Out-of-hospital cardiac arrest (OHCA) results in severe shock, and the interruption of blood flow leads to disruption in the delivery of oxygen and metabolic substrates, which affects every system including the immune system. After the return of spontaneous circulation (ROSC), OHCA patients present with a “sepsis-like” syndrome, which is characteristic of the high levels of circulating cytokines and the presence of endotoxin in plasma.[1, 2] In vitro, the cytokine production and proliferation abilities of circulatory lymphocytes of OHCA patients were impaired.[2, 3, 4] This is similar to lymphocytes observed in sepsis. After ROSC, OHCA patients are prone to infection, and infections occur in more than 2 out of 3 OHCA patients after successful resuscitation during hospitalization.[6, 7, 8] Therefore, immune dysregulation is an important feature of OHCA patients after ROSC.
Modulation of the blood immune response is an important feature following ischemia/reperfusion injury, and T lymphocytes, primarily CD4+ and CD8+, play an important role in organ ischemia reperfusion injury. CD4+ T cells can be further divided into different subsets by their phenotypes and functions. In addition to the classical differentiation of T-helper type (Th) 1 and Th2 cells, Th17, Th9, T follicular-helper, and T-regulatory cells have been recognized. T-helper subsets are crucial for directing appropriate immune responses during host defense and have been extensively studied in infection and immune-mediated inflammatory diseases.[11, 12, 13, 14, 15] In previous cardiac arrest/cardiopulmonary resuscitation porcine model studies, an imbalance of Th1/Th2 cells was observed in splenic, lung, and myocardial tissue.[16, 17, 18] Serum interferon gamma (IFN-γ)/interleukin 4 (IL-4), which are secreted by Th1/Th2 cells and involved in the differentiation of naive T lymphocytes into Th1/Th2 cells, presented increased IL-4 and decreased IFN-γ levels. IL-10, secreted by Th2 cells, was also found to be elevated in OHCA patients and animal studies.[2, 19] The above studies indicate a potential imbalance of Th1/Th2 in the circulation. Nevertheless, to date, there have been few clinical reports regarding T-helper subsets in OHCA patients. Therefore, in this study, we observed the changes in blood T-helper subsets including Th1, Th2, and Th17 cells, to explore the early immune changes in OHCA patients after ROSC.
This study was approved by the local Medical Ethics Committees of the participating hospitals, including Beijing Chao-Yang Hospital, Beijing Shijingshan Hospital, Beijing Luhe Hospital, and Beijing Friendship Hospital, and was in accordance with the Helsinki Declaration of 1975, as revised in 2000. The requirement for informed consent was waived because this study was observational, and biomarker expression was measured on residual blood after completion of routine tests every morning.
During July–September 2016 and March–September 2017, OHCA patients admitted to the emergency departments of participating hospitals were evaluated for potential enrollment. According to the 2015 International Consensus on Cardiopulmonary Resuscitation, rescuers should begin cardiopulmonary resuscitation if an adult is unresponsive and not breathing normally (disregarding occasional gasps). The inclusion criteria were as follows: ROSC >12 h and Glasgow Coma Scale (GCS) score <8 after ROSC. The exclusion criteria were as follows: age <18 years, obvious infection of any organ or tissue, terminal stage of disease, and immunosuppressive therapy in the last 3 months. All patients were treated according to the 2015 International Consensus on Cardiopulmonary Resuscitation. In addition, healthy individuals, approximately matched by age and sex, who underwent health physical examination, were enrolled in this study.
Participant data, including demographics; resuscitation data, including prehospital adrenaline dose, initial cardiac rhythm, and time to ROSC; and clinical and laboratory data were recorded. Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores were calculated to assess severity. The expression of Th1, Th2, and Th17 cells in residual heparin lithium anticoagulant blood samples, after completion of routine clinical tests every morning or health physical examination, were analyzed. In this study, blood samples were collected on day 1 (22.7 ± 7.9 h after OHCA) and day 3 (71.1 ± 12.1 h after OHCA). During follow-up, the survival outcomes after 28 days were collected. The flowchart of the participant selection and analysis for this study is shown in Figure 1.
