Britton, Noel
(2021)
The Respiratory Mycobiome in Critical Illness.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
In critically ill patients, variation in the host inflammatory responses has been associated with poor outcomes. However, the biological mechanisms underlying this heterogeneity have not yet been defined. We investigated whether variation in fungal communities (mycobiome) in the respiratory tract are associated with host inflammation and innate immune system activation and clinical and patient-centered outcomes. We collected endotracheal aspirates (ETA) and plasma samples from 226 critically ill patients. We used extracted DNA from ETAs and performed fungal (ITS) and bacterial (16S) rRNA gene sequencing on the Illumina MiSeq platform to characterize the lower respiratory tract microbiome. We derived diversity metrics to classify patients into strata based on the alpha diversity of the mycobiome and examined associations between these diversity metrics and clinical and patient-centered outcomes. We performed network analyses using probabilistic graphical models to identify associations between bacterial and fungal taxa, clinical features, biomarkers, and patient-centered outcomes. Fungal communities had very low alpha diversity overall. Low alpha diversity was associated with a higher likelihood of ARDS diagnosis and increased severity of disease. Patients with lower alpha diversity in the mycobiome of the lung had higher levels of plasma biomarkers associated with inflammation and immune system activation as well as host-response to infection. Critically ill patients with low diversity of fungal communities in the lung had longer ICU stays, longer time to liberation from mechanical ventilation, and fewer ventilator-free days. Our findings suggest that the mycobiome of the lung may play a role in accentuated host inflammation and adverse clinical outcomes in critical illness through interaction with other microbiota and the host immune system. While the lung mycobiome has been understudied, our findings represent a significant contribution to public health as they suggest that the lung mycobiome may be an important source of biological heterogeneity and clinical variation among critically ill patients and may represent a potential therapeutic target for the prevention and treatment of lung injury and ARDS. Continued investigation of the respiratory microbiome with culture-independent approaches and in vitro models of microbiome-mycobiome interaction will allow for further delineation of microbiome-mycobiome-host interactions in the respiratory tract of mechanically ventilated patients.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
19 January 2021 |
| Date Type: |
Publication |
| Defense Date: |
2 December 2020 |
| Approval Date: |
19 January 2021 |
| Submission Date: |
20 November 2020 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
236 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Epidemiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ARDS, Microbiome, Mycobiome, Critical Illness, Respiratory, Lung, Fungus, Fungi, acute respiratory distress syndrome, lung injury |
| Date Deposited: |
19 Jan 2021 19:53 |
| Last Modified: |
19 Jan 2023 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39916 |
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