key: cord-284365-g46myqe7
authors: Guo, Qian; Zheng, Yuchen; Shi, Jia; Wang, Jijun; Li, Guanjun; Li, Chunbo; Fromson, John A.; Xu, Yong; Liu, Xiaohua; Xu, Hua; Zhang, Tianhong; Lu, Yunfei; Chen, Xiaorong; Hu, Hao; Tang, Yingying; Yang, Shuwen; Zhou, Han; Wang, Xiaoliang; Chen, Haiying; Wang, Zhen; Yang, Zongguo
title: Immediate psychological distress in quarantined patients with COVID-19 and its association with peripheral inflammation: a mixed-method study
date: 2020-05-19
journal: Brain Behav Immun
DOI: 10.1016/j.bbi.2020.05.038
sha: 
doc_id: 284365
cord_uid: g46myqe7

Since the end of 2019, Corona Virus Disease 2019 (COVID-19) has been the cause of a worldwide pandemic. The mental status of patients with COVID-19 who have been quarantined and the interactions between their psychological distress and physiological levels of inflammation have yet to be analyzed. Using a mixed-method triangulation design (QUAN + QUAL), this study investigated and compared the mental status and inflammatory markers of 103 patients who, while hospitalized with mild symptoms, tested positive with COVID-19 and 103 matched controls that were COVID-19 negative. The severity of depression, anxiety, and post-traumatic stress symptoms (PTSS) was measured via an on-line survey. Using a convenience sampling technique, qualitative data were collected until the point of data saturation. In addition, a semi-structured interview was conducted among five patients with COVID-19. Peripheral inflammatory markers were also collected in patients, both at baseline and within ± three days of completing the on-line survey. Results revealed that COVID-19 patients, when compared to non-COVID controls, manifested higher levels of depression (P < 0.001), anxiety (P < 0.001), and post-traumatic stress symptoms (P < 0.001). A gender effect was observed in the score of “Perceived Helplessness”, the subscale of PSS-10, with female patients showing higher scores compared to male patients (Z = 2.56, P = 0.010), female (Z = 2.37, P = 0.018) and male controls (Z = 2.87, P = 0.004). Levels of CRP, a peripheral inflammatory indicator, correlated positively with the PHQ-9 total score (R = .37, P = 0.003, Spearman’s correlation) of patients who presented symptoms of depression. Moreover, the change of CRP level from baseline inversely correlated with the PHQ-9 total score (R = -0.31, P = 0.002), indicative of improvement of depression symptoms. Qualitative analysis revealed similar results with respect to patient reports of negative feelings, including fear, guilt, and helplessness. Stigma and uncertainty of viral disease progression were two main concerns expressed by COVID-19 patients. Our results indicate that significant psychological distress was experienced by hospitalized COVID-19 patients and that levels of depressive features may be related to the inflammation markers in these patients. Thus, we recommend that necessary measures should be provided to address depression and other psychiatric symptoms for COVID-19 patients and attention should be paid to patient perceived stigma and coping strategies when delivering psychological interventions.

Since December 2019, a novel coronavirus with person-to-person transmission, which was named by WHO as Corona Virus Disease 2019 , emerged from China and rapidly spread to many other countries becoming a worldwide pandemic (Chan et al., 2020; Cheng and Shan, 2020; Li et al., 2020a; Phan et al., 2020; Zhu et al., 2020) . The escalating global morbidity and mortality of COVID-19 has raised significant public health and economic concerns. As of April 20th, 2020, the PRC officially reported that the total number of confirmed COVID-19 cases had reached more than 88,000, while the total number of international cases surged to more than 2,400,000. Previous studies of similar viral respiratory diseases, such as severe acute respiratory syndrome (SARS), have shown that the infected patients present with varying degrees of mental health problems even after being discharged from hospital, indicating that the mental status of these individuals should not be ignored (Cheng et al., 2004; Mak et al., 2009 ).

