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
*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.
Shock. 2016 Dec;46(6):635-641. 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.
抗菌药物耐药性有可能破坏严重感染的治疗效果；迫切需要新的治疗策略。临床前研究表明，用P4肽增强被动免疫疗法可提高吞噬活性，并有望成为一种新的治疗策略。我们的目的是确定在因严重感染入住重症监护病房的目标患者群体中P4的体外活性。
我们前瞻性招募了患有严重脓毒症的英国重症监护病房患者，并观察其临床病程（出院后≥3个月）。在疾病的早期（诊断后≤48小时，n = 54）、潜伏期（诊断后7天，n = 39）和恢复期（诊断后3 - 6个月，n = 18）采集血样。主要观察指标是在有和没有P4肽刺激的情况下，中性粒细胞对调理过的肺炎链球菌的杀伤作用。我们还使用流式细胞术全血吞噬试验来确定吞噬细胞与吞噬体内报告珠的结合及氧化情况。
在脓毒症的所有阶段，P4肽均可使中性粒细胞对调理过的肺炎球菌的杀伤作用提高8.6%（置信区间6.35 - 10.76，P < 0.001），与感染源和微生物学状态无关。与早期样本中未受刺激的中性粒细胞（15.6%）相比，这意味着细菌杀伤作用增加了54.9%。同样，P4肽治疗显著增加了中性粒细胞和单核细胞与吞噬体内报告珠的结合及氧化，与感染源无关。
我们将临床前研究扩展至证明，P4肽可显著提高严重脓毒症目标患者群体样本中的吞噬作用和细菌杀伤作用。本研究支持了增强被动免疫疗法作为严重脓毒症治疗策略的理论依据。