Isolation of peripheral lymphocytes and incubation
Peripheral blood mononuclear cells (PBMCs) were isolated through differential centrifugation by lymphocyte separation medium (Haoyang, Tianjin, China) from whole blood within 2 h of collection. Then, 3–5 × 105 PBMCs were suspended in 500 μl of RPMI-1640 medium (Corning, Manassas, USA) supplemented with 10% fetal bovine serum (Sijiqing, Zhejiang, China). One microliter of the mixture of ionomycin and Brefeldin A (BD Bioscience, San Diego, USA) was added to the medium, and lymphocytes were incubated in a humidified incubator at 37°C with an atmosphere comprising 5% CO2 for 260 min.
Determination of Th1/Th2/Th17
After incubation, surface staining for CD3 and CD8 was performed for 20 min in a dark area, and PBMCs were washed with stain buffer (BD Bioscience). Then, PBMCs were fixed at 4°C for 40 min and washed with Perm/Wash Buffer (BD Bioscience), followed by intracellular staining for IFN-γ + (Th1), IL-4 (Th2), and IL-17 (Th17) at 4°C for 40 min. According to the manufacturer's recommendations, the following monoclonal antibodies and their isotype controls were used: APC-H7 labeled anti-CD3 (2 μl, clone SK7; BD Bioscience), eFluor® 450-labeled anti-CD8 (2 μl, clone RPA-T8; eBioscience, San Jose, USA), PE-Cy7 labeled anti-IFN-γ (2 μl, BD Bioscience), APC-labeled anti-IL-4 (2 μl, BD Bioscience), and PE-labeled anti-IL-17 (5 μl, BD Bioscience). Finally, PBMCs were washed with Perm/Wash Buffer.
The sample measurements were performed using the Gallios™ Flow Cytometer (Beckman Coulter, Inc.) and analyzed with Gallios Software Version 1.0. The lymphocytes were gated by forward scatter and side scatter. For the determination of Th1/Th2/Th17 cells, CD4+ T cells were gated as CD3+ CD8− cells [Figure 2]. Th1, Th2, and Th17 cells were gated as CD3+ CD8− IFN-γ+, CD3+ CD8− IL-4+, and CD3+ CD8− IL-17+ cells, respectively. The threshold was defined using an isotype control. The results are expressed as the percentage in CD4+ cells.
T lymphocyte counts
Absolute CD3+ lymphocyte counts were obtained using Flow-Count Fluorospheres (Beckman Coulter, Inc.) according to the manufacturer's instructions. Approximately 50 μl of peripheral blood sample was stained with Pacific Blue-labeled anti-CD3 (1 μl, Clone UCHT1; BD Bioscience) and FITC labeled anti-CD4 (1 μl, Clone OKT4; eBioscience) for 20 min in a dark area. Erythrocytes were lysed for 15 min, and the cells were washed twice. Then, CD4+/CD3+ lymphocyte ratios and CD3+ CD4+ lymphocyte counts were calculated. Th1, Th2, and Th17 cell counts were calculated by multiplying CD3+ CD4+ counts by their ratios in CD3+ CD4+ lymphocytes.
All data were analyzed using SPSS version 22.0 software (SPSS Inc., Chicago, IL, USA). For normally distributed data, continuous variables were presented as mean ± standard deviation. For data with skewed distributions, variables were expressed as median (25th and 75th percentiles). The Kruskal–Wallis test was applied for multigroup comparisons, and the Mann–Whitney U-test was performed for two-group comparisons. The Wilcoxon-signed rank test was performed for paired sample comparisons. Qualitative parameters were analyzed using a 2 × 2 contingency table followed by the Chi-square test. The correlation was analyzed using Spearman's rank correlation. All statistical tests were two-tailed, and P < 0.05 was considered statistically significant.