Based on this observation, the National Health Commission of China released several mental health guidelines for COVID-19 patients. One focused on basic principles for emergency psychological crisis interventions in pneumonia for novel coronavirus infections (National Health Commission of China, 2020) . However, these documents were developed and disseminated based on evidence-based studies from non-COVID epidemics. To date, only one brief report (Bo et al., 2020) has investigated the post-traumatic stress symptoms experienced by COVID-19 patients.

According to previous studies, survivors of viral infectious diseases are prone to depression (Kuhlman et al., 2018) , anxiety (Wheaton et al., 2012) , adjustment disorder (van Hoek et al., 2011) , acute stress-related disorder (Koopman et al., 1995) , and post-traumatic disorder (Noone, 2013) . Studies exploring the psychological effects during the 2002-2004 SARS outbreak in China highlighted the anxiety and depression that emerged immediately after the epidemic (Cheng et al., 2004; Wu et al., 2005) . At six months post-hospital discharge, approximately 25 percent of survivors experienced significant depression, and approximately 8.3 percent of survivors had adjustment disorder or Posttraumatic Stress Disorder (PTSD) (Wing and Ho, 2004) . At 30 months post-SARS, 25 percent of the patients met diagnostic criteria for PTSD, while 15.6 percent had depressive disorders (Mak et al., 2009) .

Previous studies were usually conducted after the patients were discharged from hospital and thus over relied on quantitative methodology. Conversely, combining quantitative and qualitative approaches and collecting data germane to the immediate psychological distress experienced by infected patients may result in a more accurate and comprehensive understanding of a viruses' impact on mental status (Guetterman et al., 2015; Pluye and Hong, 2014) .

Additionally, the presence of mood and anxiety disorders may be highly correlated to the severity of physiological status, especially as it is reflected in blood levels of peripheral inflammation markers. Studies have consistently reported that altered levels of peripheral C-reactive protein (CRP) (Valkanova et al., 2013) , white blood cell (WBC) count (Shafiee et al., 2017) , and excessive cytokines (Köhler et al., 2017) correlate with symptoms of depression and anxiety. Therefore, this investigation into the interactions between mental status and inflammatory marker levels in patients may assist in a better understanding of the psychological impacts of this disease.

In our study, we used a mixed-methods approach to examine the immediate impact of social-psychological factors on COVID-19 patients (mild cases) who are in quarantine. We also explored the relationship between psychological distress and levels of peripheral inflammatory markers found in blood tests of COVID-19 patients.

This cross-sectional study utilized a mixed-methods approach to investigate the mental status of hospitalized patients with COVID-19 and how it relates to the presence bio-markers of peripheral inflammation. Data were collected during the COVID-19 pandemic from February 10th to February 28th, 2020. Patients were recruited primarily from the Shanghai Public Health Clinical Center (Shanghai, China) , except for two patients from two other provinces (Sichuan and Hubei) who were willing to participate in a telephone interview. Patients were eligible for inclusion if they volunteered, were 18 years or older, and could respond to on-line survey questions. Using diagnostic criteria found in the the 4th version of "Diagnosis and management program of novel coronavirus-infected pneumonia" released by the National Health Commission of The People's Republic of China (China., 2020) , 103 patients diagnosed with mild cases of COVID-19 were included in this study.

Peripheral blood samples were voluntarily obtained from hospitalized patients and all were found to contain viral nucleic acid consistent with COVID-19. None of the participants had lymphatic system disorders or malignant hematologic diseases, ensuring that the whole blood parameters were representative of typical baseline values. The 103 normal controls (NCs) were matched with the patients for age, gender, education level, and place of residence. None of the NCs had been diagnosed with COVID-19 or suspected for infection with COVID-19. NCs were recruited from local communities and volunteered to participate in our on-line survey. None of them reported a history of being diagnosed with any mental disorder, using diagnostic criteria of the International Classification of Diseases, tenth version (ICD-10).

