Noninvasive monitoring of infection and rejection after lung transplantation

Abstract

The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.organ transplantation | cell-free DNA | infection | rejection | diagnosis

Integrative omics for health and disease

“…For instance, sequencing cell-free DNA can detect circulating donor DNA 128 , the levels of which are correlated with the severity of organ rejection 129 . Additionally, sequencing this cell-free DNA can simultaneously detect viral DNA to indicate a marker of infection 130 . Additional omics data, such as RNA or protein expression, may also be used to assess compatibility of donor–recipient pairs, as well as monitor for markers of rejection (for a recent review, see REF.…”

High-Definition Medicine

“…Circulating DNA methylation profiles can further refine tissue-specific cell death signatures (Lehmann-Werman et al, 2016), and circulating RNA profiles can allow the assessment of the state of tissues, such as the brain, which are otherwise inaccessible (Koh et al, 2014). These capabilities allow for the detection of organ specific disease processes such as early detection of organ transplant rejection (De Vlaminck et al, 2015), and a variety of other tissue-specific degenerative conditions, such as neurodegeneration (Quinn et al, 2015). Thus, longitudinal profiling of circulating nucleotides has the potential to be utilized as a more general health surveillance tool, where changes from baseline levels of circulating DNA from each tissue source indicate either tissue specific neoplastic or tissue specific degenerative processes.…”

“…As described above, proof of principal studies have demonstrated that failure of curative tumor resections in cancer patients (Tie et al, 2016), and failure of immunosuppression therapy in organ transplant patients can be detected via sequencing of circulating DNA (De Vlaminck et al, 2015). The emergence of therapy resistant cancer clones can also be detected via ctDNA sequencing prior to clinical recurrence (Murtaza et al, 2013).…”

Rapid Detection of Cell-Free Mycobacterium tuberculosis DNA in Tuberculous Pleural Effusion

“…It is well-known that cell-free tumor cell DNA and fetal cfDNA can be detected in various body fluids, such as plasma, urine, and PE (18)(19)(20). Recently, the detection of cfDNA from pathogens, including fungi, bacteria, and parasites, has been reported (21)(22)(23). A nucleic acid amplification test (NAAT) detecting cfDNA from the pathogen has shown better sensitivity than just the detection of genomic DNA from the same pathogen.…”