Katrina Bazemore1, Michael Rohly2, Nitipong Permpalung3, Kai Yu4, Irina Timofte5, A Whitney Brown6, Jonathan Orens7, Aldo Iacono5, Steven D Nathan5, Robin K Avery3, Hannah Valantine8, Sean Agbor-Enoh9, Pali D Shah10. 1. Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore. 2. Columbus State University, Columbus, Georgia. 3. Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore. 4. National Cancer Institute, National Institutes of Health, Rockville, Maryland. 5. Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Department of Medicine, University of Maryland, College Park, Maryland. 6. Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, Virginia. 7. Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland. 8. Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. 9. Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: Sean.agbor-enoh@nih.gov. 10. Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland. Electronic address: pdedhiy2@jhmi.edu.
Abstract
BACKGROUND: Acute and chronic forms of lung allograft injury are associated with specific respiratory pathogens. Donor-derived cell free DNA (ddcfDNA) has been shown to be elevated with acute lung allograft injury and predictive of long-term outcomes. We examined the %ddcfDNA values at times of microbial isolation from bronchoalveolar lavage (BAL). METHODS: Two hundred and six BAL samples from 51 Lung Transplant Recipients (LTRs) with concurrently available plasma %ddcfDNA were analyzed along with microbiology and histopathology. Microbial species were grouped into bacterial, fungal, and viral and "higher risk" and "lower risk" cohorts based on historical association with downstream allograft dysfunction. Analyses were performed to determine pathogen category association with %ddcfDNA, independent of inter-subject variability. RESULTS: Presence of microbial isolates in BAL was not associated with elevated %ddcfDNA compared to samples without isolates. However, "higher risk" bacterial and viral microbes showed greater %ddcfDNA values than lower risk species (1.19% vs. 0.65%, p < 0.01), independent of inter-subject variability. Histopathologic abnormalities concurrent with pathogen isolation were associated with higher %ddcfDNA compared to isolation episodes with normal histopathology (medians 1.23% and 0.66%, p = 0.05). Assessments showed no evidence of correlation between histopathology or bronchoscopy indication and presence of higher risk vs. lower risk pathogens. CONCLUSION: %ddcfDNA is higher among cases of microbial isolation with concurrent abnormal histopathology and with isolation of higher risk pathogens known to increase risk of allograft dysfunction. Future studies should assess if %ddcfDNA can be used to stratify pathogens for risk of CLAD and identify pathogen associated injury prior to histopathology.
BACKGROUND: Acute and chronic forms of lung allograft injury are associated with specific respiratory pathogens. Donor-derived cell free DNA (ddcfDNA) has been shown to be elevated with acute lung allograft injury and predictive of long-term outcomes. We examined the %ddcfDNA values at times of microbial isolation from bronchoalveolar lavage (BAL). METHODS: Two hundred and six BAL samples from 51 Lung Transplant Recipients (LTRs) with concurrently available plasma %ddcfDNA were analyzed along with microbiology and histopathology. Microbial species were grouped into bacterial, fungal, and viral and "higher risk" and "lower risk" cohorts based on historical association with downstream allograft dysfunction. Analyses were performed to determine pathogen category association with %ddcfDNA, independent of inter-subject variability. RESULTS: Presence of microbial isolates in BAL was not associated with elevated %ddcfDNA compared to samples without isolates. However, "higher risk" bacterial and viral microbes showed greater %ddcfDNA values than lower risk species (1.19% vs. 0.65%, p < 0.01), independent of inter-subject variability. Histopathologic abnormalities concurrent with pathogen isolation were associated with higher %ddcfDNA compared to isolation episodes with normal histopathology (medians 1.23% and 0.66%, p = 0.05). Assessments showed no evidence of correlation between histopathology or bronchoscopy indication and presence of higher risk vs. lower risk pathogens. CONCLUSION: %ddcfDNA is higher among cases of microbial isolation with concurrent abnormal histopathology and with isolation of higher risk pathogens known to increase risk of allograft dysfunction. Future studies should assess if %ddcfDNA can be used to stratify pathogens for risk of CLAD and identify pathogen associated injury prior to histopathology.
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