The purpose of the on-line survey was explained in plain language to patients, "We are trying to understand how the infection of COVID-19 affects your mental status and daily-life." The NCs were told, "We are trying to understand how the outbreak of COVID-19 affects your mental status and daily-life recently." Verbal informed consent was provided to participants prior to the enrollment and all participants answered "Agreed" to the informed consent associated with the on-line survey. This study was approved by the Local Research Ethics Committee, Institutional Review Board, Shanghai Mental Health Center (2020-17) .

All participants completed the on-line survey with their cell phones using the Chinese professional survey website Wenjuanxing (www.sojump.com). Socio-demographic information, including the participants' gender, age, marital status (single, married, divorced, widowhood), and socio-economic background (e.g., education level, occupation), was collected. Open-ended questions with free form response fields were posed regarding current concerns and opinions regarding on-line psychological support.

The Patient Health Questionnaire, 9-item version (PHQ-9) (Kroenke et al., 2001) , Generalized Anxiety Disorder Assessment 7-item version (GAD-7), Perceived Stress Scale, 10-item version (PSS-10) (Barbosa-Leiker et al., 2013a) , and the PTSD Checklist for DSM-5 (PCL-5) were used to assess the levels of psychological distress of all participants (Wortmann et al., 2016) . All were self-report scales with clear cutoff scores determining severity of symptoms. For PHQ-9, the total scores of 5, 10, 15, and 20 represented mild, moderate, moderately severe, and severe depression, respectively. The cutoff points used for the GAD-7 for mild, moderate, and severe anxiety were 5, 10, and 15, respectively. The PSS-10 consisted of two factors, with six negatively worded items (Items 1-3, 6, 9, 10) comprising the first factor and four positively worded items (Items 4, 5, 7, 8) comprising the second factor (Barbosa-Leiker et al., 2013b; Golden-Kreutz et al., 2004; Siqueira Reis et al., 2010) .

Specifically, the first factor represents negative feelings associated with stress, i.e., "Perceived Helplessness", and the second factor reflects positive feelings counter to stress, "Perceived Self-Efficacy" (Roberti et al., 2006) . The post-traumatic and stress-related symptoms were measured by PCL-5. The PCL-5 is a 20-item that evaluates DSM-5 PTSD symptoms caused by a currently distressing event in the past month (Wortmann et al., 2016) . Four subscale scores can be calculated by summing items as follows: intrusions (Items 1-5), avoidance (Items 6-7), negative alterations The peripheral inflammatory biomarkers were collected twice in the patient group, at the first day of hospitalization and within ± three days of fulfilling the on-line survey.

These biomarkers included leukocyte count, platelet count, neutrophil count, lymphocyte count, monocyte count, hypersensitive C-reactive protein (HS-CRP) level, procalcitonin (PCT), and erythrocyte sedimentation rate level (ESR). Blood specimens were collected between 6:30 am and 7:00 am by venipuncture into EDTA tubes, and were analyzed in a central laboratory within 2 hours. Blood cell counts were determined using Sysmex XT-4000i Automatic Hematology Analyzer (Sysmex Corporation, Kobe, Japan). HS-CRP was determined by nephelometry method using the Lifotronic PA-990 (Lifotronic, Shenzhen, China). PCT was measured by electrochemiluminescence immunoassay (ECLIA) using the Roche Elecsys Modular and Cobas e602 (Roche, Zurich, Switzerland). ESR was measured by the Automatic dynamic ESR analyzer, Vision-B (YHLO Biotech Co, Shenzhen, China).

Two psychologists interviewed the five patients who participated in a "semi-interview" by telephone. The semi-interviews were structured to collect insights into the perceived stress and the post-traumatic symptoms of the patients with COVID-19 (for details of the list see Supplementary List 1.). The patients were informed that all information they deemed as confidential would not be recorded in the interview. If any questions made them uncomfortable, they could refuse to answer them. The audiotaped interviews were transcribed for data analysis.

