**5. Macrolides in asthma treatment**

Macrolides, such as clarithromycin and azithromycin, have been extensively studied for decades as a potential treatment for asthma. Although the results of clinical trials have been controversial, they are now included in severe adult asthma treatment guidelines as an additive agent due to their antibacterial, antiviral, anti-inflammatory, and immunomodulatory features [90–92]. The anti-inflammatory effects of macrolides may be particularly beneficial for patients with type 2 inflammation, while the

antibiotic and antiviral effects may prevent respiratory infections in patients with neutrophilic inflammation [93].

Macrolides have been found to be effective in treating both eosinophilic and noneosinophilic asthma phenotypes as adjunctive therapy in severe asthma [91, 94].

It is well-known that severe asthma can present with different phenotypes, such as increased concentrations of eosinophils or neutrophils and IL-8 in the airways. Patients with neutrophilic asthma have been shown to respond better to macrolide therapy and this type of asthma is thought to be more associated with bacterial pathogens and IL-8 [95]. Infection-mediated asthma is particularly related to neutrophilic, steroid-resistant asthma, leading many studies to focus on atypical bacterial infections in asthma and the effectiveness of macrolide treatment [96].

Two randomized, double-blind, placebo-controlled studies have reported contrasting results. Kraft and colleagues reported that clarithromycin treatment substantially increased FEV1 in asthmatic patients with PCR evidence of *C. pneumoniae* or *M. pneumoniae* infection in upper or lower airway samples [97]. However, the study conducted by Sutherland and colleagues did not support these findings [98]. The contrasting results can be attributed to the difficulty of accurately diagnosing atypical bacterial infections, as reported in a related meta-analysis [99].
