Early adaptive immune suppression in children with septic shock: a prospective observational study

Abstract

IntroductionInnate immune suppression occurs commonly in pediatric critical illness, in which it is associated with adverse outcomes. Less is known about the adaptive immune response in critically ill children with sepsis. We designed a single-center prospective, observational study to test the hypothesis that children with septic shock would have decreased adaptive immune function compared with healthy children and that among children with sepsis, lower adaptive immune function would be associated with the development of persistent infection or new nosocomial infection.MethodsChildren (18 years or younger) who were admitted to the pediatric intensive care unit with septic shock (by International Consensus Criteria) were enrolled in the study. Blood samples were taken within 48 hours of sepsis onset and again on Day 7 of illness. Adaptive immune function was assessed with ex vivo phytohemagglutinin (PHA)-induced cytokine production capacity of isolated CD4+ T cells. Percentage of regulatory T cells was measured with flow cytometry. Absolute lymphocyte counts were recorded when available.ResultsIn total, 22 children with septic shock and eight healthy controls were enrolled. Compared with those from healthy children, CD4+ T cells isolated from septic shock children on Days 1 to 2 of illness and stimulated with PHA produced less of the pro-inflammatory cytokine interferon gamma (IFN-γ) (P = 0.002), and the antiinflammatory cytokines interleukin (IL)-4 (P = 0.03) and IL-10 (P = 0.02). Among septic shock children, those who went on to develop persistent or nosocomial infection had decreased T-cell ex vivo PHA-induced production of IFN-γ (P = 0.01), IL-2 (P = 0.01), IL-4 (P = 0.008), and IL-10 (P = 0.001) compared with septic shock children who did not. Percentage of regulatory T cells (CD4+CD25+CD127lo) did not differ among groups.ConclusionsAdaptive immune suppression may occur early in the course of pediatric septic shock and is associated with adverse infection-related outcomes.

Immunoparalysis in Pediatric Critical Care

“…Reduction in the ability of lymphocytes to produce interferon (IFN)-γ when incubated ex vivo with the lymphocyte stimulants phytohemagglutinin (PHA) or anti-CD3/anti-CD28 antibody has been associated with infections complications and death in the setting of pediatric and adult sepsis. 21, 22 These findings are in agreement with mRNA studies which suggest that early suppression of lymphocyte signaling pathways are associated with pediatric sepsis mortality. 23 Lastly, expression of co-inhibitory molecules such as programmed death (PD)-1 on lymphocytes, and its ligands PD-L1 and PD-L2 on antigen-presenting cells, is known to be upregulated in critically ill adults, with higher expression levels predicting adverse outcomes.…”

“…19, 21 Muszynski et al demonstrated, in children with septic shock, that infectious complications were associated with lower lymphocyte counts and reduced ability of lymphocytes to respond to ex vivo stimulation with PHA. 22 This reduction was not limited to pro-inflammatory cytokines such as IFNγ but extended to anti-inflammatory cytokines as well, implying global down-regulation of cytokine responses. These data were consistent with transcriptome profiling done by Wong et al which suggested that early down-regulation of lymphocyte signaling pathways predicts mortality and organ failure duration in pediatric sepsis.…”

Critical Illness–Induced Immune Suppression: Current State of the Science

“…[39][40][41] The function of the remaining T cells is poor in some circumstances, with the degree of T-cell dysfunction predictive of adverse outcomes. [42][43][44] Lymphocytes can also express high levels of negative costimulatory cell surface molecules, such as programmed death (PD)-1, in critical illness. 45,46 These molecules, when ligated, promote apoptosis or cellular deactivation.…”

Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome

“…Prolonged lymphopenia, with absolute lymphocyte counts < 1,000 cells/mm 3 , has been reported to independently predict secondary infection and mortality risks in pediatric MODS (65). Autopsy studies have demonstrated marked lymphocyte apoptosis in lymphoid organs from nonsurvivors of sepsis-induced MODS (124,125). Reduced capacity of lymphocytes to produce pro-inflammatory cytokines such as interferon-γ and IL-2 has been associated with increased risk of infectious complications in septic children (126).…”