Sixty-five OHCA patients and 30 healthy individuals were enrolled in the study. Demographic and clinical characteristics are presented in Table 1. In this study, acute cardiac and cerebral events were the main causes of OHCA, and other causes of OHCA including poisoning, hypokalemia, and unexplained causes. Of the 65 OHCA patients, 12 patients who survived for <3 days were analyzed for the expression of Th1/Th2/Th17 cells on day 1 only. Of the 53 patients who survived for greater than 3 days, the expression of Th1/Th2/Th17 cells were analyzed in 12 patients on day 1 only, 13 patients on day 3 only, and 28 patients on both day 1 and day 3. Dynamic changes were analyzed in these 28 patients. According to 28-day survival, the 28 OHCA patients whose blood samples were analyzed on day 1 and day 3 were divided into survivors and nonsurvivors, and the characteristics of patients and initial resuscitation data are shown in Table 2.
Changes in T lymphocyte counts in out-of-hospital cardiac arrest patients during the first 3 days after return of spontaneous circulation
Compared with healthy individuals, circulatory CD3+ T lymphocyte counts decreased on day 1 after ROSC and maintained at a low level on day 3 (1464 [1198, 2152] vs. 779 [481, 1140] vs. 581 [324, 1118]/μl, χ2 = 30.342, P < 0.001). The ratios of CD4+/CD3+ lymphocytes showed no change (0.58 [0.49, 0.63] vs. 0.55 [0.47, 0.67] vs. 0.55 [0.50, 0.67], χ2 = 0.171, P = 0.918). However, CD3 + CD4+ lymphocyte counts significantly decreased on day 1, without further decrease on day 3 (875 [601, 1228] vs. 447 [281, 690] vs. 359 [181, 620]/μl, χ2 = 27.274, P < 0.001). On day 1, no difference in CD3+ and CD3+ CD4+ lymphocyte counts or CD4+/CD3+ lymphocyte ratios were found between survivors and nonsurvivors.
Changes in circulatory Th1 cells in out-of-hospital cardiac arrest patients in the first 3 days after return of spontaneous circulation
On day 1 after ROSC, both Th1/CD4+ lymphocyte ratios and circulatory Th1 cell counts decreased and were maintained at a low level on day 3 [Figure 3a and 3b]. In this study, dynamic expression of both Th1/CD4+ lymphocyte ratios and Th1 cell counts in 28 OHCA patients were analyzed. No significant difference was found between day 1 and day 3 in both survivors and nonsurvivors [Figure 3c and 3d]. Meanwhile, the results showed no difference between survivors and nonsurvivors on days 1 and 3.
Changes in circulatory Th2 cells in out-of-hospital cardiac arrest patients in the first 3 days after return of spontaneous circulation
Compared with healthy individuals, Th2/CD4+ lymphocyte ratios were elevated on day 1 (Z = −2.751, P = 0.006) and began to decline on day 3 (Z = −1.393, P = 0.164) [Figure 4a]. Circulatory Th2 lymphocyte counts showed a downward trend on day 1 (Z = −1.822, P = 0.069) and further decreased on day 3 (Z = −3.228, P < 0.001) [Figure 4b]. Both Th2/CD4+ lymphocyte ratios and circulatory Th2 lymphocyte counts showed no significant difference between survivors and nonsurvivors on days 1 and 3. No dynamic changes in Th2/CD4+ lymphocyte ratios and circulatory Th2 lymphocyte counts were seen in both survivors and nonsurvivors [Figure 4c and 4d].
Changes in Th17 cells in out-of-hospital cardiac arrest patients in the first 3 days after return of spontaneous circulation
Compared with healthy individuals, Th17/CD4+ lymphocyte ratios showed an upward trend; however, no significant difference was found on days 1 (Z = −1.492, P = 0.136) and 3 (Z = −1.393, P = 0.170) [Figure 5a]. Circulatory Th17 lymphocyte counts showed a downward trend on day 1 (Z = −1.724, P = 0.085), and further decreased on day 3 (Z = −2.294, P = 0.022) [Figure 5b]. No dynamic changes in Th17/CD4+ lymphocyte ratios and Th17 lymphocyte counts were seen between days 1 and 3 in both survivors and nonsurvivors [Figure 5c and 5d]. Meanwhile, both showed no significant differences between survivors and nonsurvivors on days 1 and 3.
