title: Augmented Passive Immunotherapy with P4 Peptide Improves Phagocyte Activity in Severe Sepsis.
abstract: Antimicrobial resistance threatens to undermine treatment of severe infection; new therapeutic strategies are urgently needed. Preclinical work shows that augmented passive immunotherapy with P4 peptide increases phagocytic activity and shows promise as a novel therapeutic strategy. Our aim was to determine ex vivo P4 activity in a target population of patients admitted to critical care with severe infection.
  
  
  
  We prospectively recruited UK critical care unit patients with severe sepsis and observed clinical course (≥3 months postdischarge). Blood samples were taken in early (≤48 h postdiagnosis, n = 54), latent (7 days postdiagnosis, n = 39), and convalescent (3-6 months postdiagnosis, n = 18) phases of disease. The primary outcome measure was killing of opsonized Streptococcus pneumoniae by neutrophils with and without P4 peptide stimulation. We also used a flow cytometric whole blood phagocytosis assay to determine phagocyte association and oxidation of intraphagosomal reporter beads.
  
  
  
  P4 peptide increased neutrophil killing of opsonized pneumococci by 8.6% (confidence interval 6.35-10.76, P < 0.001) in all phases of sepsis, independent of infection source and microbiological status. This represented a 54.9% increase in bacterial killing compared with unstimulated neutrophils (15.6%) in early phase samples. Similarly, P4 peptide treatment significantly increased neutrophil and monocyte intraphagosomal reporter bead association and oxidation, independent of infection source.
  
  
  
  We have extended preclinical work to demonstrate that P4 peptide significantly increases phagocytosis and bacterial killing in samples from a target patient population with severe sepsis. This study supports the rationale for augmented passive immunotherapy as a therapeutic strategy in severe sepsis.
authors.affiliation: *Aintree University Hospital NHS Foundation Trust, Liverpool, UK †Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK ‡Clinical Infection, Microbiology and Immunology, Institute of Infection & Global Health, University of Liverpool, Liverpool, UK §Local Comprehensive Research Network, Northwest Coast, Liverpool, UK ||Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK ¶Division of Bacterial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia #Clinical Infection, Microbiology and Immunology, Institute of Infection & Global Health, University of Liverpool, Liverpool, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Morton
authors.forename: Elena
authors.initials: E
authors.lastname: Mitsi
authors.forename: Shaun H
authors.initials: SH
authors.lastname: Pennington
authors.forename: Jesús
authors.initials: J
authors.lastname: Reiné
authors.forename: Angela D
authors.initials: AD
authors.lastname: Wright
authors.forename: Robert
authors.initials: R
authors.lastname: Parker
authors.forename: Ingeborg D
authors.initials: ID
authors.lastname: Welters
authors.forename: John D
authors.initials: JD
authors.lastname: Blakey
authors.forename: Gowrisankar
authors.initials: G
authors.lastname: Rajam
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Ades
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Ferreira
authors.forename: Duolao
authors.initials: D
authors.lastname: Wang
authors.forename: Aras
authors.initials: A
authors.lastname: Kadioglu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gordon
mesh_terms: D000368:Aged; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009842:Oligopeptides / Q000627:therapeutic use*; D010586:Phagocytes / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000276:immunology
chemical_list: D009842:Oligopeptides; C560821:peptide P4