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.
*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
Address reprint requests to Dr. Ben Morton, Clinical Sciences, CTID Building, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK. E-mail: email@example.com
Received 18 April, 2016
Revised 16 May, 2016
Accepted 20 June, 2016
Authors’ contributions: BM, EM, SHP, ADW, RP, IDW, JDB, GR, EWA, DMF, AK, and SBG contributed substantially to the conception or design of the work. BM, EM, SHP, JR, ADW, and RP helped in acquisition of data. BM, EM, SHP, JR, DMF, DW, and SBG analyzed the data. BM, EM, SHP, JR, RP, IDW, JDB, GR, EWA, DMF, DW, AK, and SBG interpreted the data. BM, EM, SHP, JR, ADW, RP, IDW, JDB, GR, EWA, DMF, DW, and SBG drafted work for important intellectual content. BM, EM, SHP, JR, ADW, RP, IDW, JDB, GR, EWA, DMF, DW, AK, and SBG approved the final version to be published. BM, EM, SHP, JR, ADW, RP, IDW, JDB, GR, EWA, DMF, DW, AK, and SBG are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
BM and EM contributed equally to this work.
This work was supported by funds from Liverpool Health Partners, University of Liverpool (2013 to SBG), and the Medical Research Council Confidence in Concept Scheme (2013 to SBG). These funding sources had no role in study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
BM has received an honorarium for a lecture related to P4 peptide presented to Grifols Inc in 2014. The remaining authors report no conflicts of interest.
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