Asian Journal of Psychiatry 80 (2023) 103409

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Asian Journal of Psychiatry

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Long term neuropsychiatric consequences in COVID-19 survivors:

Cognitive impairment and inflammatory underpinnings fifteen months
after discharge
Danmei He a, b, c, 1, Minlan Yuan a, d, *, 1, Wen Dang a, b, c, Lin Bai a, Runnan Yang a, Jingyi Wang a,
Yao Ma a, Bo Liu a, Shiyu Liu a, Simai Zhang b, c, Xiao Liao a, Wei Zhang a, b, c, d, *
a
Mental Health Center and Psychiatric Laboratory, West China Hospital of Sichuan University, Chengdu, China
b
West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
c
Med-X Center for Informatics, Sichuan University, Chengdu, China
d
Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Emerging evidence shows that cognitive dysfunction may occur following coronavirus disease 19
COVID-19 (COVID-19) infection which is one of the most common symptoms reported in researches of “Long COVID”.
Cognitive function Several inflammatory markers are known to be elevated in COVID-19 survivors and the relationship between
Systematic inflammation
long-term inflammation changes and cognitive function remains unknown.
Long-COVID
Methods: We assessed cognitive function and neuropsychiatric symptoms of 66 COVID-19 survivors and 79
healthy controls (HCs) matched with sex, age, and education level using a digital, gamified cognitive function
evaluation tool and questionnaires at 15 months after discharge. Venous blood samples were collected to
measure cytokine levels. We performed correlation analyses and multiple linear regression analysis to identify
the factors potentially related to cognitive function.
Results: The COVID-19 survivors performed less well on the Trails (p = 0.047) than the HCs, but most of them did
not report subjective neuropsychiatric symptoms. Intensive care unit experience (β = − 2.247, p < 0.0001) and
self-perceived disease severity (β = − 1.522, p = 0.007) were positively correlated, whereas years of education (β
= 0.098, p = 0.013) was negatively associated with the performance on the Trails. Moreover, the abnormally
elevated TNF-α levels (r = − 0.19, p = 0.040) were negatively correlated with performance on the Trails in
COVID-19 group.
Conclusion: Our findings suggest that COVID-19 survivors show long-term cognitive impairment in executive
function, even at 15 months after discharge. Serum TNF-α levels may be an underlying mechanism of long-term
cognitive impairment in patients recovering from COVID-19.

1. Background system (CNS)4 damage suggests a possible role for the virus in the
development of long-term neuropsychiatric sequelae (Kumar et al.,
Coronavirus disease 19 (COVID-19),2 caused by the severe acute 2021; Tandon, 2022).
respiratory syndrome coronavirus 2 (SARS-CoV-2),3 primarily causes Growing evidence suggests that there is a high frequency of persis­
respiratory symptoms, with fever and cough with or without sputum tent neuropsychiatric symptoms after the initial illness including fa­
being the most common manifestations in symptomatic patients. How­ tigue, cognitive dysfunction, sleep disorders, mood disorder, and
ever, the finding that the virus has the potential to cause central nervous anxiety disorders that often refers to as ‘Long-COVID’(Badenoch et al.,

* Correspondence to: Mental Health Center, West China Hospital of Sichuan University, Dianxin South Road No. 28, Chengdu 610041, China.
E-mail addresses: [email protected], [email protected] (M. Yuan), [email protected] (W. Zhang).
1
These authors contributed equally: Danmei He and Minlan Yuan.
2
COVID-19: The Coronavirus disease 19
3
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2
4
CNS: Central Nervous System

https://doi.org/10.1016/j.ajp.2022.103409
Received 8 October 2022; Received in revised form 8 December 2022; Accepted 12 December 2022
Available online 15 December 2022
1876-2018/© 2022 Elsevier B.V. All rights reserved.
D. He et al. Asian Journal of Psychiatry 80 (2023) 103409