Changes in circulatory Th1/Th2 ratio in out-of-hospital cardiac arrest patients in the first three days after return of spontaneous circulation
Compared with healthy individuals, the Th1/Th2 ratio significantly decreased on day 1, without further decrease on day 3 (9.40 [7.33, 13.48] vs. 3.05 [1.85, 5.55] vs. 4.20 [2.80, 5.85], χ2 = 44.262, P < 0.001). On day 1, no significant difference was seen between survivors and nonsurvivors (3.70 [2.30, 6.10] vs. 2.60 [1.75, 4.45], Z = −1.093, P = 0.274). Meanwhile, no changes with time were seen in both survivors and nonsurvivors.
After ROSC, the immune dysfunction due to systemic ischemia-reperfusion is an important feature of OHCA patients. In view of the immune regulatory role of CD4+ lymphocytes, we explored the early changes in T lymphocyte subsets. The present results showed decreased circulatory Th1, Th2, and Th17 cell counts and an imbalance of Th1/Th2 cells in the circulation of OHCA patients after ROSC.
In this study, the total T lymphocyte count and subsets, including Th1, Th2, and Th17 cell counts, of OHCA patients decreased in the first 3 days after ROSC. Different changes were seen in the T lymphocyte subsets. First, the Th1/CD4+ lymphocyte ratio decreased on days 1 and 3. Second, the Th2/CD4+ lymphocyte ratio increased on day 1 and declined from its peak value on day 3. Third, the Th1/Th2 cell ratio significantly decreased on days 1 and 3. Fourth, despite the slightly elevated Th17/CD4+ lymphocyte ratio seen in the OHCA group, this difference was not statistically different compared with that of healthy individuals. Finally, we did not find any difference in the above T lymphocyte subset ratios and counts between survivors and nonsurvivors on days 1 and 3.
The balance between Th1 and Th2 cells is important in regulating immune function and the inflammatory response. Th1 cells produce IFN-γ and IL-2, favoring cell-mediated immunity, and Th2 lymphocytes secrete IL-4, IL-5, and IL-10, favoring humoral immunity.[22, 23] In this study, we determined Th1 and Th2 cells by their intracellular expression of IFN-γ and IL-4. IFN-γ, a key cytokine secreted by Th1 cells, can promote naïve T lymphocytes to differentiate into Th1 cells, and inhibit the proliferation of Th2 cells. IL-4 can stimulate and activate the proliferation of B and T lymphocytes, promote the differentiation of naïve T lymphocytes into Th2 cells, and inhibit the differentiation of naïve T lymphocytes into Th1 cells. The present results showed that both Th1 cell count and Th1/CD4+ lymphocyte ratio decreased in the first 3 days after ROSC. This result is consistent with previous studies that IFN-γ produced by the T lymphocytes of OHCA patients was significantly reduced and also supports that OHCA patients have impaired cell-mediated immunity. Comparatively, despite the decreased Th2 cell counts, the Th2/CD4+ lymphocyte ratio had a relative increase on day 1. Th2 cells not only favor humoral immunity but also produce IL-4 and IL-10, which can suppress cell-mediated immunity and systematic immunity.[24, 25, 26] The results are consistent with the transiently elevated expression of IL-10 observed in OHCA patients and the cardiac arrest animal model.[2, 19] Thus, the relatively elevated Th2 cell ratio in the early period after ROSC may negatively affect the immunity of OHCA patients.
