDREN (REVIEW)
The objective of this paper is to estimate the relative effects of FP/SAL and BUD/F in terms of asthma control, safety and lung function. To do so, randomized studies comparing fixed dose FP/SAL and BUD/F for a minimum of 12 weeks were reviewed for three primary outcomes: i) exacerbations requiring oral glucocorticoid bursts, ii) hospital admission, and iii) serious adverse events. 5537 participants from five studies were analyzed and the odds ratio of exacerbation requiring oral glucocorticoids did not differ significantly between treatments. Likewise, neither did hospital admissions or adverse events. Secondary outcomes also did not differ significantly and include lung function outcomes, symptoms, and rescue medication use. The authors state that the confidence intervals reported do not exclude clinically important differences between treatments in reducing exacerbations or causing adverse events. Likewise, the width of the confidence intervals for the primary outcomes justifies additional trials to better determine the relative effects of these drug combinations. Editor's comment: Thus far, treatment outcomes for fixed combinations of long-acting beta-agonists and ICS do not seem to differ. Lasserson TJ, et al., The Cochrane Collaboration, The Cochrane Library 2008; Issue 3.
6. USE OF MULTIPLE DOSES OF EPINEPHRINE (E) IN FOOD-INDUCED ANAPHYLAXIS IN CHILDREN
A total of 413 anonymous questionnaires distributed to families of children with food allergies during allergy outpatient visits were analyzed. 78 children (median, 4.5 yrs of age; range, 0.5 - 17.5 yrs) reported 95 reactions for which E was administered. Two doses of E were given in 12 (13%) and three doses in 6 (6%). Peanut, tree nuts, and cow's milk were responsible for >75% of these reactions requiring E. Patients with asthma were more likely to receive multiple doses of E (P = .027). The amount of food ingested or a delay in the initial E were not risk factors for multiple doses. The second dose was administered by a healthcare professional in 94% of the reactions. The authors conclude that 19% of food-induced anaphylactic reactions were treated with more than one dose of E and that prospective studies are necessary to establish risk factors for prescribing multiple E autoinjectors for children with food allergy. Editor's comment: Multiple E autoinjectors should be prescribed for food-induced anaphylaxis. Järvinen KM, et al., JACI 2008; 122:133.
7. COMPARISON OF A COMBINATION OF TIOTROPIUM (T) PLUS FORMOTEROL (F) TO SALMETEROL (S) PLUS FLUTICASONE (F) IN MODERATE COPD
605 patients with moderate COPD were randomized and treated in a 6-week multicenter, randomized, double-blind, parallel-group study to compare lung function with T, 18 µg qd, plus f, 12 µg bid, to S, 50 µg bid, plus F, 500 µg bid. A total of 592 patients (baseline FEV1, 1.32 ± 0.43 L/min) were analyzed and the 12-h lung function profiles in the T + F were statistically greater than those in the S + F. Differences in FEV1 and FVC at peak and each individual time point were all statistically significant in favor of TF. Predose FVC was significantly higher with the TF combo. The authors conclude that T + F is superior to S + F in patients with moderate COPD. Editor's comment: S probably should be added to T or vice-versa before adding an inhalational glucocorticosteroid for moderate COPD. Rabe KF, et al., Chest 2008; 134:255.
8. LONG TERM PROGNOSIS IN PRESCHOOL CHILDREN WITH WHEEZE: LONGITUDINAL POSTAL QUESTIONNAIRE STUDY 1993-2004
The object of this study was to follow a population of preschool children with and without a history of wheeze (as reported by their parents) for 6-11 years to determine prognosis and important predictive factors. 628 children aged less than five years at recruitment and with at least six years follow-up data were analyzed from two general practice populations in Great Britain. 201 (32%) parents reported wheeze at baseline, 27% of whom still had the symptom on the second occasion (persistent asthma). Predictors of persistent asthma were exercise induced wheeze (OR 3.94, 95% CI 1.72 to 9.00) and a history of atopic disorders (OR 4.44, 95% CI 1.94 to 10.13). If both predictors were present, it indicates a likelihood of 53.2% of developing asthma; whereas if one was present, the likelihood decreased to 17.2%, and neither present, the likelihood decreased even further to 10.9%. Family history was not predictive of persistent asthma. The authors conclude that a history of atopic disorders and exercise induced asthma are good predictors of asthma persisting into the future. Editor's comment: Here's new data indicating that exercise induced asthma and atopic disease early in life are good predictors of asthma in the future. Frank PI, et al., BMJ 2008; 336:1423.
9. THE DEVELOPMENT OF ALLERGIC INFLAMMATION
This article in Nature is a superb review of allergic inflammation with the following sections: Allergy and Gene-Environment Interactions; Allergen Sensitization and Epithelial Barriers; Features of Allergic Inflammation; IgE and the Exacerbation of Allergic Disorders; Suppression and Resolution of Allergic Inflammation; and Management of Allergies and Allergic Inflammation. It ends with a section on "What Next?", implying that molecular biology will alter the treatment of allergic diseases. Perhaps the most wonderful thing about this review is the extraordinary six figures included in the article. Editor's comment: This is a wonderful review and update for all physicians, no matter what their degree of knowledge about allergic inflammation. Galli SJ, et al., Nature 2008; 454:445.
10. SUBLINGUAL IMMUNOTHERAPY (SLIT) FOR LARGE LOCAL REACTIONS CAUSED BY HONEYBEE STING: A DOUBLE-BLIND, PLACEBO-CONTROLLED (DBPC) TRIAL
26 of 30 patients completed a SLIT randomized, DBPC study of large local reactions. After the baseline sting challenge, they were randomized to SLIT or placebo for six months. After a 6-week build-up period, they were maintained with 525 µg (35 µg every other day) of venom monthly. The sting challenge was repeated after six months. The median of the peak maximal diameter of the LLRs decreased from 20.5 to 8.5 cm (P = .014), whereas no change was seen in the placebo group (23.0 vs 20.5 cm, I = ns). There was one dropout in the active and three in the placebo group. No adverse reactions were reported. The authors call for more SLIT dose-ranging studies and studies of systemic reactions. Editor's comment: This study of LLRs is encouraging and may indicate that SLIT could be beneficial for systemic reactions to Hymenoptera insects. Severino MG, et al., JACI 2008; 122:44.