2022; Hampshire et al., 2021). There are several mechanisms through and quality of life. It is important to understand the neuropsychiatric
which SARS-CoV-2 could damage the CNS, including direct invasion and consequences as millions of individuals have been affected and more
indirect infection (Alvarez et al., 2022; Du et al., 2021; Iodice et al., unfound. Similarly, evaluating cognitive consequences following
2021; Kumar et al., 2021). SARS-CoV-2 can invade the nervous system COVID-19 is essential, particularly by evaluating the capacity of an in­
through the recognition of the virus’s spike proteins by cell membrane dividual to work effectively, participate in daily family activities, or
receptors (Amruta et al., 2021; Du et al., 2021). Another possible make reasoned decisions (Kumar et al., 2021).
mechanism that the virus can indirectly infect the nervous system is the This study aimed to evaluate the cognitive function and neuropsy­
cytokine storm which refers to an uncontrolled excessive inflammatory chiatric symptoms in patients who recovered from COVID-19 at 15
reaction. It starts locally and spreads further in the body through sys­ months of follow-up after their discharge from hospital, and to investi­
temic circulation. (Jose and Manuel, 2020). However, it is unclear which gate the potential associated factors, including systematic inflammation.
is the dominant mechanism that underlies the neuropsychiatric We assessed the cognitive function of COVID-19 survivors using THINC-
sequelae. integrated tool (THINC-it),8 which is a digital, gamified cognitive
Several inflammatory markers, including interleukin (IL)5-1β, IL-6, function evaluation tool (Harrison et al., 2018; Zhang et al., 2020).
interferon (IFN)6-γ, tumor necrosis factor (TNF)-α,7 chemokine inter­ Using this tool, we evaluated comprehensive neuro­
feron-γ inducible protein-10, Monocyte chemoattractant protein-1, and psychiatric/cognitive function in COVID-19 survivors after 15 months
macrophage inflammatory protein 1-α, and T helper 2 cytokines, and in matched healthy controls (HC).
including the IL-4, IL-10, and IL-1 receptors, are elevated in the serum of
patients with COVID-19 during the cytokine storm particularly related 2. Methods
to the illness (Coperchini et al., 2020; Mehta et al., 2020). The persis­
tence of the SARS-CoV2 and extension and amplification of the inherent 2.1. Study design and participants
immune mechanism will cause the dysfunction of immune response
once the human immune system could not produce an appropriate im­ This was an observational cross-sectional study. We recruited 66
mune response to the virus. This will lead a high inflammatory state of patients hospitalized for SARS-CoV-2 infection who were willing to
cytokine storm. (Pelaia et al., 2020) Previously, systemic inflammation participate in this study. Voluntary COVID-19 survivors who visited the
has been shown to lead to cognitive decline, suggesting that COVID-19 second outpatient clinic, West China Hospital, Sichuan University, about
survivors could experience cognitive deficits in the following years fifteenth-month after their discharge from April 2021 to August 2021
(Gorelick, 2010; Poletti et al., 2022). were enrolled in the study. Healthy volunteers were recruited from
It is known from previous pandemics that there are not only acute nearby communities between August 2021 and December 2021. All
effects of the viral infection but also long-term sequelae such as subjects gave written informed consent.
depressed mood, anxiety symptoms, insomnia, loss of smell, ageusia,
fatigue, and headache due to the virus infection itself as well as social 2.2. The patients with COVID-19 group
effects due to quarantine, social distancing, and lockdown (Han et al.,
2022; Kumar et al., 2021; Méndez et al., 2022). The COVID-19 pandemic The criteria for enrollment of patients with COVID-19 were as fol­
has prompted many countries to adopt restraining measures to mitigate lows: (1) patients who were hospitalized and willing to participate in the
the spread of the disease (Nogueira et al., 2021). As the disease has a follow-up process, and (2) participants who signed an informed consent
high level of transmissibility, the patients with COVID-19 are required to form and were able to understand and complete the tests. The exclusion
stay in isolated units. In Wuhan, patients with mild symptoms received criteria were as follows: (1) Patients have some neurological diseases
treatment in temporary quarantined hospital facilities, whereas those such as cerebrovascular disease, neurodegenerative diseases, encepha­
with more severe symptoms received treatment from a designated hos­ litis, and traumatic brain injury which may cause cognitive impairment
pital for more aggressive therapy (Hu et al., 2020). Isolation has been based on MRI examination (3-T MRI system Philips Achieva) (2) patients
shown to influence cognitive function (Wang et al., 2022). who could not understand or read the informed consent form, and (3)
Some earlier studies found significant differences between patients patients who is taking psychotropic medicines. Finally, we recruited 66
with COVID-19 and matched control groups via self-report question­ COVID-19 survivors aged 13–66 years old into the study.
naires on various measures, indicating short-term memory loss, trouble
focusing attention, and concentration impairment/disorder in the pa­ 2.3. HC group
tients (Amin-Chowdhury et al., 2021; González-Hermosillo et al., 2021;
Klein et al., 2021). However, most of the existing studies have focused In total, 79 healthy participants matched with sex, gender, and ed­
on assessing patients at 5 days to one year of follow-up after discharge ucation level were recruited voluntarily. Both male and female partici­
from the hospital (Ceban et al., 2022; Miskowiak et al., 2022). Research pants aged between 17 and 61 years were included. Clinical
focusing on neuropsychiatric consequences over one year is limited and examination eliminated cognitive impairment caused by physical
should be investigated (Kawakami et al., 2022). Furthermore, changes illness, as well as family history of psychiatric disorders. We excluded
in the levels of inflammatory factors in people who recovered from participants who were pregnant or lactating women and those who had
COVID-19 and their relationship with cognitive function remain un­ hearing or visual impairments.
known. Moreover, most of the existing studies rely on patients’ com­
plaints in medical records or self-reported symptoms via telephone to 3. Assessment
evaluate and describe neuropsychiatric symptoms and neurocognitive
function. Few studies have evaluated the neurocognitive function of 3.1. Demographic data and basic clinical information
COVID-19 survivors using integrated tools in which both self-reported
questionnaires and neuropsychological tests were used. Demographic data, including age, sex, marital status, educational
In summary, SARS-CoV-2, which causes neuronal damage, can have background, smoking history, occupation, and religion were collected.
a prolonged negative impact on cognitive function, daily functioning, Meanwhile, routine clinical data, including length of hospital stay,
isolation time, duration of nucleic acid positivity, and self-perceived
disease severity were collected. The self-perception of disease severity
5
IL-: Interleukin-
6
IFN-: Interferon-
7 8
TNF-α: Tumor Necrosis Factor alpha THINC-it: THINC-Integrated Tool

