Pulmonary exacerbations in cystic fibrosis during the era of CFTR modulator therapy

Extract Recurrent acute drops in lung function, referred to as pulmonary exacerbations, are a key risk factor determining lung function decline and long-term outcomes in people with cystic fibrosis (CF) [1, 2]. Pulmonary exacerbations have a greater negative impact on health-related quality of life than baseline lung function, nutritional status or demographic variables [3, 4]. Registry data indicate that following a pulmonary exacerbation, about one quarter of patients do not regain their baseline lung function [5]. The definitions of pulmonary exacerbation in CF vary [6], but among the most widely adopted are the (modified) Fuchs criteria, which are based on the presence of at least four out of 12 possible signs and symptoms. These are change in sputum volume or colour, new or increased haemoptysis, increased cough, increased dyspnoea, increased malaise, fatigue or lethargy, fever, anorexia or weight loss, sinus pain or tenderness, change in sinus discharge, change in physical findings on examination of the chest, decrease in pulmonary function by 10% or more, and radiographic changes [7]. A low forced expiratory volume in 1 s (FEV1) is a known risk factor for pulmonary exacerbations in CF [8, 9]. However, more than lung function itself, the number of prior pulmonary exacerbations appears to determine the frequency of future exacerbations [10]. This means that even patients with preserved lung function may experience clinical instability and require regular monitoring to preserve long-term lung health. Our understanding of the pathophysiology of pulmonary exacerbations, particularly the interactions between impaired mucociliary clearance, chronic bacterial infection, and inflammation, remains incomplete. Pulmonary exacerbations are predominantly associated with alterations in the bacterial load of the existing airway microbiota, particularly Pseudomonas aeruginosa, rather than the acquisition of novel pathogens [11]. Furthermore, the contribution of viral infections to these events warrants further investigation. Treatment of pulmonary exacerbations with intravenous antibiotics has been shown to reduce bacterial density in sputum and improve lung function in people with CF, as measured by FEV1 [12, 13]. However, robust evidence guiding the optimal management of pulmonary exacerbations is still pending [14, 15].