October 2006 World Medical Journal Review

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

1. ALENDRONATE IS MORE EFFECTIVE THAN ALFACALCIDOL IN PREVENTING GLUCOCORTICOID-INDUCED BONE LOSS
Subjects (n=201) who were starting glucocorticoids at a daily dose equivalent to 7.5 mg of prednisone secondary to rheumatic disease were enrolled in double-blind, placebo-controlled trial for an 18-month period. Subjects were randomized to receive alendronate (10 mg) plus placebo or alfacalcidol (1 mg) plus placebo daily. Measurement of bone mineral density and incidence of morphometric vertebral deformities were primary and secondary outcomes, respectively. In subjects receiving alendronate, lumbar spine bone mineral density scores increased by 2.1% while lumbar spine bone mineral density scores decreased by 1.9% in the alfacalcidiol group. Editor’s comment: Alendronate effectively inhibits bone loss due to sustained glucocorticoid use. De Nijs RNJ, Jacobs JWG, Lems WF, et al. N Engl J Med 2006; 355:675-84

2. MAST CELLS REGULATE T CELL TOLERANCE
Mast cells are known to propagate allergic inflammation in response to allergen challenge. Observations that successful skin grafts in mice become infiltrated with T regulatory cells (T_reg) and mast cells led to the hypothesis that T_reg - mast cell interactions may mediate graft tolerance. To evaluate this, investigators attempted to induce therapeutic tolerance in genetically engineered, mast cell-deficient mice by skin graft transplantation. All transplant attempts in mast cell deficient mice were quickly rejected. Reconstitution of mast cell populations in deficient mice restored the host’s ability to accept grafts for prolonged periods of time. Editor’s comment: Mast cells may possess immunomodulatory functions that go well beyond their established role in allergy. Please see excellent accompanying editorial. Lu L, Lind EF, Gondek DC, et al. Nature 2006;442:997-1002, Waldmann H, 987-8

3. ANTI-INFLAMMATORY EFFECTS OF AZITHROMYCIN IN COPD
Macrolide antibiotics may possess anti-inflammatory properties. Chronic obstructive pulmonary disease (COPD) is associated with increased apoptosis and impaired phagocytosis in the airways. Alveolar macrophages were obtained by bronchoalveolar lavage (BAL) from 9 subjects with COPD and 10 healthy controls. Alveolar macrophages were purified, then ability to phagocytose apoptotic epithelial cells or neutrophils was measured by flow cytometry in the presence or absence of aziththromycin (500 ng/ml^-1). Phagocytosis by alveolar macrophages was reduced in subjects with COPD as compared to healthy controls. Incubation of alveolar macrophages from COPD subjects in azithromycin improved phagocytosis of epithelial cells and neutrophils to levels near those of healthy controls. Editor’s comment: Low dose azithromycin may serve as an adjunct therapy in COPD by promoting increased alveolar macrophage phagocytosis. Hodge S, Hodge G, Brozyna H, et al. Eur Resp J 2006; 28:486-95

4. WAIT AND SEE PRESCTIPTION LIMITS ANTIBIOTIC USE IN ACUTE OTITIS MEDIA
Two-hundred and eighty-three pediatric patients diagnosed with acute otitis media in an emergency department were randomized to receive a "wait and see prescription" (only to be filled if symptoms were unchanged or worse in 48 hours) or a standard prescription for antibiotics. Structured phone interviews were conducted 4 to 6, 11 to 14, and 30 to 40 days after enrollment to determine outcomes. Parents of subjects who received a wait and see prescription were more likely not to fill the antibiotic prescription than parents who received a standard prescription (62% vs. 13% p < 0.001). There was no difference between groups in regard to frequency of subsequent fever, otalgia or unscheduled visits for medical care. Editor’s comment: Watchful waiting reduces antibiotic usage in acute otitis media. Spiro DM, Tay K, Arnold DH, et al. JAMA 2006; 296:1235-41

5. PROLONGED BREASTFEEDING ASSOCIATED WITH INCREASED RISK OF ATOPIC DERMATITIS
Two-hundred healthy newborns were enrolled in a prospective 20-year follow-up study to determine if prolonged breastfeeding (greater than 6 months) conferred additional protection against the development of atopy. Mothers of subjects were encouraged to exclusively breastfeed for as long as possible. Subjects were examined and skin prick tested at ages 5, 11 and 20 years. Exclusive breastfeeding for nine months or more was associated with higher incidence of atopic dermatitis (p = 0.002) at age 5. Editor’s comment: Breastfeeding for the first six months of life is currently recommended; prolonged breastfeeding greater than nine months may promote development of atopic dermatitis. Pesonen M, Kallio MJT, Ranki A, Siimes MA. Clin Exp Allergy 2006; 36:1011-18