2
D. He et al. Asian Journal of Psychiatry 80 (2023) 103409

was registered on an ordinal scale. members, relatives, and friends, and being insulted by others. All the
above factors were registered on an ordinal scale assigning degrees of
3.2. Neuropsychiatric interview “none,” “somewhat,” “moderate,” “severe,” and “extraordinarily
severe.”
The Mini International Neuropsychiatric Interview (MINI version
5.0.0)9(Si et al., 2009) was conducted to determine the mental health
3.5. Serum sample collection and analysis
diagnoses of all participants. The results were evaluated by a trained
physician. In addition, the severity of anxiety, depression symptoms,
Venous blood samples (5 ml) were collected from each patient. The
and post-traumatic stress disorder (PTSD)10 symptoms was self-reported
blood samples were centrifuged at 3500 r/min for 15 min, and serum
using the Generalized Anxiety Disorder Assessment (GAD-7)11(He et al.,
was extracted for analysis. Cytokines in the serum/plasma were
2010) Patient Health Questionnaire-9 (PHQ-9)12(Sun et al., 2017) and a
measured by a multiplexed flow cytometric assay using a human cyto­
4-item Post-traumatic Stress Disorder Checklist for Diagnostic and Sta­
kine (kit catalog number: HSTCMAG-28SK) on a Luminex ® system
tistical manual of Mental disorders-5 scale (PCL-5)13(Fung et al., 2019)
(MAGPX ® WITH xPONENT, version 4.2, Merck Millipore, USA). In
for the COVID-19 group.
serum/plasma, measurements of interferon-inducible T cell alpha che­
moattractant (I-TAC), granulocyte-macrophage colony-stimulating fac­
3.3. Cognitive assessment tor (GM-CSF),19 fractalkine, IFN-γ, IL-10, macrophage inflammatory
protein-3α (MIP-3α),20 IL-2(p70), IL-13, IL-17A, IL-β, IL-2, IL-4, IL-23,
Cognitive assessment was performed using a digital, simplified Chi­ IL-5, IL-6, IL-7, IL-8, MIP-1, MIP-β, and TNF-α were performed. The
nese version of the THINC-it tool, which has been proven to have good analysis was performed according to the manufacturer’s instructions
reliability and validity in the Chinese adult population (Liu et al., 2021). (MILLIPLEX Analyst 5.1, Merck Millipore, USA). The samples were
It includes a 5-item Perceived Deficits Questionnaire for Depression measured in duplicates. The range of the standard curves for all
(PHQ-5D),14 Spotter, Symbol Check, Codebreaker, and Trails (Hou et al., measured cytokines was pg/ml.
2020; Zhang et al., 2020). The validity of the four objective test sections
of the THINC-it tool (Spotter, Symbol Check, Codebreaker, and Trails)
4. Statistical analysis
was used to evaluate the subjunctive’s attention/concentration, execu­
tive function, working memory, and processing speed. The five consis­
In this study, the COVID-19 survivors and HC group were matched by
tent criterion tests were the Deficits Questionnaire for Depression
propensity score matching to control for covariates including age, sex,
(PDQ-5D), Reaction time paradigm (RTI),15 Digit Symbol Substitution
and years of education. All the collected data were analyzed using the R
Test (DSST),16 Trail Making Test-Part-B (TMT-B),17 and One-back Task
(version 4.1.1) package with an alpha set for significance at p < 0.05,
(1-back)18 (Zhang et al., 2020). RTI was selected as a measure of
which represents an acceptable probability of Type I error in a statistical
attention and executive function; 1-back paradigm was selected to test
test. The Shapiro–Wilk method was used to assess the normality of
the attention, memory, and reaction speed of the participants; DSST was
continuous variables. T-tests were used for normally distributed data,
chosen to identify the executive function, processing speed, and atten­
