Early and dynamic alterations of Th2/Th1 in previously immunocompetent patients with community-acquired severe sepsis: a prospective observational study

Ming Xue, Jianfeng Xie, Ling Liu, Yingzi Huang, Fengmei Guo, Jingyuan Xu, Yi Yang, Haibo Qiu, Ming Xue, Jianfeng Xie, Ling Liu, Yingzi Huang, Fengmei Guo, Jingyuan Xu, Yi Yang, Haibo Qiu

Abstract

Background: T helper (Th) cells regulate sepsis processes, including primary pathogen clear and secondary pathogen defence. The objectives of this study were to determine the early and dynamic alterations of Th1 and Th2 populations to community-acquired severe sepsis upon onset among previously immunocompetent patients and whether it was related to clinical outcomes.

Methods: This prospective observational cohort study was conducted at a general intensive care unit (ICU) of a tertiary teaching hospital in China. Immunocompetent patients with community-acquired severe sepsis within 24 h upon onset were included as septic group. Healthy volunteers and critically ill patients without severe sepsis were recruited as controls. Whole blood was collected on D0, 3rd day (D3) and 7th day (D7) for septic group and once upon enrollment for controls. Th1 and Th2 populations were measured by flow cytometry and assessed for associations with 28-day mortality using cox proportional hazard models. Associations of dynamic alterations of Th cell subpopulations with clinical outcomes were investigated.

Results: This study demonstrated that community-acquired severe sepsis patients (n = 71) had increased Th2/Th1 and Th2 populations, compared to healthy controls (n = 7) and critically ill patients without severe sepsis (n = 7) at admission. Among the septic cohort, values of Th2/Th1 were significantly higher in non-survivors than survivors on D0 (p = 0.04), D3 (p < 0.001) and D7 (p < 0.001). Patients with persistently increasing Th2/Th1 demonstrated the highest mortality (47.1%) and incidence of ICU-acquired infections (64.7%).

Conclusions: Th2/Th1 was markedly up-regulated with Th2 dominance upon community-acquired severe sepsis onset among previously immunocompetent patients and its persistently dynamic increase was associated with ICU-acquired infections and 28-day death. Trial registration Institutional Ethics Committee of Zhongda Hospital, 2014ZDSYLL086, registered in June 2014-prospectively registered; ClinicalTrials.gov, NCT02883218, registered on 25 Aug 2016-retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02883218?cond=NCT02883218&rank=1.

Keywords: Community-acquired severe sepsis; ICU-acquired infection; Mortality; T helper cells.

Figures

Fig. 1
Fig. 1
Values of Th1, Th2 and Th2/Th1 in heathy control, ICU control and septic groups upon enrollment. a Gating strategy used for flow cytometric analysis. CD3 positive (CD3+) cells were analysed and further specified according to size/granularity in E1. R1 in green represents CD3+ CD8− T cells, which approximately equal to CD4+ T cells while R2 in yellow stands for CD8+ T cells. Th1 cells are defined as INF-gamma+ cells in CD3–CD8+ cells as R3 shows in blue. Th2 cells are defined IL4+ cells in CD3–CD8+ cells as R4 shows in orange. Values of Th1 (b), Th2 (c) and Th2/Th1 (d) upon enrollment in heathy control, ICU control and septic groups are presented as scatter dot plots with lines for median value and quartiles
Fig. 2
Fig. 2
Values of Th1, Th2 and Th2/Th1 in community-acquired severe sepsis cohort stratified by 28-day survival status. Values of Th1 (a), Th2 (b) and Th2/Th1 (c) at different time points in community-acquired severe sepsis cohort stratified by 28-day survival status on D0, D3 and D7. The black scatter dot plots stand for 28-day survivors; the gray scatter dot plots stand for 28-day non-survivors; lines presented median value and quartiles. Values of Th1 (d), Th2 (e) and Th2/Th1 (f) on D0, D3 and D7 among 28-day survivors; Th1 (g), Th2 (h) and Th2/Th1 (i) on D0, D3 and D7 among 28-day non-survivors
Fig. 3
Fig. 3
Death hazard ratios in cox-proportional hazards models. a Hazard ratios for severity scores, absolute values of peripheral blood cell count and T helper population. Significant risk factors are in red; Factors without significance are in blue; Significant protective factors are in green. b Hazard ratios for severity scores, alterations of peripheral blood cell count and T helper population within study period. Significant risk factors are in red; Factors without significance are in blue; Significant protective factors are in green. APACHE is for acute physiology and chronic health evaluation; SOFA is for sequential organ failure assessment; WBC is for white blood count; ALC is for absolute lymphocyte count; ΔTh2/Th1 D7-3 is change of Th2/Th1 from D7 to D3; ΔTh2/Th1 D7-3 is change of Th2/Th1 from D7 to D3. Significant associations with p < 0.05 are in bold
Fig. 4
Fig. 4
Receiver operating characteristic (ROC) curves. The area under curves (AUCs) with 95% confidence interval (CI) were presented with ROC curves. APACHE is for acute physiology and chronic health evaluation; AUC is for area under curve; CI is for confidence interval; Th is for T helper
Fig. 5
Fig. 5
The persistent increasing of Th2/Th1 was associated with occurrence of ICU-acquired infections and 28-day death. a Depicts stratification by Th2/Th1 alterations. b Values of Th2/Th1 in subgroups. c Incidence of ICU-acquired infections of patients (n = 71) in subgroups. d Depicts survival curves of patients (n = 71) with community-acquired severe sepsis in subgroups

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