6. SELF-REPLICATING DNA VACCINE ENCODING Phl p5 PREVENTS ALLERGIC SENSITIZATION
Immunization with DNA-based allergen vaccines has yielded promising results as a potentially novel modality of immunotherapy. Limitations to this approach include reduced immunologic responses in humans and relatively high concentrations of DNA vaccine required to induce immunity. Investigators examined the effectiveness of using a self-replicating (replicon) DNA vaccine to induce protection against allergenic sensitization in a mouse model. Mice were immunized intradermally with replicon Phl p5 DNA or conventional DNA vaccines followed by sensitization and intranasal challenge with Phl p5. Titers of IgG1, IgG2a and IgE were measured from sera, while eosinophil counts and cytokine levels were measured from BAL fluid. Lung sections were analyzed for presence of inflammatory infiltrates, increased mucus production and epithelial damage. Replicon DNA vaccination with Phl p5 resulted in reduced expression of specific IgE, Th1-biased cytokine expression, fewer eosinophils and reduced markers of airway inflammation at a dose 100-fold less than a comparable conventional DNA vaccine. Editor’s comment: Self-replicating DNA vaccines may pave the way for usage of DNA allergen vaccines in humans. Gabler M, Scheiblhofer S, Kern K, et al. J Allergy Clin Immunol 2006; 118:734-41

7. EVIDENCE FOR SUPERANTIGENS IN CHRONIC RHINOSINUSITIS
Superantigens have been implicated as a cause of chronic rhinosinusitis through the oligoclonal expansion of T cell populations with subsequent mucosal inflammation. Eighteen subjects with chronic rhinosinusitis with nasal polyposis scheduled for surgery were prospectively recruited. Nasal polyp tissue and blood samples were analyzed by flow cytometry for the distribution of 24 specific T cell receptor (TCR) Vβ domains typically associated with a superantigen response. Each of the 18 subjects demonstrated expansion of nasal polyp lymphocytes expressing TCRs with specific Vβ domains. The average number of Vβ clones was greater in nasal polyps as compared to peripheral blood lymphocytes implicating the nasal mucosa as an antigen source. Editor’s comment: Staphylococcal toxins may be central to the development of chronic rhinosinusitis with nasal polyposis. Conley DB, Tripathi A, Seiberling KA, et al. Am J Rhinol 2006; 20:451-5

8. AIRWAY RETICULAR BASEMENT MEMBRANE THICKENING IN ASTHMA IS DISTINCT FROM THAT SEEN IN FIBROSIS
Airway reticular basement membrane (RBM) thickening in asthma is thought to be a consequence of subepithelial fibrosis that is characterized by an irreversible accumulation of interstitial collagen. Abnormal thickening of the RBM in asthma can be seen as early as age 4 and may be maximally thickened by ages 6-16 in severely asthmatic children, although this may be partially reversible. Asthmatic adults (n =10), children (aged 6-10 yrs (n = 10)), and infants (aged 0.3-2 yrs (n = 10)) as well as age-matched non-asthmatic controls were recruited. All subjects underwent bronchoscopy and endobronchial biopsy. Specimens were examined by electron microscopy. Histologic examination of the thickened RBM in asthmatics revealed a normal ratio of fibrils to matrix and the fibrils did not resemble those of interstitial collagen. These features were comparable to age-matched controls. Editor’s comment: Airway remodeling in asthma may result from a different process than that seen in fibrotic lung disease. Saglani S, Molyneux C, Gong H, et.al. Eur Resp J 2006; 28:505-12

9. REVIEW OF VIRAL INFECTIONS, CHEMOKINE EXPRESSION AND ASTHMA
This article reviews the current literature supporting the role for chemokines in promoting airway inflammation during viral upper respiratory tract infections. Excessive airway inflammation driven by viral-induced chemokine expression is thought to contribute to asthma exacerbations in certain individuals. Commonly implicated viruses and associated chemokine profiles are discussed. Editor’s comment: Inflammation driven by viral infection often flares asthma. Schaller M, Hogaboam CM, Lukacs N, Kunkel SL. J Allergy Clin Immunol 2006;118:295-302

10. REVIEW OF ASPIRIN-INDUCED ASTHMA
This is a clearly written, concise review of aspirin-exacerbated respiratory disease. History of the disease, epidemiology, pathogenesis, and desensitization protocols are discussed. Editor’s comment: Aspirin sensitivity should be considered in the evaluation of asthmatic patients because desensitization provides an effective means of disease control. Culp JA, Borish L, Mozena JD. J Respir Dis 2006:27(7):282-90. No abstract is available.

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