title: 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.
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305;
authors.forename: Iwijn
authors.initials: I
authors.lastname: De Vlaminck
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305;
authors.forename: Lance
authors.initials: L
authors.lastname: Martin
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305;
authors.forename: Michael
authors.initials: M
authors.lastname: Kertesz
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Kapil
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305;
authors.forename: Mark
authors.initials: M
authors.lastname: Kowarsky
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Calvin
authors.initials: C
authors.lastname: Strehl
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Garrett
authors.initials: G
authors.lastname: Cohen
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Helen
authors.initials: H
authors.lastname: Luikart
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305;
authors.forename: Norma F
authors.initials: NF
authors.lastname: Neff
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Okamoto
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nicolls
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: David
authors.initials: D
authors.lastname: Cornfield
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: David
authors.initials: D
authors.lastname: Weill
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Hannah
authors.initials: H
authors.lastname: Valantine
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Khush
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305; quake@stanford.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
mesh_terms: D001483:Base Sequence; D003587:Cytomegalovirus / Q000235:genetics; D004279:DNA, Viral / Q000097:blood*; D006084:Graft Rejection / Q000175:diagnosis*; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011182:Postoperative Care / Q000379:methods*; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D013530:Surgical Wound Infection / Q000175:diagnosis* / Q000821:virology
chemical_list: D004279:DNA, Viral
keywords: cell-free DNA; diagnosis; infection; organ transplantation; rejection