and non-parametric Mann–Whitney U tests were applied for continu­
tion/concentration; and TMT-B was selected to assess the executive
ously skewed data. Categorical data were analyzed using the chi-square
function of the participants.
test. An association test was conducted using the Spearman method if
In addition to these four objective measures of cognition, the PHQ-
the data were not normally distributed. Multiple linear regression
5D questionnaire was included as a subjective measure of general
analysis was used to explore factors related to cognitive function. Outlier
cognitive function, including attention/concentration, retrospective and
and influential points were detected before all analyses. The sample size
prospective memory, and planning/organization, using a 5-points
with adequate power was calculated by GPower (version 3.1.9.7). For
ordinal categorical response scale to reflect the frequency of experi­
non-normally distributed data, effect size r were estimated (Fritz et al.,
encing a specific cognitive problem in the past 7 days (Harrison et al.,
2012).
2018; Lam et al., 2018).
Demographic data and basic clinical information were displayed as
frequencies and expressed as percentages (n, %). In the cognitive test,
3.4. Social support scale and discrimination evaluation Symbol Check and Codebreaker were negatively associated with the
severity of cognitive impairment; however, the scores of Spotter and
Xiao revised a Chinese version of the social support scale based on Trails showed the opposite trend. To maintain the direction of each test
the relevant information (Xiao, 1994). Its validity and reliability have result consistently, the results of PDQ-5D, Spotter, and Trails were
been previously confirmed (Liu et al., 2008). The social support scale converted into standard z-scores and multiplied by − 1, so that the re­
contains 10 items, including 3 objective support, 4 subjective support, sults of each sub-part of THINC-it would follow a trend where the higher
and 3 support utilizations. The score varies from 12 to 65 points, with a the score, the better the cognitive function (McIntyre et al., 2017; Zhang
higher score representing greater social support and diversity of social et al., 2020).
networks (Su et al., 2012). We also gathered information regarding A multiple linear regression model was used to assess the indepen­
discrimination factors, including being ostracized by neighbors, family dent predictors of the test scores for significantly different cognitive
functions. We included 13 independent variables, including age, sex,
years of education, length of hospital stay, nucleic acid test positive
9
MINI: Mini International Neuropsychiatric Interview time, isolation time, self-perception of disease severity, being ostracized
10
PTSD: Post-traumatic stress disorder by family, neighbors, and community, being verbally abused, social
11
GAD-7: Generalized Anxiety Disorder Assessment
12 support score, PHQ-9 score, and GAD-7 score. All categorical indepen­
PHQ-9: Patient Health Questionnaire-9
13 dent variables were recoded into dummy variables, which were used in
PCL-5: Post-traumatic Stress Disorder Checklist for Diagnostic and Statisti­
cal manual of Mental disorders-5 scale
the regression analysis to represent subgroups of the sample in the
14
PHQ-5D: 5-item Perceived Deficits Questionnaire for Depression model.
15
RTI: Reaction time paradigm
16
DSST：Digit Symbol Substitution Test
17 19
TMT-B: Trail Making Test-Part-B GM-CSF: Granulocyte-macrophage Colony-stimulating Factor
18 20
1-back: One-back Task MIP: Macrophage Inflammatory Protein

