January 2007 World Medical Journal Review
Reviewed by Prof. Richard F. Lockey, MD., WAO Web Editor-in-Chief
1. Rapid effects of inhaled corticosteroids in acute asthma
Seventeen studies (470 adults and 663 children and adolescents) met the criteria for inclusion in this review of treatment with inhaled corticosteroids (ICS) within one to four hours of presentation of an asthma exacerbation. Final outcomes were admission and ED discharge rates. After the 2- to 4- hour protocol, a greater reduction of admission rate was observed in trials that used multiple doses of ICS, especially when compared with placebo (odds ratio{OR}, 0.30; 95% confidence interval {CI}, 0.16 to 0.55). ICS patients improve more rapidly when compared with placebo or systemic corticosteroids (SCS) increasing the probability of early ED discharge (OR 4.70; 95% CI, 2.97 to 7.42; p = 0.0001). Spirometric and clinical measures improved as early as 60 minutes with ICS. Benefits were obtained only when patients received multiple doses of ICS with ß-agonist compared with placebo or SCS. In conclusion, ICS used early in multiple doses administered in time intervals of < or = to 30 minutes over 90 to 120 minutes are especially beneficial. Editor's comment: High dose ICS plus ß-agonists used within four hours on multiple occasions for acute asthma effectively decreases morbidity from severe asthma exacerbations. Rodrigo GJ, Chest 2006; 130: 1301
2. Effects of continuing or stopping alendronate (A) after 5 years of treatment
One thousand and ninety-nine (1099) postmenopausal women with a mean of five years of prior A treatment were randomized to A, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (P) (n = 437) for five years. Compared with A, switching to P resulted in declines in bone mineral density (BMD) at the total hip (P< .001) and spine (P<.001), but mean levels remained at or were above pretreatment levels 10 years earlier. The cumulative risk for nonvertebral fractures was not significantly different between the two groups. Those on A had significantly lower risks of clinically recognized vertebral fractures (5.3% for P, 2.4% for A) but no significant reduction in morphometric vertebral fractures (11.3% for P, 9.8% for A). The authors suggest that the discontinuation of A after five years does not significantly increase the fracture risk, however, women at high risk of clinical vertebral fractures may benefit by continuation of A. Editor's comment: Physicians who treat asthma and allergic and immunologic diseases need to know how to diagnosis and treat osteopenia and osteoporosis. SG. Black DM, et al. JAMA 2006; 296: 2927. Editorial, Colón-Emeric C. JAMA 2006; 296: 2968.
3. Long-term proton pump inhibitor (PPI) therapy and risk of hip fracture
This is a nested, case-control study using a research database from the United Kingdom. The cohort consisted of users of PPI therapy versus nonusers of acid suppression drugs older than 50 years. Similar nested, case-control analysis for histamine 2 receptor antagonists was performed. The adjusted odds ratio (AOR) for hip fractures associated with more than one year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). For long-term high dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The risk increased with duration of PPI therapy, i.e., up to four years. The authors conclude that PPI therapy significantly increases the risk of hip fracture, possibly secondary to acid suppression and decreased calcium absorption. Editor's comment: The risk-benefit of PPI therapy needs to be considered. Individuals with asthma commonly have gastroesophageal reflux disease. Using the lowest effective PPI dose and increasing consumption of dairy products, calcium supplements with meals, and vitamin D therapy make sense. Yang Y-X, et al. JAMA 2006; 296: 2947.
4. Asthma, influenza, and vaccination - Review
Influenza (I) viruses, like other viruses, exacerbate asthma (AS) and are frequently associated with hospitalization. Inactivated I vaccine (V) does not exacerbate AS. Likewise, medium- or high-dose inhaled or short-term systemic corticosteroids (CS) do not affect antibody responses to I A-antigens. High-dose inhaled CS may affect the response, but this is controversial. There is still a question of whether inactivated I V prevents the exacerbation of asthma. Live attenuated I V, given by nasal spray, is better accepted by children and is more efficacious. Universal I vaccination of all children will facilitate control of epidemic I and provide an infrastructure for control of future I pandemics. Editor's comment: I V is indicated for all asthmatics, and I V immunization of all children will facilitate control of this disease. Glezen W P, JACI 2006; 118: 1199.
