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Sepsis-Induced Immunosuppression in Neonates.

ABSTRACT: Neonates, especially those born preterm, are at increased risk of sepsis and adverse long-term effects associated with infection-related inflammation. Distinct neonatal immune responses and dysregulated inflammation are central to this unique susceptibility. The traditional separation of sepsis into an initial hyper-inflammatory response followed by hypo-inflammation is continually under review with new developments in this area of research. There is evidence to support the association of mortality in the early acute phase of sepsis with an overwhelming hyper-inflammatory immune response. Emerging evidence from adults suggests that hypo- and hyper-inflammation can occur during any phase of sepsis and that sepsis-immunosuppression is associated with increased mortality, morbidity, and risk to subsequent infection. In adults, sepsis-induced immunosuppression (SII) is characterised by alterations of innate and adaptive immune responses, including, but not limited to, a prominent bias toward anti-inflammatory cytokine secretion, diminished antigen presentation to T cells, and reduced activation and proliferation of T cells. It is unclear if sepsis-immunosuppression also plays a role in the adverse outcomes associated with neonatal sepsis. This review will focus on exploring if key characteristics associated with SII in adults are observed in neonates with sepsis.

SUBMITTER: Hibbert JE

PROVIDER: S-EPMC6281766 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Sepsis-Induced Immunosuppression in Neonates.

Hibbert Julie E JE Currie Andrew A Strunk Tobias T

Frontiers in pediatrics 20181129

Neonates, especially those born preterm, are at increased risk of sepsis and adverse long-term effects associated with infection-related inflammation. Distinct neonatal immune responses and dysregulated inflammation are central to this unique susceptibility. The traditional separation of sepsis into an initial hyper-inflammatory response followed by hypo-inflammation is continually under review with new developments in this area of research. There is evidence to support the association of mortal ...[more]

PMID: 30555806

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Project description:BACKGROUND:The sepsis-induced immunodepression contributes to impaired clinical outcomes of various stress conditions. This syndrome is well documented and characterized by attenuated function of innate and adaptive immune cells. Several pharmacological interventions aimed to restore the immune response are emerging of which interferon-gamma (IFN?) is one. It is of paramount relevance to obtain clinical information on optimal timing of the IFN?-treatment, -tolerance, -effectiveness and outcome before performing a RCT. We describe the effects of IFN? in a cohort of 18 adult and 2 pediatric sepsis patients. METHODS:In this open-label prospective multi-center case-series, IFN? treatment was initiated in patients selected on clinical and immunological criteria early (<?4?days) or late (>?7?days) following the onset of sepsis. The data collected in 18 adults and 2 liver transplanted pediatric patients were: clinical scores, monocyte expression of HLA-DR (flow cytometry), lymphocyte immune-phenotyping (flow cytometry), IL-6 and IL-10 plasma levels (ELISA), bacterial cultures, disease severity, and mortality. RESULTS:In 15 out of 18 patients IFN? treatment was associated with an increase of median HLA-DR expression from 2666 [IQ 1547; 4991] to 12,451 [IQ 4166; 19,707], while the absolute number of lymphocyte subpopulations were not affected, except for the decrease number of NK cells 94.5 [23; 136] to 32.5 [13; 90.8] (0.0625)]. Plasma levels of IL-6 464 [201-770] to 108 (89-140) ng/mL (p?=?0.04) and IL-10 from IL-10 from 29 [12-59] to 9 [1-15] pg/mL decreased significantly. Three patients who received IFN? early after ICU admission (<4?days) died. The other patients had a rapid clinical improvement assessed by the SOFA score and bacterial cultures that were repeatedly positive became negative. The 2 pediatric cases improved rapidly, but 1 died for hemorrhagic complication. CONCLUSION:Guided by clinical and immunological monitoring, adjunctive immunotherapy with IFN? appears well-tolerated in our cases and improves immune host defense in sepsis induced immuno suppression. Randomized clinical studies to assess its potential clinical benefit are warranted.