3
D. He et al. Asian Journal of Psychiatry 80 (2023) 103409

5. Result Trails, which evaluates executive function, compared with the HC group
at 15-months of follow-up. A potential correlation between serum TNF-α
5.1. Demographic information and clinical characteristics levels and executive function has also been reported. In hospitalized
COVID-19 survivors, executive function was negatively correlated with
The demographic information, cognitive performance, and neuro­ the experience of ICU stay and self-perceived disease severity. These
psychiatric data of the participants are presented in Table 1. In total, 66 associations were independent of age, sex, and years of education.
patients hospitalized for COVID-19 and 79 HC volunteers were included Cognitive deficit is one of the most common symptoms reported in
in the present study after adjusting for age, sex, and educational back­ research into Long COVID. Those who experienced “post-COVID-19
ground. There were no significant differences in age, sex, or education. syndrome”/ “post-acute sequalae SARS-CoV-2”/ “Long COVID”
Only 4 COVID-19 survivors had a MINI diagnosis consistent with following the COVID-19 infection may have cognitive dysfunction (Guo
depression and anxiety and most COVID-19 survivors did not report et al., 2022). Based on our understanding of the mechanism of the virus
subjective neuropsychiatric symptoms. The COVID-19 group performed in the CNS and the emerging evidences available, one can expect to have
less well in the Trails with a small effect size (r = 0.21, p = 0.047) than a variety of cognitive consequences of COVID-19 infection including
the HC group. attention, dysexecutive symptoms and hypoperfusion (Kumar et al.,
The clinical characteristics of the COVID-19 survivors are displayed 2021). In this study, COVID-19 survivors were admitted for a clinical
in Table 2. The median length of hospital stays, isolation time of hos­ physical examination to rule out cognitive impairment due to physical
pitalized survivors, and duration of nucleic acid positivity were 20.50 illness. We examined the objectively cognitive function of the 66 hos­
(14.25–30.00), 45.00 (30.00–60.00), and 20.00 (10.00–30.00) days, pitalized COVID-19 survivors 15 months after hospital discharge, as well
respectively. The majority of the survivors’ self-perceived disease as in 79 recurred healthy participants based on age, sex, and educational
severity was general and mild. Furthermore, participants rarely had the background. We reported the differences in executive function between
experience of intensive care unit (ICU) stay, and none of them had the two groups. Our results are in line with the results of a previous study
extraordinarily severe ostracization by neighbors, community, family that reported a significant difference in executive function between
members, relatives, or friends. patients with COVID-19 and a healthy control group (Johnsen et al.,
2021). Similarly, another study showed that the most pronounced im­
5.2. Multiple linear regression for the prediction of cognitive function pairments in patients with COVID-19 were seen in verbal learning and
executive function evaluated using TMT-B, based on age, sex, and edu­
To streamline the presentation of the results, Table 3 reports the cation, compared to a matched HC group (Miskowiak et al., 2021).
findings from the linear multiple regressions. The associations between We did not find any group differences in attention, memory, reaction
the basic clinical data, discrimination data, and cognitive function are speed, or processing speed, which is contrary to earlier research (Fer­
summarized in Table 3. In the model, the results of multiple linear rucci et al., 2021). A previous study using the Montreal Cognitive
regression indicated that the four predictors explained 32.76 % of the Assessment indicated an improvement in cognitive function from
variance (R2 = 0.328, F (20,38) = 2.584, p = 0.004). Multiple linear discharge time to 6 months of follow-up, while another study showed a
regression analysis revealed a significant association between ICU greater increase in duration to complete the TMT-B at follow-up time in
