key: cord-0720973-z8rlmg8h authors: Wu, Congchong; Zhou, Zhiying; Ni, Li; Cao, Jiang; Tan, Meifang; Wu, Xiu; Hu, Jianbo; Xu, Yi title: Correlation between anxiety-depression symptoms and immune characteristics in inpatients with 2019 novel coronavirus in Wuhan, China date: 2021-07-15 journal: J Psychiatr Res DOI: 10.1016/j.jpsychires.2021.07.027 sha: b660c104624a05ced8ed88d9cd1c6a4246e42948 doc_id: 720973 cord_uid: z8rlmg8h BACKGROUND: Coronavirus disease 2019 (COVID-19) is widely acknowledged as a severe traumatic event, and depression, anxiety, and psychological distress are common in diagnosed patients. However, the correlations of biological indicators with emotion are rarely reported. The primary objective of this study was to explore the dysfunction of immune-inflammatory characteristics in patients with depression-anxiety symptoms. METHODS: We investigated the mental status of inpatients with COVID-19 in Wuhan and compared the differences in cytokines and lymphocytes between patients with and without depression-anxiety symptoms at admission. After two weeks of treatment, we evaluated the mental conditions and measured the cytokines and lymphocytes of the patients with depression and anxiety symptoms and explored the changes and their associations. RESULTS: Approximately half of the patients with COVID-19 had depression and anxiety symptoms, and the symptoms were related to the ratio of CD4+/CD8+ and the level of CD4(+)T lymphocytes. When compared with patients without depression-anxiety symptoms, CD4(+)T lymphocytes level was significantly higher in COVID-19 patients with depression-anxiety symptoms. CONCLUSION: This study provided novel evidence regarding the association between depression and anxiety symptoms and immune characteristics, especially CD4(+)T lymphocyte levels, in COVID-19 patients. We emphasized the importance of paying attention to the dynamic immune process of patients diagnosed with COVID-19 with depression/anxiety. failure). For statistical convenience, we combined mild and moderate cases, which were defined as non-1 severe; and severe and critical cases were combined as severe types. 2 All patients in this study not only received antiviral treatment but also had online self-help 3 psychological guidance or a one-on-one face-to-face psychological crisis intervention including 4 supportive psychotherapy, mindfulness exercises, relaxation training. The psychological intervention 5 lasted for 2 weeks and was performed twice a week for 20 to 30 minutes each time. These 6 psychotherapies were provided by a professional psychological treatment team including a chief 7 physician, a co-chief psychotherapist, and four nurses of psychiatric wards from the First Affiliated 8 Hospital, College of Medicine, Zhejiang University. 9 This study was approved by the local Medical Ethics Committee of the First Affiliated Hospital of 10 Zhejiang University. Informed consent was obtained from all participants before the commencement of 11 the study. 12 13 14 General demographic information (age, sex, occupation, education, and marital status) and mental 15 health status were collected through an electronic structured questionnaire. Depression and anxiety 16 status were evaluated by PHQ-9 and GAD-7, which are quick and easy-to-administer screening tools 17 for depression and anxiety, respectively. The item options of both of these tools range from 0 to 3, and 18 total scores of 5, 10 and 15 represent mild, moderate, and severe depression or anxiety, respectively. 19 The average time to complete the questionnaires ranged from 2 to 5 minutes. The participants were 20 required to complete the online questionnaire through a hyperlink before and after the psychological 21 intervention, and the researcher extracted the questionnaire responses from the database. Fasting blood 22 samples were collected in the morning on the second day of admission and the second day after the end 1 of the two-week psychological intervention by a nurse. All data were cross-checked for consistency 2 before data entry and statistical analysis by two independent researchers. Participants underwent a fasting blood draw in the morning. Whole blood samples were drawn 6 from the antecubital vein and divided into two tubes. One was centrifuged at 3000 r/min for 20 min, All of data were analyzed with IBM SPSS Statistics 20.0 (IBM Corporation, New York, USA). For 18 general demographic and clinical data, descriptive statistics were performed. Quantitative variables are 19 expressed as the mean and standard deviation when they were normally distributed; otherwise, they 20 were expressed as the median and interquartile range. Differences in demographic and clinical 21 characteristics between two groups were tested using t-test or Mann-Whitney U test, and the level of 22 change between the pre-and post-psychological intervention time points in respective variables was 1 tested by paired t-tests or paired Wilcoxon test, as appropriate. Relationships between variables were 2 assessed with Pearson's and Spearman's correlations. All statistical tests were two-tailed, with a 3 significance level of P < 0.05. A total of 61 patients with confirmed COVID-19 were enrolled at the Cancer Center of Wuhan 8 Union Hospital from March 1 to March 15, 2020, of whom 57 were included in the study. Four patients 9 who did not complete the questionnaire were excluded. According to the results of the PHQ-9 and GAD-10 7, 20 patients suffered from both depression and anxiety. To determine whether the mental health are 11 related to demographic characteristics, we analyzed severity of initial infection, sex, age, education 12 between the patients with and without depression-anxiety. There were no statistically significant 13 differences of these data found between both groups. The detailed clinical and demographic data are 14 shown in Table 1 . Table 2 presents the immunologic characteristics for the two groups. CD4+ T lymphocytes, IL-6 and 19 TNF-α were found to exhibit highly significant differences between the two groups. Participants with 20 depression-anxiety symptoms showed a higher level of CD4+ T lymphocytes than subjects without 21 depression-anxiety symptoms. Compared to participants without depression-anxiety symptoms, the 22 J o u r n a l P r e -p r o o f levels of IL-6 and TNF-α were lower in the participants with depression-anxiety symptoms. However, 1 other factors (CD4+/CD8+, CD3+, CD8+, IL-2, IL-4, IL-10, IFN-γ) were not significantly different 2 between the two groups. The changes in scores of PHQ-9 and GAD-7 and cytokines and lymphocytes after two weeks 5 of treatment. 