Clinical aspects and treatment options in non-CF bronchiectasis

Bronchiectasis is a heterogenous disease and is diagnosed in patients of all ages, with geographic variability around the globe. The prevalence of bronchiectasis worldwide rose by 40% between 2004 and 2014, and still increases with a growing recognition of the disease.
The variety of known etiologies of bronchiectasis was described in chapter 2 of this thesis. In this retrospective analysis, the most common identified etiologies were post-infective (39.5%) and idiopathic (12.5%). This study demonstrated also the clinical important differences between the etiology of bronchiectasis and the QoL based on the QoL-B questionnaire. A significant lower QoL was found in patients with COPD as compared to the other etiologies. And overall, a high disease burden is described in this heterogenous population.
In the frequent exacerbating bronchiectasis patient, convincing evidence in favor of long-term macrolide treatment was described. Momentarily, AZM is one of the most widely used macrolide agents for maintenance treatment in bronchiectasis. In chapter 3 we studied the effect of long-term AZM treatment on radiological features of bronchiectasis. In this study an improvement of the radiological features was found after one year of AZM treatment as compared to placebo, with a significant improvement of the total Bhalla score and the parenchyma changes (Brody) and the consolidation (Bhalla) sub-scores. This is the first study that prospectively evaluated this long-term effect of AZM on radiological features and indicates that CT features indicative for active bronchial inflammation are most responsive to change. The benefits of macrolides are believed to be based on a combination of antimicrobial and immunomodulatory effects. In chapter 4, we evaluated the inflammatory profile in expectorated sputum of patients with bronchiectasis treated with maintenance AZM or placebo for one year. In concordance with previous studies, an upregulation of inflammatory markers in this population was correlated to functional measurements of disease severity and an increase in exacerbations. Our most remarkable finding was the fact that markers of airway inflammation remained stable or even increased during long-term macrolide treatment. In the retrospective analysis described in chapter 5, we evaluated the effect and safety of AZM up to 5 years of maintenance treatment. During these 5 years, the number of exacerbations remained low. Mild side effects occurred, whereby diarrhea was the most frequent adverse event.
Another treatment option for the frequent exacerbating bronchiectasis patient is the use of inhalation of antibiotics. The BATTLE study is the first randomized placebo-controlled trial whereby this OD dosing is investigated with number of exacerbations as primary outcome. In addition, not only patients chronically infected with P. aeruginosa were included, but also patients with a chronic infection with the other most common gram-negative bacteria and S. aureus. This provides more information about a possible treatment strategy also for patients without P. aeruginosa chronic infection.
The results of our BATTLE study were described in chapter 8. A non-significant decrease in number of exacerbations with a RR of 0.74 (95% CI 0.49-1.14) was found for patients treated with TIS as compared to placebo, and an improvement in QoL. Unfortunately, in our analysis, the predefined 50% reduction in number of exacerbations in patients with ≥ 2 exacerbations in the preceding year was not reached.
Long-term TIS OD was well tolerated with no additional safety concerns. These analyses are described in detail in chapter 9 of this thesis. During a longer treatment period the development of airway hyperresponsiveness related to the inhaled medication was seen. Based on this observation, closely monitoring in the first weeks after the start of maintenance inhalation treatment seems relevant.