5. Anti-IL-5 (MEPOLIZUMAB) therapy for eosinophilic esophagitis
This is an open-label, phase I/II, safety and efficacy study of anti-IL-5 in four adult patients with eosinophilic esophagitis (EE) with longstanding dysphagia and esophageal strictures. They were given three infusions of anti-IL-5 without a change in current therapy. Peripheral blood eosinophils and percent of CCR3+ cells decreased by 6.4- and 7.9-fold (P<.05), respectively, as did mean and maximal esophageal eosinophilia, (P< .001) and (P<.05), respectively. Patients' clinical outcome and quality of life improved (P = .03) and therapy was tolerated. IL-5 may be a therapeutic option for EE. Editor's comment: More studies are needed with anti-IL-5 for EE. Stein ML, et al. J Allergy Clin Immunol 2006; 118: 1312.
Numbers 6 & 7 were reviewed by Gary Hellermann, PhD, University of South Florida, Tampa, Florida
6. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells
RANKL, the ligand of RANK (receptor activator of NF-?B), is up-regulated in keratinocytes when skin is UV irradiated and binds to RANK expressed on dendritic cells of the skin, the Langerhans cells (LC). The evidence comes primarily from experiments on transgenic mice over-expressing RANKL, and these mice show 2-3 times greater systemic numbers of CD4+CD25+ T regulatory cells (Tregs) than the wild type. The Tregs from RANKL-transgenic mice suppress effector T cells and produce characteristic biomarkers such as IL-10. The authors conclude that the peripheral expansion of Tregs results from an increase in cutaneous RANKL, which stimulates LC via binding to RANK, to promote proliferation of Tregs. Editor's comment: Cutaneous stimulation of LC by increasing RANKL in the presence of a specific antigen may provide a new treatment for suppressing allergic inflammation. Loser K, et al. Nature Medicine 2006; 12: 1372.
7. Natural killer T Cells and CD8+ T Cells are dispensable for T Cell-dependent allergic airway inflammation (AAI)
Das et al compare the contribution of T helper type 2 (Th2) cells, natural killer T cells (NKT) and CD8+ T cells to AAI. Ovalbumin-sensitized transgenic mice with gene knockouts that eliminated CD4+ T cells show no eosinophil infiltrate or increased mucus in the lungs after ovalbumin challenge. However, mice deficient in NKT and CD8+ T cells had ovalbumin-induced AAI comparable to the wild type. Therefore, the authors conclude that NKT cells with or without memory CD8+ cells are not required for AAI. The authors of an earlier paper (Akbari et al.), which supports the role of NKT and DC8+ cells in AAI, reply that airway hyper-responsiveness (AHR) is a better measure of asthma than eosinophilia and mucus production and cite two studies supporting involvement of NKT cells in AHR. They point out that while allergen-specific Th2 cells are necessary in allergic rhinitis, the AHR characteristic of asthma appears to involve NKT cell regulation of other factors in the lower respiratory tract. Editor's comment: The complexity of the immune system is legendary, and the jury is still out on the relative contributions of all players. Das J, et al. Nature Medicine 2006; 12: 1345.
8. Validation of current joint AAAAI & ACAAI guidelines for antibody response to the 23 pneumococcal vaccine (PPV) using a population of HIV-infected children
This case-controlled study compared changes in PPV AB titers in 95 immunocompetent children versus 22 immunodeficient HIV-infected children, ages 2 to 15 years. Authors confirm the proposed recommendations of a 4-fold increase in titers after PPV immunization for at least 50% of the serotypes tested (6 out of 12) as adequate responses in children between 2 and 15 years. For children who have previously received the 7-pneumococcal conjugate vaccine, positive responses for two out of four serotypes not included in this vaccine are considered adequate. Editor's comment: This study outlines criteria to accurately identify children who lack optimal responses to one immunization with PPV. Kamchaisatian W, et al. JACI 2006; 118: 1336. Potential conflict of interest: authors are USF colleagues of RFL.
