Difficult-to-treat asthma is a major health problem that has been intensively researched. Patients with difficult-to-treat asthma have the highest incidence of hospitalizations and emergency department visits, [1] Dolan C.M. Fraher K.E. Bleecker E.R. et al. Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2004; 92: 32-39 Abstract Full Text PDF PubMed Scopus (267) Google Scholar have the greatest risk of fatal asthma attacks, [2] Tough S.C. Hessel P.A. Ruff M. Green F.H. Mitchell I. Butt J.C. Features that distinguish those who die from asthma from community controls with asthma. J Asthma. 1998; 35: 657-665 Crossref PubMed Scopus (72) Google Scholar and use up to 3 times more resources. [3] Van Ganse E. Laforest L. Pietri G. et al. Persistent asthma: disease control, resource utilisation and direct costs. Eur Respir J. 2002; 20: 260-267 Crossref PubMed Scopus (116) Google Scholar Previous studies of patients using macrolides for 6 to 16 weeks have reported lung function and symptom improvement in asthma patients with evidence of Chlamydia pneumoniae or Mycoplasma pneumoniae infection in the upper or lower airways. [4] Friedlander A.L. Albert R.K. Chronic macrolide therapy in inflammatory airways diseases. Chest. 2010; 138: 1202-1212 Crossref PubMed Scopus (124) Google Scholar Besides antibiotic effects, macrolides have anti-inflammatory and immunomodulating properties. For instance, macrolides regulate the production of the proinflammatory cytokines tumor necrosis factor α and interleukin 8 (IL-8) by decreasing the binding of transcription factors NF-κB and AP-1. [5] Shinkai M. Henke M.O. Rubin B.K. Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action. Pharmacol Ther. 2008; 117: 393-405 Crossref PubMed Scopus (181) Google Scholar Macrolides effectively inhibit IL-8 release and induce apoptosis in eosinophils. 6 Kohyama T. Takizawa H. Kawasaki S. Akiyama N. Sato M. Ito K. Fourteen-member macrolides inhibit interleukin-8 release by human eosinophils from atopic donors. Antimicrob Agents Chemother. 1999; 43: 907-911 PubMed Google Scholar , 7 Adachi T. Motojima S. Hirata A. et al. Eosinophil apoptosis caused by theophylline, glucocorticoids, and macrolides after stimulation with IL-5. J Allergy Clin Immunol. 1996; 98: S207-S215 Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Long-term treatment with macrolides is recommended in a few lung diseases, such as diffuse panbronchiolitis, cystic fibrosis, posttransplantation bronchiolitis obliterans, and chronic obstructive pulmonary disease. 4 Friedlander A.L. Albert R.K. Chronic macrolide therapy in inflammatory airways diseases. Chest. 2010; 138: 1202-1212 Crossref PubMed Scopus (124) Google Scholar , 8 Albert R.K. Connett J. Bailey W.C. et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011; 365: 689-698 Crossref PubMed Scopus (917) Google Scholar Results from a recent randomized controlled trial demonstrated that azithromycin taken for 1 year decreased exacerbations of chronic obstructive pulmonary disease. [8] Albert R.K. Connett J. Bailey W.C. et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011; 365: 689-698 Crossref PubMed Scopus (917) Google Scholar The authors attributed these results to the antibacterial properties of this antibiotic; however, one must assume that the immunomodulatory effects of macrolides played an important role as well. Until now, evidence has been insufficient to support long-term macrolide use in asthma, but it might be beneficial in a subgroup of asthma patients.