Th1 cells are crucial in the host defense against intracellular pathogens whereas Th2 cells are known to be important for the elimination of helminthic parasites.[27, 28] Thus, the Th1/Th2 cell balance is useful for classifying immune responses that occur in the elimination of microbial pathogens. In this study, a consistently decreased Th1/Th2 ratio was seen in OHCA patients after ROSC. An imbalance in the Th1/Th2 cell ratio is found in septic patients. In these patients, there is an obvious shift from a Th1 response to a Th2 response, which results in patients who are more vulnerable to infections. In other words, patients with low Th1/Th2 cell ratios develop infections more easily. Therefore, decreased Th1/Th2 cell ratios in the early period after ROSC may contribute to the high rate of infections found in OHCA patients during hospitalization.[6, 7, 8]
We also observed changes in Th17 cells. Th17 cells have recently been identified as a unique CD4+ T-helper cell subset, characterized by IL-17 production that promotes tissue inflammation.[31, 32] In this study, similar to Th1 and Th2 cells, circulatory Th17 cell counts also decreased. Although no difference was observed compared with those of healthy individuals, a slight upward trend in the circulatory Th17/CD4+ lymphocyte ratios of OHCA patients was shown. This result may imply that circulatory Th17 cells are involved in the systemic inflammatory response of OHCA patients, similar to that found in sepsis and burn injury.[14, 15] Th17 cells account for a small proportion of blood lymphocytes; therefore, a larger number of samples are needed to evaluate the expression of circulatory Th17 cells. Moreover, its major immunomodulatory secretory products, IL-17 and IL-22, need be monitored to further evaluate the impact of Th17 cells in future studies.
We did not find any difference in Th1, Th2, and Th17 lymphocyte counts between survivors and nonsurvivors. This can be explained by the similar time to ROSC and APACHE II and SOFA scores of both groups, which indicate systemic ischemic hypoxia. It is possible that different degrees of systemic ischemic hypoxia lead to different degrees of change. We also analyzed dynamic changes in the above indicators in OHCA patients who survived for more than 3 days and found no significant between changes on days 1 and 3. This implies that persistent immune dysfunction may exist in OHCA patients in the early period after ROSC.
Impaired cell immunity was found in OHCA patients, and an imbalance in the Th1/Th2 cell ratio in the early period after ROSC was associated with impaired cell immunity, which may make patients more prone to infection. Hospital-acquired infections significantly extend the length of the Intensive Care Unit and hospital-stay after OHCA.[33, 34] Therefore, timely clinical intervention by doctors may be necessary to protect patients from infection in future studies. At present, prophylactic antibiotics are commonly prescribed for OHCA patients after ROSC. Whether promoting cell immunity is more effective than prophylactic antibiotics for the prevention of hospital-acquired infection is unknown. The present study provides theoretical evidence for future studies.
This study has some limitations. First, due to clinical complexities, such as fever of central origin/therapeutic hypothermia, the impact of stress on white blood cells, and interobserver agreement in the interpretation of chest radiographs, the exact affirmation of infection is difficult.[33, 35] Therefore, we did not analyze the correlation between T lymphocyte subsets and infection and only emphasized early changes in T lymphocyte subsets. Second, in order to assess obvious changes, we only enrolled OHCA patients who had obvious signs of systemic ischemic hypoxia, such as GCS <8 after ROSC. The changes in T lymphocyte subsets in patients with mild systemic ischemic hypoxia need to be further studied. Third, because the accurate no-flow time of most patients could not be assessed, we did not analyze the impact of no-flow time.
In conclusion, circulatory T lymphocyte levels, including Th1, Th2, and Th17 cell counts, decrease in the early period after ROSC. Despite the unchanged CD4+/CD3+ lymphocyte ratio, a shift from a Th1 to Th2 response occurs in the circulation. The changes in Th1, Th2, and Th17 subsets may contribute to immune regulatory dysfunction in OHCA patients in the early period after ROSC.
Financial support and sponsorship
This study was supported by grants from the National Natural Science Foundation of China (No. 81372025) and the 2015 Annual Special Cultivation and Development Project for the Technology Innovation Base of the Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation (No. Z151100001615056).
Conflicts of interest
There are no conflicts of interest.
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Edited by: Li-Shao Guo
Keywords:© 2018 Chinese Medical Association
Out-of-Hospital Cardiac Arrest; T Helper Type 1 Cell; T Helper Type 17 Cell; T Helper Type 2 Cell