Statistical analyses of demographic, clinical data were conducted using R (Version 3.6.0), with package "psych" and package "ggplot2" (Team, R.D.C., 2011) . ANOVA (Analysis of Variance) models were used to compare continuous and normally distributed variables between groups. The Mann-Whitney U tests were used to analyze continuous and abnormal distributed variables. Categorical variables were described by frequencies (percent), and Chi-square tests were used to detect group differences. The relationship between patient psychological assessments and their measured levels of peripheral inflammation levels was also examined with Spearman's correlation tests.

Qualitative data were managed and analyzed using NVivo, version 11. The entire dataset, i.e., the complete responses of all participants, was coded by one author (Y.

Zheng), and the content related to the aims of research was specifically noted during coding. The descriptive phenomenological approach was utilized in this study to render the results of analyzing our data accurate. The coded data corresponding to the quantitative variables in the measures, including PSS-10 and PCL-5, were extracted and compared between the two groups. The extracted narratives of patients were translated into English.

Demographic data did not differ in age, gender, education level, and marital status between patients with COVID-19 and NCs (Table 1) The total scores of PHQ-9, GAD-7, and PCL-5 were significantly higher in patients when compared to the NCs (Table 1 and 17.61, P < 0.001). Given that 18 (17.5 percent) and 7 (6.8 percent) patients suffered from moderate to severe levels of depression and anxiety (Table 2 and Table 3) , respectively, the depression symptoms (DS) appeared to be more prominent in patients with COVID-19 than anxiety symptoms. When stratified by gender, these outcomes did not differ between males and the females in each group.

Four factors of PCL-5 were also extracted and compared between groups. The patients showed significant higher scores in intrusive symptoms (Z = 4.67, P < .001), NACM (Z = 3.47, P = .001), and AR (Z = 3.17, P = .002) compared to normal controls. Since the PCL-5 score of 33 showed optimal efficiency for detecting PTSD cases according to PCL-5 scoring criteria, we calculate the proportions of participants who had PCL-5 score more than 33. The results revealed that only one patient (1.0 percent) and two NCs (1.9 percent) had exceeded the cutoff score. No gender effect was detected in this analysis.

The total score of PSS-10 did not differ between the two groups. We calculated the scores of "Perceived Helplessness" and "Perceived Self-efficacy" using gender stratification. The analysis revealed that the score of "Perceived Helplessness" showed a trending difference between patients and NCs (Z = 1.85, P = 0.064), while no between-group difference was observed in the score of "Perceived Self-Efficacy". However, when stratified by gender, the female patients exhibited a significantly higher score of "Perceived Helplessness" compared to male patients (Z = 2.56, P = 0.010), female (Z = 2.37, p = 0.018) and male controls (Z = 2.87, P = 0.004), respectively ( Figure 2 ).

The correlation analysis revealed no significant relationship between psychological assessments and inflammatory indicators when looking at the entire patient group.

However, among patients presenting depressive features (total score of PHQ-9 above 4), the level of CRP was positively correlated with the total score of PHQ-9 (R = 0.37, P = 0.003, Spearman's correlation). After controlling for age and duration of hospitalization, the association remained significant (R = 0.28, P = 0.028, Spearman's correlation). The CRP level and other inflammatory markers did not show statistical difference between patients with and without DS. There was no significant relationship found between other psychological assessments and the level of CRP.

We further investigated the impact of inflammatory changes, from the first day of hospitalization to the point of our survey, on the outcomes of depression level among patients. As displayed in Table 4 , the patients without DS showed significant amelioration in CRP level (t = 3.76, P = 0.001), whereas the patients with DS did not show statistical change (t = 1.36, P = 0.179). Moreover, the change of CRP level from baseline reversely correlated with the total PHQ-9 score (R = -0.31, P = 0.002) at point of our survey, indicating that the improved CRP level may have resulted in less depressive symptoms at the time of our survey. Trending association between the change of CRP level and PHQ-9 total score of was also observed among patients with DS (R = -0.25, P = 0.053). Since hospitalization length of stay and age may affect the inflammatory outcomes, we compared the two variables between patients with and without DS and found no group-difference (for age: t = 1.23, P = 0.223; for hospitalization duration: t = -0.05, P = 0.958).

