Augmented Passive Immunotherapy with P4 Peptide Improves Phagocyte Activity in Severe Sepsis

• Published in: Shock (Augusta, Ga.) Vol. 46; no. 6; p. 635
• Main Authors: Morton, Ben, Mitsi, Elena, Pennington, Shaun H, Reiné, Jesús, Wright, Angela D, Parker, Robert, Welters, Ingeborg D, Blakey, John D, Rajam, Gowrisankar, Ades, Edwin W, Ferreira, Daniela M, Wang, Duolao, Kadioglu, Aras, Gordon, Stephen B
• Format: Journal Article
• Language: English
• Published: United States 01.12.2016
• Subjects: Aged; Female; Flow Cytometry; Humans; Immunization, Passive - methods; Male; Middle Aged; Neutrophils - immunology; Neutrophils - metabolism; Oligopeptides - therapeutic use; Phagocytes - drug effects; Phagocytosis - drug effects; Prospective Studies; Sepsis - drug therapy; Sepsis - metabolism; Streptococcus pneumoniae - immunology
• ISSN: 1540-0514
• DOI: 10.1097/SHK.0000000000000715

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.