Effect of Clarithromycin on Cytokines and Chemokines in Children With an Acute Exacerbation of Recurrent Wheezing: A Double-Blind, Randomized, Placebo-Controlled Trial

Abstract

Fonseca-Aten M, Okada PJ, Bowlware KL, et al. Ann Allergy Asthma Immunol. 2006;97:457–463 PURPOSE OF THE STUDY. To evaluate the effect of clarithromycin on serum and nasopharyngeal cytokine and chemokine concentrations in children with an acute exacerbation of recurrent wheezing. STUDY POPULATION. Forty-three children (mean age: 8.8 years) with a history of recurrent wheezing or asthma were enrolled when presenting to the emergency department of Children's Medical Center (Dallas, TX) with an acute exacerbation of wheezing. METHODS. Study participants were randomly assigned to receive oral clarithromycin or placebo for 5 days. All participants received systemic steroids for 5 to 6 days and aerosolized β agonists. On enrollment (visit 1), after 3 to 5 days (visit 2), and after 3 to 8 weeks (visit 3), children were clinically evaluated and respiratory samples (nasopharyngeal swab and aspirate) were obtained. Nasopharyngeal swabs were tested for Chlamydia pneumoniae and Mycoplasma pneumoniae. Nasopharyngeal aspirates were analyzed for cytokine and chemokine concentrations (tumor necrosis factor α [TNF-α], interferon γ, interleukin 1β [IL-1β], IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, granulocyte/macrophage colony-stimulating factor, regulated upon activation, normal T cells expressed and secreted [RANTES], eotaxin, macrophage inflammatory protein 1α, macrophage inflammatory protein 1β, and monocyte chemotactic protein 1). Serum was analyzed for cytokine concentrations (TNF-α, interferon γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and granulocyte/macrophage colony-stimulating factor). RESULTS. Evidence of M pneumoniae infection was found in 20 patients (48%), and C pneumoniae was found in 12 patients (28%). Nine patients had dual infection. No significant differences in nasopharyngeal aspirate or serum cytokine or chemokine concentrations were found between patients with evidence of C pneumoniae and/or M pneumoniae infection and those without evidence of infection before treatment with clarithromycin or placebo. No difference in asthma severity was found. No difference in resolution of symptoms was noted in patients treated with clarithromycin versus placebo. No correlation was identified between asthma severity and nasopharyngeal concentrations of cytokines and chemokines. Correlation was found between serum IL-10 concentration and asthma severity (P = .02). Nasopharyngeal concentrations of TNF-α, IL-1β, and IL-10 were significantly and persistently lower in children treated with clarithromycin compared with placebo. There tended to be a greater effect of clarithromycin on nasopharyngeal cytokine concentrations in patients with evidence of M pneumoniae or C pneumoniae infection. No significant differences were detected in serum cytokines. CONCLUSIONS. Five days of clarithromycin therapy significantly decreased nasal concentrations of TNF-α, IL-1β, and IL-10 out to 3 to 8 weeks, indicating that macrolides may have a long-lasting effect on immune mediators beyond the time that therapy is completed. REVIEWER COMMENTS. Clarithromycin is postulated to have immunomodulatory and antiinflammatory properties in addition to its antimicrobial activity. Clarithromycin had a greater effect diminishing cytokine concentrations in those children with evidence of M pneumoniae and/or C pneumoniae infection compared with those children without infection. However, in this small, short-term study, no obvious clinical improvement was seen with clarithromycin therapy, although half the children who presented with acute wheezing had evidence of atypical infection.