The qualitative results were extracted from the narratives of patients during the semi-structured interview and were matched with the quantitative measurements (Table 5 ). The quantitative data were found to be matched with the content of items 1, 2, 6 in PSS-10, and items 6, 7, 10, 11 in PCL-5. The severities of the above items were subsequently compared between patients and NCs. The COVID-19 patients showed significant higher scores in the items 1, 6 of PSS-10 (item 1, Z = 2.02, P = 0.044; item 6, Z = 2.62, P = 0.009) and items 10, 11 of PCL-5 (item 10, Z = 3.55, P < 0.001; item 11, Z = 5.52, P < 0.001), whereas trending group differences were showed in the item 2 in in PSS-10 (Z = 1.84, P = 0.065) and items 6, 7 in PCL-5 (item 6, Z = 1.83, P = 0.068; item 7, Z = 1.78, P = 0.076).

The primary factors related to the patient's perception of stress were the unexpectedness, loss of control (uncertainty), and sense of powerlessness. The 

To our knowledge, this is the first study utilizing a mixed-method triangulation design to investigate the immediate psychological impact of COVID-19 on the patients and its association with inflammatory biomarkers. Compared with normal controls, patients with COVID-19 presented higher levels of depression, anxiety, and post-traumatic stress symptoms. Though the total score of PSS-10 did not differ between patients and NCs, subgroup analysis demonstrated that female patients reported significantly more "Perceived Helplessness" than male patients and NCs. As for interactions between psychological distress and inflammatory biomarkers, the results revealed that depression levels were statistically directly related to the levels of Qiu et al., 2020) , and the healthcare workers (HCWs) (Lai et al., 2020; Li et al., 2020b) . These studies consistently report that citizens of Wuhan or Hubei province were prone to higher levels of post-traumatic stress symptoms (Bo et al., 2020; Liu et al., 2020) or psychological distress (Qiu et al., 2020) than other regions of China. Similar to our study, the nationwide on-line survey conducted by Qiu's group observed a gender effect on psychological outcomes (Qiu et al., 2020) , with females showing significantly higher psychological distress than males. Two other investigations focusing on HCWs found a comparable proportion of participants with symptoms of depression (50.4 percent), anxiety (44.6 percent) as in our data (Lai et al., 2020) . They also found that the general public and non-front-line nurses exhibited much higher vicarious traumatization than front-line nurses (Li et al., 2020b) . An initial report of 217 hospitalized patients in Wuhan, China, observed neurologic symptoms in nearly half of those with severe infection, with lower blood lymphocyte counts and elevated plasma CRP in patients with CNS-associated or muscular symptoms (Mao et al., 2020) . Notably, the elevated CRP levels or neutrophil counts combined with lower lymphocyte counts were considered to be prognostic of poorer COVID-19 outcomes. Our data demonstrated increased lymphocyte counts and decreased plasma CRP in the recovery phase of the illness. However, CRP levels in patients with DS were not significantly diminished, which may lead to mild neuropsychiatric symptoms, such as those associated with depression.

This result aligned with the prior CoV-related findings in psychoneuroimmunology (Brietzke et al., 2020) , in which the mood disturbance could be a direct result of the virus infection in the brain or due to the activation of immune-inflammatory response (Cheng et al., 2004) . Our data, however, may be in support for the latter hypothesis.

