Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children

Abstract

The cystic fibrosis (CF) lung microbiome has been studied in children and adults; however, little is known about its relationship to early disease progression. To better understand the relationship between the lung microbiome and early respiratory disease, we characterized the lower airways microbiome using bronchoalveolar lavage (BAL) samples obtained from clinically stable CF infants and preschoolers who underwent bronchoscopy and chest computed tomography (CT). Cross-sectional samples suggested a progression of the lower airways microbiome with age, beginning with relatively sterile airways in infancy. By age two, bacterial sequences typically associated with the oral cavity dominated lower airways samples in many CF subjects. The presence of an oral-like lower airways microbiome correlated with a significant increase in bacterial density and inflammation. These early changes occurred in many patients, despite the use of antibiotic prophylaxis in our cohort during the first two years of life. The majority of CF subjects older than four harbored a pathogen dominated airway microbiome, which was associated with a further increase in inflammation and the onset of structural lung disease, despite a negligible increase in bacterial density compared to younger patients with an oral-like airway microbiome. Our findings suggest that changes within the CF lower airways microbiome occur during the first years of life and that distinct microbial signatures are associated with the progression of early CF lung disease.

Host-associated microbiomes are predicted by immune system complexity and climate

“…Do abiotic conditions have stronger effects on ectotherms compared with endothermic hosts? Are microbial therapies effective [17,[51][52][53]?…”

CrossTalk opposing view: mucosal acidification does not drive early progressive lung disease in cystic fibrosis

“…, Muhlebach et al . ). The most consistent observation in humans with cystic fibrosis is the strong association between early progressive lung disease and neutrophilic inflammation (Sly et al .…”

“…Prospectively collected cross-sectional and longitudinal data obtained through the Australian AREST CF early surveillance programme demonstrate that by the age of 3 months 85% of children diagnosed with cystic fibrosis after newborn screening have evidence of lung disease (Sly et al 2009(Sly et al , 2013. Only a small proportion of these have evidence of lower airway infection using standard clinical laboratory methods, and furthermore, pathogenic phyla are largely absent from lower airway microbiota early in life (Pittman et al 2017, Muhlebach et al 2018. The most consistent observation in humans with cystic fibrosis is the strong association between early progressive lung disease and neutrophilic inflammation (Sly et al 2009(Sly et al , 2013Stick et al 2009;Mott et al 2010;Garratt et al 2015;Esther et al 2016).…”

Rebuttal from Stephen M. Stick and André Schultz

“…Recent studies using sensitive RNA sequencing techniques suggest a transition from an essentially sterile airway microenvironment to one that is dominated by recognised CF lung pathogens at a time when airway inflammation is already established (Muhlebach et al . 2018), although the associations of microbiota with inflammation and lung damage are complex (Frayman et al . 2017).…”

“…Few of these infants had evidence of infection with pathogens in bronchoalveolar lavage (BAL) fluid using standard microbiological techniques. Recent studies using sensitive RNA sequencing techniques suggest a transition from an essentially sterile airway microenvironment to one that is dominated by recognised CF lung pathogens at a time when airway inflammation is already established (Muhlebach et al 2018), although the associations of microbiota with inflammation and lung damage are complex (Frayman et al 2017). Nonetheless it seems highly unlikely that pathogen colonisation that is undetectable by BAL and conventional culture techniques can be responsible for the extent of early lung disease that is identified by computed tomography and BAL (Sly et al 2009).…”