9. Does allergen-specific immunotherapy represent a therapeutic option for patients with atopic dermatitis (AD)?
This review article summarizes the evidence associated with house dust mite (HDM) allergens as an allergic trigger factor for AD. They offer evidence that the enzymatic activity of HDM facilitates allergenic penetration into the impaired, epidermal skin barrier of AD inducing both immediate- and delayed-type reactions which contribute to the impairment of AD. The authors review data on specific immunotherapy (SIT) and AD. They conclude that the value of SIT for treatment of AD is uncertain at this time. Editor's comment: This is must reading for all physicians who treat severe AD. More controlled studies are necessary on treatment efficacy of IT for AD. Bussmann C, et al. JACI 2006; 118: 1292.
10. Why do we develop food allergies?
This author reviews how the immune system detects the differences between food and pathogens in a systematic discussion on how food represents a special challenge for the immune system of the gut, which is designed to guard against invaders. In-utero immunologic responses, secretory immunoglobulin A and oral tolerance all contribute to the immunologic acceptance of multiple food antigens. The author reviews work that demonstrates that oral tolerance to food is directly linked to the development of CD25+ Treg cells. He goes on to state that the current increase of allergies in industrialized countries is a small price to pay for the remarkable reduction in infant mortality, provided by the intermission of pathogens through improved hygiene. Editors comment: A wonderful update on the pathogenesis of food allergy. Brandtzaeg P, American Scientist 2006; 95: 28.
11. High prevalence of aeroallergen sensitization among infants of atopic parents
A birth cohort of infants was first identified from birth records and enrolled in this study if a parent reported allergic respiratory symptoms and had a positive skin prick test (SPT) to a common aeroallergen. At one-year, these infants were tested to the same 15 aeroallergens. Of 680 infants, 28 % were SPT positive to one or more aeroallergens and/or food and 18 % positive to one or more aeroallergens (9.7 %, pollen; 7.5 %, molds; 4.3 % house dust mite and/or cockroach; and 3.4% dog and/or cat). Sixty-six percent remained positive at 2-years. The authors conclude that infants born to atopic parents who are SPT positive are at increased risk for aeroallergen sensitization during infancy, which persists to age 2-years and suggest that SPT before age 2 may be indicated to identify such children. Editor's comment: Allergic sensitization starts early in life to both food and inhalant allergens. LeMasters G, et al. J Pediatrics 2006; 149:505. Potential conflict of interest: Drs.Grace LeMasters and James Lockey are relatives of RFL.
12. Immunologic response to administration of standardardized dog allergen extract at differing doses
Cluster immunotherapy was administered to 28 patients with dog allergy randomly assigned to placebo or an acetone-precipitated extract containing 0.6 µg, 3.0 µg, or 15 µg Can f 1 per 0.5 ml maintenance dose. Results show a significant dose-dependant response in suppression of titrated skin prick tests and delayed cutaneous responses. Dog-specific IgG4 increased significantly in both high-dose and low-dose therapy, and there was a dose-dependant suppression of secreted TNF- and increase in secreted TGF-ß. Likewise, there was a dose-dependant trend in suppression of secreted IL-4 with a significant decrease from baseline in the high-dose group. No changes occurred in symptom scores: lymphocyte proliferation; secreted IFN-γ , IL-10, or IL-5; or intracellular cytokine production. The lack of clinical response was attributed to a misunderstanding in the conduct of nasal challenges resulting in suboptimal dosing. The authors conclude that a maintenance dose of 15 µg of Can f 1 produces the greatest and most consistent immunologic response. Editor's comment: Immunotherapy with similar doses of Fel d 1 and Can f 1 produces similar immunologic responses. Lent AM, et al. JACI 2006; 118:1249.