experience (β = − 2.247, p < 0.0001), years of education (β = 0.098, p = patients with COVID-19 compared to healthy controls (Douaud et al.,
0.013), and self-perception of disease severity (somewhat severe) (β = 2022; Nersesjan et al., 2022). We can only speculate that the possible
− 1.522, p = 0.007). The factors of ICU stay and self-perceived disease reason for the difference in results from previous studies might be that
severity were negatively associated with cognitive function. In contrast, the cognitive function of COVID-19 survivors improved over time, and
years of education was positively associated with executive function. most of the earlier evaluations were performed using objective tools.
Further, we found that the experience of ICU stay and self-perceived
5.3. Associations between neuropsychiatric symptoms, inflammatory disease severity were negatively associated with cognitive function.
factors, and the cognitive test Patients with COVID-19 who had experienced ICU stay showed worse
executive function at 15 months of follow-up. This result was in line with
There is no statistically significance between scores for depression/ that from an earlier study which indicated that new or worse cognitive
anxiety/PTSD and cytokine levels and cognition. Comparison tests impairment commonly occurs and persists in survivors of ICU stay
revealed significant differences after false discovery rate (FDR)21 (McLoughlin et al., 2020). The COVID-19 survivors suffered some de­
correction between the COVID-19 (n = 55) and HC groups (n = 79) with gree of isolation and discrimination; however, no significant correlation
regard to the I-TAC (adjusted p = 0.021), IL-8 (adjusted p < 0.0001), and between discrimination or other social isolation factors and cognitive
TNF-α (adjusted p < 0.0001). The HC groups show higher I-TAC level function have been identified. One possible reason might be that most of
(87.68 ± 32.56) compared with COVID-19 group (33.95 ± 9.59) in the discrimination faced by the patients with COVID-19 was mild, and
follow-up. Similarly, the IL.8 level is 18.58 ± 11.54 for HC groups which none of them had experienced extraordinarily severe discrimination. As
is higher than COVID-19 group (6.55 ± 6.51). However, the TNF-α is shown in Table 2, they received adequate social support from family
8.39 ± 1.76 which is elevated in COVID-19 group than in HC group members, friends, and society. Another possible reason is that the pri­
(6.58 ± 1.76). Eleven COVID-19 survivors did not participate in blood vacy of patients in Sichuan is well-protected and a certain degree of
sample collection. Moreover, the correlation analyses indicated that psychological education is provided to them, making them less vulner­
TNF-α levels were negatively correlated with the composite z-score of able to social isolation and discrimination.
the Trails after FDR correlation (Spearman’s Rho; r = − 0.19, p = 0.040) SARS-CoV-2 can damage the nervous system through indirect
(Fig. 1). infection such as cytokine storm which refers to an uncontrolled
excessive inflammatory reaction (Du et al., 2021). In current study, we
6. Discussion demonstrated that there were differences in I-TAC, IL-8, and TNF-α
levels after FDR correction between the two groups. Our finding is
To our knowledge, this is the first study on neurocognitive evaluation consistent with the higher levels of inflammatory factors reported in
using the THINC-it tool for COVID-19 survivors in a 15-month follow-up other studies (Heneka et al., 2020; Huang et al., 2020). In contrast, we
time. Our analysis exhibited differences in the performance on the did not find any differences in the levels of IL-13, IL-1b, IL-6, IL-23,
fractalkine, MIP-3a, IL-17A, IL-5, IFN-γ, GM-CSF, IL-7, IL-4, IL-21,
MIP-1a, IL-2 between the COVID-19 and HC groups. Furthermore, there
21
FDR: false discovery rate was a significant correlation between the serum TNF-α levels and

4
D. He et al. Asian Journal of Psychiatry 80 (2023) 103409

Table 1
Demographics and cognitive performance of the study population.
No. (%)

