title: Increased PD-1 Expression and Altered T Cell Repertoire Diversity Predict Mortality in Patients with Septic Shock: A Preliminary Study.
abstract: Sepsis causes impairment of innate and adaptive immunity by multiple mechanisms, including depletion of immune effector cells and T cell exhaustion. Although lymphocyte dysfunction is associated with increased mortality and potential reactivation of latent viral infection in patients with septic shock, the relation between viral reactivation and lymphocyte dysfunction is obscure. The objectives of this study were 1) to determine the relation of lymphocyte dysfunction to viral reactivation and mortality, and 2) to evaluate recovery of lymphocyte function during septic shock, including T cell receptor (TCR) diversity and the expression of programmed death 1 (PD-1). In 18 patients with septic shock and latent cytomegalovirus (CMV) infection, serial blood samples were obtained on days 1, 3, and 7 after the onset of shock, and immune cell subsets and receptor expression were characterized by flow cytometry. TCR diversity of peripheral blood mononuclear cells was analyzed by Multi-N-plex PCR, and CMV DNA was quantified using a real-time PCR kit. A decrease of TCR diversity and monocyte HLA-DR expression were observed in the early stage of septic shock, while CD4+ T cells displayed an increase of PD-1 expression. Significant lymphopenia persisted for at least 7 days following the onset of septic shock. Normalization of TCR diversity and PD-1 expression was observed by day 7, except in patients who died. CMV reactivation was detected in 3 of the 18 patients during the first week of their ICU stay and all 3 patients died. These changes are consistent with the early stage of immune cell exhaustion and indicate the importance of normal lymphocyte function for recovery from septic shock. Ongoing lymphocyte dysfunction is associated with CMV reactivation and dissemination, as well as with unfavorable outcomes.
authors.affiliation: Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: Atsutoshi
authors.initials: A
authors.lastname: Tomino
authors.affiliation: Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: Ruri
authors.initials: R
authors.lastname: Aoki
authors.affiliation: Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kajita
authors.affiliation: Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Hashiba
authors.affiliation: Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: Tsuguaki
authors.initials: T
authors.lastname: Terajima
authors.affiliation: Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kano
authors.affiliation: Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan.
authors.forename: Naoshi
authors.identifier: http://orcid.org/0000-0001-7358-2716
authors.initials: N
authors.lastname: Takeyama
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D016022:Case-Control Studies; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D005260:Female; D015870:Gene Expression; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D006684:HLA-DR Antigens; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell