Progressive Pulmonary Disease – Bronchiectasis
Bronchiectasis is a rare chronic irreversible progressive pulmonary disorder that causes damage to the walls of bronchial tubes by destroying smooth muscle elasticity and the ability to clear mucus. Bronchiectasis leads to the development of serious recalcitrant lung infections, inflammation and progressive pulmonary decline. The pathogenic mechanism of bronchiectasis is set in motion by a cascade of underlying structural and functional factors.
Current treatment options for complications of progressive pulmonary disease and bronchiectasis are limited. Targeting just one aspect of the “Vicious Cycle” (see figure below) in isolation is unlikely to significantly impact outcomes.
In cystic fibrosis (CF) and non-CF bronchiectasis, the accumulation of thick, sticky mucus in the lungs results in clogged airways. Pulmonary changes to the epithelia and mucus abnormalities trigger adherence of bacteria causing infection and leading to biofilm accumulation, airway clogging, inflammation, pulmonary exacerbations, as well as antibiotic resistance and tolerance (persisters). Pulmonary surface hydration also plays a key role in improving airway clearance while biofilms form a barrier to antibiotic penetration.
In this devastating disease, bronchiectasis imposes a significant burden on patients with impaired mucus clearance, chronic cough, frequent infections and pulmonary exacerbations (PEx), extreme fatigue, respiratory failure, significant morbidity and severely affects QoL. Life-threatening recalcitrant pulmonary infections from emerging and virulent pathogens (e.g. non-tuberculosis mycobacterium [NTM], Pseudomonas aeruginosa [Pa], Burkholderia cepacia complex [BCC] and methicillin resistant Staphylococcus aureus [MRSA]), affect a majority of patients and directly impacts the progression of lung disease, clinical outcomes, inflammation and survival.
Persister Cells: Specialized Survivors
Antibiotic treatment often fails to eradicate recalcitrant bacterial infection, leaving behind an antibiotic-tolerant subpopulation of bacterial cells, called persisters, usually within the biofilm layer.