Respiratory Microbiome Disruption and Risk for Ventilator-Associated Lower Respiratory Tract Infection

Abstract

Background: Ventilator-associated lower respiratory tract infection (VA-LRTI) is common among critically ill patients and has been associated with increased morbidity and mortality. In acute critical illness, respiratory microbiome disruption indices (MDIs) have been shown to predict risk for VA-LRTI, but their utility beyond the first days of critical illness is unknown. We sought to characterize how MDIs previously shown to predict VA-LRTI at initiation of mechanical ventilation change with prolonged mechanical ventilation, and if they remain associated with VA-LRTI risk.

Methods: We developed a cohort of 83 subjects admitted to a long-term acute care hospital due to their prolonged dependence on mechanical ventilation; performed dense, longitudinal sampling of the lower respiratory tract, collecting 1066 specimens; and characterized the lower respiratory microbiome by 16S rRNA sequencing as well as total bacterial abundance by 16S rRNA quantitative polymerase chain reaction.

Results: Cross-sectional MDIs, including low Shannon diversity and high total bacterial abundance, were associated with risk for VA-LRTI, but associations had wide posterior credible intervals. Persistent lower respiratory microbiome disruption showed a more robust association with VA-LRTI risk, with each day of (base e) Shannon diversity <2.0 associated with a VA-LRTI odds ratio of 1.36 (95% credible interval, 1.10-1.72). The observed association was consistent across multiple clinical definitions of VA-LRTI.

Conclusions: Cross-sectional MDIs have limited ability to discriminate VA-LRTI risk during prolonged mechanical ventilation, but persistent lower respiratory tract microbiome disruption, best characterized by consecutive days with low Shannon diversity, may identify a population at high risk for infection and may help target infection-prevention interventions.

Keywords: long-term acute care; mechanical ventilation; microbiome; ventilator-associated pneumonia.

Figure 1.

Longitudinal stability of MDIs during long-term acute care. Boxplots show the distribution of MDI values at enrollment and over the duration of long-term mechanical ventilation, with median values shown as thick horizontal bars, IQRs shown as boxes, whiskers extending to 1.5 × IQR, and outliers depicted as points. Abbreviations: ASV, amplicon sequence-variant; IQR, interquartile range; Max, maximum; MDI, microbiome disruption index; rRNA, ribosomal RNA.

Figure 2.

Concurrent probability of VA-LRTI in relation to cross-sectional MDIs. The results of logistic regression models relating the daily risk of VA-LRTI to MDIs are shown, with the range of observed MDI values on the horizontal axis and the posterior probability of VA-LRTI on the vertical axis. The dark line indicates the posterior median, and the shading indicates a range of posterior credible intervals as shown. Abbreviations: ASV, amplicon sequence-variant; IQR, interquartile range; Max, maximum; MDI, microbiome disruption index; qPCR, quantitative polymerase chain reaction; rRNA, ribosomal RNA; VA-LRTI, ventilator-associated lower respiratory tract infection.

Figure 3.

Persistent respiratory microbiome disruption predicts VA-LRTI during long-term acute care. The odds ratio of VA-LRTI associated with each 1-day increase in the persistence of respiratory bacterial microbiome disruption is shown, with persistent microbiome disruption defined as either low (below median) Shannon diversity, high (>50%) maximum ASV proportional abundance, or high (above median) total bacterial abundance. The point indicates the posterior median, and the shading indicates a range of posterior credible intervals as shown. Abbreviations: ASV, amplicon sequence-variant; IQR, interquartile range; Max, maximum; MDI, microbiome disruption index; qPCR, quantitative polymerase chain reaction; rRNA, ribosomal RNA; VA-LRTI, ventilator-associated lower respiratory tract infection.