Characteristic COVID-19 (n = 66) HC (n = 79) 95% CI P-value

Age (median [IQR]), y 35.50 [26.25, 46.00] 29.00 [25.00, 39.00] / 0.104a
Gender 0.496b
Female 23 (34.8) 33 (41.8)
Male 43(65.3) 46(58.2)
Marriage Status / 0.013b
Single 21 (31.8) 43 (54.4)
Divorced 2 (3.0) 4 (5.1)
Married 43 (65.2) 32 (40.5)
Education Background
Years of education (median [IQR]), y 15.00 [9.75, 16.00] 15.00 [15.00, 16.00] / 0.088a
Primary school 4 (6.1) 3 (3.8)
Junior high school 13 (19.7) 11 (13.9)
Senior high school 7 (10.6) 1 (1.3)
College 15 (22.7) 25 (31.6)
Undergraduate 22 (33.3) 26 (32.9)
Graduate 5 (7.6) 13 (16.5)
Smoking History / 0.334b
Non-smoker 49 (74.2) 55 (69.6)
Occasionally smoking 3 (4.5) 7 (8.9)
Smoker 7 (10.6) 13 (16.5)
Smoking cessation 7 (10.6) 4 (5.1)
Occupation / 0.079b
Full-time or part-time job 53 (80.3) 56 (70.9)
Retired or Jobless 4 (6.1) 7 (8.9)
Students 6 (9.1) 16 (20.3)
Others 3 (4.5) 0(0.0)
Religion / 0.982b
Have religion 6 (9.1) 6(7.5)
THINC-it test
Response time of Nback (median [IQR])c 50.98 [44.38, 59.00] 49.83 [42.53, 59.05] / 0.435a
Response time of DSST (median [IQR]) 118.88[117.64,119.53] 119.10[118.23,119.51] / 0.362a
The composite z-score of PDQ-5D (median [IQR]) 0.07 [− 0.54, 0.68] 0.10 [− 0.51, 1.02] / 0.767a
Correct number of Symbol Check (median [IQR]) 21.50 [13.00, 29.00] 24.00 [13.50, 33.00] / 0.236a
Correct number of Codebreaker (mean (SD)) 40.41 ± 14.44 41.41 ± 17.86 -6.30–4.31 0.711d
The composite z-score of Spotter (mean (SD)) 0.03 ± 0.98 0.00 ± 1.01 -0.29–0.36 0.843d
The composite z-score of Trail (median [IQR]) 0.23 [0.04, 0.33] 0.33 [0.01, 0.47] / 0.047a
Neuropsychiatric test
PHQ-9 score (median [IQR]) 0.00 [0.00, 0.00] / / /
GAD-9 score(median [IQR]) 0.00 [0.00, 0.00] / / /
PCL-5 score (median [IQR]) 0.00 [0.00, 0.00] / / /
M.I.N.I teste
Major depression disorder (n) 4 0 / /
General anxiety disorder (n) 3 0 / /
a
The analysis was conducted by Mann-Whitney U test.
b
The analysis was conducted by χ2 test.
c
IQR: Interquartile range
d
The analysis was conducted by Two sample T test.
e
Only 4 patients were diagnosed with depression or anxiety disorders (3 MDD patients are comorbid with anxiety disorders)

executive function at 15 months of follow-up. A pervious study showed pathologically can be involved in the process of increased apoptosis and
the systemic inflammation was a predict factor to the neurocognitive decreased neuroplasticity of nerve cells through neurotoxicity and lead
performance (Mazza et al., 2021). Inflammatory markers including to cognitive impairment(Olmos and Lladó, 2014).
TNF-α, TNF-β, IL-1β, IL-4, IL-6, IL-8, and IL-13 was found to be corre­ In an earlier study, compared with wild-type mice, TNF-α deficient
lated with post-acute sequelae of COVID-19 (Schultheiss et al., 2022). mice demonstrate a decreased latency in finding the underwater plat­
Pro-inflammatory mediators can compromise the permeability of form in the Morris water maze testing. This suggests enhanced hippo­
BBB via upregulation of cyclooxygenase-2 and activation of matrix campal memory function in TNF-α knock-out mice (Golan et al., 2004).
metalloprotease (Dehghani et al., 2022). This enables cytokines to enter Moreover, Fiore et al. conducted the same assessments to invest whether
the CNS, causing microglial activation and oxidative stress, leading to endogenous brain TNF-α elevation in transgenic mice was associated
the development of synergistic cognitive impairment (Baker et al., with changes in learning capabilities; overexpression of TNF-α impaired
2021). TNF-α is a prototypic proinflammatory cytokine that is crucial in hippocampal learning/memory function, indicating a suppressive role
initiating and sustaining the inflammatory response (Belarbi et al., for high-level TNF-α in cognition (Fiore et al., 2000).
2012). Large amount of evidences show that TNF is a main mediator of However, we did not find any correlation between depression/anx­
secondary CNS damage after acute injury and under conditions of iety/PTSD scores and cytokine levels. This is in line with an earlier study
chronic inflammation (Probert, 2015). It exerts both homeostatic and which evaluate the relationship between psychiatric symptoms and
pathophysiological effects in the CNS (Montgomery and Bowers, 2012). hematological inflammatory markers. This may because that most
In healthy adults, TNF is constitutively expressed at low level, and has COVID-19 survivors recovered from psychiatric symptoms, thereby
regulatory functions on crucial physiological processes while in patho­ inflammation is not a significant contributor to psychiatric morbidity in
logical ones, astrocytes and mainly microglia release large amounts of patients with COVID-19 in the long term. (Swami et al., 2022).
TNF-α (Olmos and Lladó, 2014; Probert, 2015). Over release of TNF-α The current study was an observational cross-sectional study that