6 Following two weeks of treatment including pharmacological interventions for COVID-19 and 7 psychological interventions for mental health, most patient conditions were improved. Fifty patients 8 recovered and were discharged, seven patients (two patients with depression-anxiety symptoms and five 9 patients without depression-anxiety symptoms) remaining in treatment. And after two weeks of 10 treatment, CD4+ T lymphocytes, IL-6 and TNF-α still differed between the two groups (P < 0.05) (See 11 table 3) . 12 The scores of PHQ-9 and GAD-7, cytokines and T lymphocytes were altered. A statistically 13 significant decrease was found in the PHQ-9 (P < 0.05) and GAD-7 (P < 0.01) scores in the patients 14 with depression and anxiety. A significant decrease was found in the level of CD4+ T lymphocytes (P 15 In this study, we found that over half of the population reported different degrees of depression and 11 anxiety, and the scores of PHQ-9 and GAD-7 were associated with the level of CD4+ T lymphocytes 12 and the CD4+/CD8+ ratio at admission. Moreover, patients with depression-anxiety symptoms showed 13 a higher level of CD4+ T lymphocytes than patients without depression-anxiety symptoms. After two 14 weeks of treatment, the mean scores of PHQ-9 and GAD-7 significantly decreased as the level of CD4+ 15 the dysregulation of inflammatory immune responses in COVID-19 patients, this is the first study to 18 investigate the relationship with mental conditions. 19 Mental health is related to internal and external environmental, social and psychological factors 20 Consistent with these studies, in this study, statistically significant differences in CD4+ T lymphocytes 16 were observed between the patients with and without depression-anxiety symptoms, and the level of 17 CD4+ T lymphocytes was associated with the severity of depression and anxiety. These findings 18 appeared to confirm the hypothesis that the immune response mechanism of patients with affective 19 disorders in early stages was adaptive in coping with stressors. Dhabhar 2019). Interestingly, in this study, we found a significant reduction in the level of CD4+ T 7 lymphocytes, which was associated with changes in the PHQ-9 score; however, the levels of IL-2, IL- There are certain limitations in our study. First, this study was conducted at a single hospital in China 18 with a relatively small sample size. Second, because of the strong infectivity of novel coronavirus and 19 shortage of health staff, all mental state assessment data were collected via self-report questionnaires, 20 potential self-report biases cannot be ruled out. Third, the underlying diseases and comorbidities that 21 Finally, considering the serious harm and adverse effects of negative mood on recovery, we used a two-1 week psychological intervention for all patients instead of setting a control group, which was hard to 2 confirm the effect of psychological intervention and the ascertain psychological or immune factor is 3 causative. 4 5 In conclusion, we demonstrated that patients with confirmed COVID-19 and depression-anxiety 7 symptoms differed from those without depression-anxiety symptoms in terms of CD4+ T lymphocytes. 8 After two weeks of treatment, a decrease in depression scores was related with changes in CD4+ and 9 CD8+ T lymphocytes. These findings further support that lymphocytes, particularly T lymphocytes, J o u r n a l P r e -p r o o f Normally distributed data (CD4+ /CD8+, CD4+, CD8+, IL-4, IL-10, IFN-γ, TNF-α) were expressed as mean and standard deviation; while data (CD3+, IL-2, IL-6) were expressed as median and interquartile range. P values indicated the comparison between patients with and without depression-anxiety status. Differences between two groups were tested using t-test for normally distributed data and the nonnormal distributed data were analyzed by Mann-Whitney U test. J o u r n a l P r e -p r o o f Normally distributed data (CD4+ /CD8+, CD4+, CD8+, IL-4, IL-10, IFN-γ, TNF-α) were expressed as mean and standard deviation; while data (CD3+, IL-2, IL-6) were expressed as median and interquartile range. (a) Correlation between CD4+ T lymphocytes and PHQ-9 scores. There are significantly positive association between CD4+ T lymphocytes and PHQ-9 scores (r = 0.378, P < 0.01). (b) Correlation between the ratio of CD4+/CD8+ and PHQ-9 scores. There are significantly positive association between the ratio of CD4+/CD8+ and PHQ-9 scores (r =0.264, P < 0.05). (c) Correlation between CD4+ T lymphocytes and GAD-7 scores. There are significantly positive association between CD4+ T lymphocytes and GAD-7 scores (r = 0.403, P < 0.01). (d) Correlation between the ratio of CD4+/CD8+ and GAD-7 scores. There are significantly positive association between the ratio of CD4+/CD8+ and GAD-7 scores (r = 0.282, P < 0.05). Abbreviations: PHQ-9, Questionnaire nine-item depression scale; GAD-7, Generalized Anxiety Disorder 7-item; CD, cluster of differentiation; COVID-19, coronavirus disease 2019. 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