Project description:BACKGROUND:While the process of sepsis-induced immunosuppression is now well described in adults, very little information is available on immune functions in pediatric sepsis. The current study investigated this in children with septic shock by performing immunomonitoring, including both innate (monocyte human leukocyte antigen-DR, mHLA-DR, expression) and adaptive immunity (lymphocyte subsets count), as well as cytokine concentrations (IL-6, IL-8, IL-10, IL-1Ra, TNF-?, IFN-?). Subsequent objectives were to assess the associations between inflammatory response, potential immunosuppression and secondary acquired infection occurrence. METHODS:Single-center prospective observational study, including children aged between 1 month and 18 years admitted to pediatric intensive care unit (PICU) for septic shock. Age-matched controls were children hospitalized for elective surgery without any infectious criteria. Blood was sampled at day 1-2, 3-5, and 7-9 after sepsis onset. mHLA-DR and lymphocyte subsets count were measured by flow cytometry and cytokine concentrations by Luminex technology. RESULTS:A total of 26 children and 30 controls were included. Patients had lymphopenia, and mHLA-DR levels were significantly lower than controls at each time point (p?<?0.0001). All cytokines peaked at day 1-2. Children with secondary acquired infection had lower day 3-5 mHLA-DR and higher pro-inflammatory cytokine concentrations (IL-6, IL-8 and TNF-?) at day 1-2 compared to children without secondary acquired infection. CONCLUSIONS:The higher initial inflammatory cytokine production was, the more innate immunity was altered, while evaluated by low mHLA-DR expression. Children with decreased mHLA-DR expression developed more secondary acquired infections. Upon confirmation in multicenter cohorts, these results pave the way for immunostimulation for the most immunosuppressed children in order to prevent nosocomial infections in PICU. Trial registration PedIRIS study NCT02848144. Retrospectively registered 28 July 2016.

Project description:Increase in mortality and in recurrent infections in the year following ICU discharge continues in survivors of septic shock, even after total clinical recovery from the initial septic event and its complications. This supports the hypothesis that sepsis could induce persistent long-term immune dysfunctions. To date, there is almost no data on ICU discharge and long-term evolution of sepsis-induced immunosuppression in septic shock survivors. The aim of this study was to assess the persistence of sepsis-induced immunosuppression by measuring expression of human leukocyte antigen DR on monocytes (mHLA-DR), CD4+ T cells, and regulatory T cells (Treg) at ICU discharge and 6 months after ICU discharge in patients admitted to the ICU for septic shock.In this prospective observational study, septic shock survivors with no preexisting immune suppression or treatment interfering with the immune system were included. mHLA-DR, CD4+ T cells, and Treg expression were assessed on day 1-2, 3-4, and 6-8 after ICU admission, at ICU discharge, and 6 months after ICU discharge.A total of 40 patients were enrolled during their ICU stay: 21 males (52.5%) and 19 females, median age 68 years (IQR 58-77), median SOFA score on day 1-2 was 8 (IQR 7-9), and median ICU length of stay was 11 days (IQR 7-24). Among these 40 patients, 33 were studied at ICU discharge and 15 were disposed for blood sampling 6 months after ICU discharge. On day 1-2, mHLA-DR expression was abnormally low for all patients [median 4212 (IQR 2640-6047) AB/C] and remained abnormally low at ICU discharge for 75% of them [median 10,281 (IQR 7719-13,035) AB/C]. On day 3-4, 46% of patients presented CD4+ lymphopenia [median 515 (IQR 343-724) mm-3] versus 34% at ICU discharge [median 642 (IQR 459-846) mm-3]. Among patients with a 6-month blood sample, normal values of mHLA-DR were found for all patients [median 32,616 (IQR 24,918-38,738) AB/C] except for one and only another one presented CD4+ lymphopenia.While immune alterations persist at ICU discharge, there is, at cellular level, no persistent immune alterations among septic shock survivors analyzed 6 months after ICU discharge.

Dataset Information

Sepsis-Induced Immunosuppression in Neonates.

Publications

Sepsis-Induced Immunosuppression in Neonates.

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