Studies have proven that COVID-19 infection triggers the overproduction of pro-inflammatory cytokines including interleukin (IL)-6, IL-8, IL-10, IL-2R and tumor necrosis factor (TNF)-alpha, which could be related to neuropsychiatric symptoms (Troyer et al., 2020) . The supporting evidence that Kuhlman and colleagues have revealed is the positive linkage between the increases in IL-6 and depressed mood and cognitive symptoms after receiving seasonal influenza vaccine (Kuhlman et al., 2018) . Studies of cases of influenza encephalitis also demonstrate very little evidence that the neurological complications of influenza are due to the direct effects of the virus (Whitlock, 1982) . Meanwhile, studies in major depression have documented the positive association between depression levels and inflammatory biomarkers (Köhler et al., 2017; Shafiee et al., 2017; Valkanova et al., 2013) , once again supporting the immune-inflammatory theory for mood disorders.

Except for the pathogen-immune-depression association, it may be meaningful to consider viral infections and subsequent immune activation as a form of stress.

Dysregulation of stress could interact with the pathogenesis of depressive illness (Gold et al., 1995) , most likely resulting from a dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis (Arborelius et al., 1999; Marques-Deak et al., 2005) . Inflammatory agents such as interleukins 6 and TNF-α can enhance HPA activation (Besedovsky et al., 1991; Wang and Dunn, 1998) . Therefore, the effective anti-inflammatory medications for COVID-19 may also be expected to relive the mood disturbance of patients. Since confounders such as medication and the hospitalization length of stay varied among our sample, future studies should focus on medication-free COVID-19 patients and follow the trajectories of inflammatory biomarkers and mental status to clarify this issue.

The study is also the first utilizing mix-methods to illustrate the perceived stress and patients. They, too, suggest that patients may experience fear of the consequences of infection , anxiety, depression, guilt, and anger (Kim and Su, 2020) . The feeling of anger was not reported directly, which might be related to social desirability bias, but could be observed when patients reported themselves blaming others. Disengagement maladaptive coping strategies were identified from avoidance behaviors and patients denying any discomfort during the interview. Previous scientific studies have shown that the internalized HIV stigma was a strong predictor of depression (Swendeman et al., 2018) . The influence of COVID-19 stigma on the mental status of patients is worth discussing in future studies.

The results of this study generate comprehensive insights into the stress and psycho-immunological changes in COVID-19 patients with valuable evidence for clinical intervention not found in other studies. In accordance with recent commentary and guidelines, these findings highlight the importance of timely mental health care for COVID-19 patients and call for more discussion. Future research could focus on the mediating role of coping strategies and gender differences in the stress-related symptoms of patients, and the cause and consequence of the stigma associated with the psychopathology symptoms of COVID-19 patients.

There are some limitations to this study. First, patients with severe and life-threatening COVID-19 were not included in this study. Second, the sample of the study was relatively small, and only five patients participated in the qualitative interview. Possible confounders, such as medication, comorbidities, and duration of hospitalization, may substantially affect the interpretation of our results.

Pro-inflammatory cytokines, which may reflect the stress and mood disturbance, were not tested in our cohort of mild cases. Third, social desirability concerns may influence the responses to measurements used in this study. Finally, this is a cross-sectional study and follow-up data was not included

Depression and anxiety symptoms were more common among COVID-19 patients than in normal controls. The associations between the severity of depression symptoms and the level of CRP may indicate that the virus could affect the central nervous system and induce neuropsychiatric symptoms by activation of immune-inflammatory response. Stigma is an important issue, which may affect the daily life of patients in the community. Necessary measures should be implemented to provide treatment to COVID-19 patients with depression and other mental problems, especially those with pre-morbid risk factors. Addressing the stigma associated with having a disease with profoundly high rates of morbidity and mortality and imparting adaptive coping strategies should be included when delivering psychological interventions.

All authors report no conflicts of interest while conducting the research. 

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PCL-5, stratified by genders. The aroids represent that there are significant between-group differences

Highlights • Compared to individuals that were COVID-19 negative, COVID-19 patients presented higher levels of depression, anxiety, and post-traumatic stress symptoms

The study was supported by following grants: