**7.4. Phosphodiesterase inhibitors**

Currently, two phosphodiesterase inhibitors are available for the treatment of COPD: theo‐ phylline and roflumilast. Theophylline is a xanthine derivative which acts as a non-selective phosphodiesterase inhibitor. It has bronchodilator effects, improves symptoms and there is evidence that it can reduce exacerbations [89-91]. It is a drug which needs therapeutic window monitoring. It can interact with many drugs and can have toxic side effects which may be potentially dangerous, like cardiac arrhythmia. Therapy with theophyllines is not recom‐ mended if LABAs are available but can be used as add-on therapy [8]. Roflumilast is a selective phosphodiesterase-4 inhibitor. It increases prebronchodilator FEV1 and can reduce exacerba‐ tions in a selected group of patients with COPD [92, 93]. In all trials patients in the roflumilast group experienced more side effects in comparison to patients in the placebo groups. The side effects were mostly gastro-intestinal related (nausea, diarrhoea, weight loss) and headache. These adverse events were associated with increased patient withdrawal in the roflumilast groups. The design of the trials limits the generalizability of these results. The included COPD patients were required to have symptoms of chronic bronchitis and AECOPD in the past. More investigation is needed to determine the exact place of this medication in the treatment of AECOPD.

influence respiratory viral infections. In one study therapy with erythromycin increased survival rates in mice infected with lethal doses of influenza virus [110]. This effect might be exerted through the inhibitory action of erythromycin against virus-induced inflammatory responses in the lung. The production of interferon-gamma (IFN-γ) in the lungs was signifi‐ cantly decreased by the administration of erythromycin to the infected mice. Two in vitro studies researching the effect of erythromycin and clarithromycin in human tracheal cells infected with rhinovirus and influenza A virus, also showed that macrolides decrease the production of pro-inflammatory cytokines and inhibited activation of nuclear factor-κB (a regulating factor in transcription of DNA in response to cellular stress) [111, 112]. These antiviral effects of macrolides have not yet been proven in patients, although there is evidence that macrolides may prevent common colds which are mostly of viral aetiology [113]. Macro‐ lides support the airway innate immune system by maintaining airway epithelial integrity [114, 115]. In vitro [116] and in vivo [117] studies show that macrolides improve alveolar macrophage phagocytosis function. Macrolide therapy stimulates the prolonged degranula‐ tion of neutrophils (suggesting anti-inflammatory activity in non-infective inflammation), decreases long term oxidative burst and can decrease the release of pro-inflammatory cyto‐ kines (such as IL-6 and IL-8) in healthy individuals [118]. In vitro it is observed that macrolides decrease the release of IL-1β, IL-6 and tumor necrosis factor-alpha (TNF-α) in sputum cells of patients with COPD [119]. Azithromycin exerts direct inhibitory effects on mucus secretion

Acute Exacerbations of Chronic Obstructive Pulmonary Disease

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Diffuse panbronchiolitis is a progressive inflammatory disorder of the airways found almost exclusively in Japan. Clinically it is characterized by chronic cough, excessive sputum pro‐ duction, exertional breathlessness, chronic sinusitis and Pseudomonas colonization [121]. Untreated, the prognosis of diffuse panbronchiolitis is poor, with progressive deterioration of lung function, the development of diffuse bronchiectasis and death caused by respiratory failure. The introduction of long-term macrolide therapy has resulted in dramatic improve‐ ments in survival, with 5-year survival rates increasing from 63 to 92% [121, 122]. Significant symptom reduction and improved pulmonary function have also been achieved [123-126]. Also in patients with cystic fibrosis (CF) who are colonized with *P. aeruginosa*, macrolide therapy had led to improvement in FEV1 and forced vital capacity (FVC), a reduction in exacerbation rate, a reduction in hospital days and days of intravenous antibiotic use, delaying time until the first exacerbation and reducing number of additional courses of antibiotics [127-132]. A Cochrane review of macrolide therapy concluded that treatment with azithro‐ mycin had a small but significant effect on pulmonary function in patients with cystic fibrosis [133]. In a in New Zealand performed randomized controlled trial in non-CF bronchiectasis, maintenance treatment with 3 times a week 500 mg azithromycin showed a reduction in exacerbations [134] though no effects were seen in quality of life and lung function. In a Dutch study where a treatment scheme was given with daily 250 mg azithromycin, the reduction in exacerbations was accompanied by an improved quality of life assessed by St George's Respiratory Questionnaire (SGRQ) and an increase in lung function [135]. As for COPD there have been few researches concerning macrolides in preventing AECOPD. One published study

from airway epithelial cells in vitro and in vivo [120].

*7.5.2. Success of macrolides in chronic lung diseases*
