Discussion
gastrointestinal manifestations, CF, lung disease, exacerbations, bronchiectasis, inflammation, infections, worse disease, airway inflammation, neutrophilia, CF lung disease
DISEASE PROGRESSION, LUNG DISEASE, BRONCHIECTASIS, INFLAMMATION, DISEASE, INFECTIONS, PATHOPHYSIOLOGY, NEUTROPHILIA, INFLAMMATORY RESPONSE
In this observational study, we provide evidence supporting that detection of BAs in BALF constitutes an early predictor of both airway inflammation and clinical outcomes in CF. Specifically, we demonstrated neutrophilia and higher airway inflammation in asymptomatic infants with CF who have BAs in BALF. Our data linking BAs to disease burden suggests that profiling BAs in BALF could also help to inform clinicians of patients with worse disease trajectories, as early as at 12 months of age. We also show distinctive patterns of microbial colonisation associated with specific prophylactic antibiotic treatment as well as with detection of BAs in BALF. Thus, our study also unveils factors that should be considered when studying the relationships between the lower airway microbiota and the progression of CF lung disease.Since the gastrointestinal environment influences the respiratory system via an uncharacterized signalisation pathway namely the gut-lung axis, it can be assumed that respiratory findings in CF patients are modulated by gastrointestinal manifestations [Determining the key processes involved in triggering the lung inflammatory response in early-life CF is a major clinical problem. Through analysis of BALF samples stratified by BA detection, we show that in CF infants, the presence of BA in BALF is strongly associated with markers of airway inflammation. However, our work does not reveal the specific role of BA in the pathophysiology of early CF lung disease, and functional studies are now required. Highlighting the complexity of the CF lung environment, BALF specimens with BA also demonstrated more diverse microbial communities enriched in oropharyngeal taxa, higher bacterial burden, and higher odds of retrieving high-cell-density microbial cultures from BALF. Thus, our findings linking BA to inflammatory markers could be confounded by alterations in the BALF-associated microbiota. While it is true that in our study, metacommunities enriched in oropharyngeal taxa exhibited higher inflammation, the effect was of lower magnitude than for BA. Furthermore, other community descriptors such as diversity or bacterial burden were either weakly associated or not correlated with markers of airway inflammation. Thus, although bacteria and BA could access lower airways via a common physiological process, our data suggest that BA themselves represent a particular pathological alteration linked to the initiation and/or maintenance of airway inflammation. Likewise, our observations support the concept that in the absence of pathogenic infections, the commensals colonising the airways may be necessary, yet insufficient for establishing the inflammatory landscape characteristic of early CF lung disease [Despite the mild lung disease expected in a paediatric cohort, we observed differences in markers of disease progression related to the detection of BA in BALF. These clinical outcomes included medication-related burden, percentage of structural lung disease at the age of one, as well as the number of exacerbations during the first year of life. Elevated markers of airway inflammation provide a plausible physiological defect linking poor clinical outcomes to the presence of BA in BALF. Thus, detection of free NE activity, a precursor of bronchiectasis in CF [As CF patients age, a relationship between lung function and microbial diversity emerges [The presence of commensals in the airways prior to pathogenic infections remains controversial [Our study has several limitations. Firstly, it was impossible to determine whether airway exposure to BA preceded the clinical and microbiological outcomes described in this work. Thus, causal inferences cannot be drawn, and further functional studies are required for this purpose. However, associations between BA in BALF and inflammation have been replicated in non-CF patients, validating observations made here [