5
D. He et al. Asian Journal of Psychiatry 80 (2023) 103409

Table 2
Clinical characteristics of the study COVID-19 survivors.
No. (%)

Clinical characteristics COVID-19 (n = 66)

Length of hospital stays (median [IQR]) 20.50 [14.25, 30.00]
Isolation time (median [IQR]) 45.00 [30.00, 60.00]
Duration of nucleic acid positivity (median [IQR]) 20.00 [10.00, 30.00]
Social support score (mean (SD)) 40.21 (7.25)
Self-perceived disease severity
Particularly severity 0 (0.0)
Severe 5 (7.6)
Somewhat severe 4 (6.1) Fig. 1. Association analysis between the composite z-score of Trail and in­
General 18 (27.3)
flammatory factors. The matrix diagram shows the correlation coefficient and
Mild 39 (59.1)
significance level after FDR correction. The TNF-α level is statistically signifi­
Experience of ICU stay
Yes 5 (7.6) cant correlated with the composite z-score of Trail. (r = − 0.19, p = 0.040). The
Ostracized by neighbors and community “* ” represents significance level, and the more of it, the more significance.
None 39 (59.1)
Somewhat 19 (28.8)
evaluated the cognitive functions of hospitalized patients with COVID-
Moderate 5 (7.6)
Severe 3 (4.5)
19 at 15 months of follow-up, and its related risk factors. However,
Extraordinary severe 0 (0.0) this study has some limitations. First, we could not gather the infor­
Ostracized by family members mation which is related to the cognitive impairment, including pro­
None 0 longed hypoxia, requirement for ventilatory support, and steroid
Somewhat 1 (1.5)
therapy from the hospitals. Second, although existing studies have
Moderate 0
Severe 0 shown that systemic or CNS inflammation can cause psychiatric symp­
Extraordinary severe 0 toms and cognitive deficits, we did not find any correlation between
Insulted by others depression/anxiety/PTSD symptoms and cognition. This may be
None 47 (71.2) because only 4 COVID-19 survivors in present study had symptoms of
Somewhat 14 (21.2)
Moderate 5 (7.6)
depression or anxiety. Third, the blood sample was collected only once
Severe 0 (0.0) at follow-up visiting so that we could not determine whether inflam­
Extraordinary severe 0 (0.0) matory levels remain correlated with cognitive decline over time. A
further study on longitudinal changes in neuropsychiatric symptoms,
cognitive function and inflammatory levels would be necessarily.
Table 3
Variables to predict the composite z-score of Trail. 7. Conclusions
Variables β Std. t- P-value
error value In conclusion, we observed that COVID-19 survivors remain subtle
cognitive impairment compared with healthy ones, especially on exec­
(Intercept) -0.546 0.628 -0.531 0.598
Experience of ICU stay (Yes)a -2.247 0.262 -3.579 P < 0.0001 utive function at 15-month from hospital discharge. Additionally, the
* ** experience of ICU stay and self-perceived illness severity were associ­
Gender (Female) -0.110 0.047 -0.422 0.675 ated with executive function. The serum TNF-α level continued to be
Age 0.017 0.018 0.355 0.724 abnormal compared with matched HC and was correlated with execu­
Social support score -0.028 0.038 -1.596 0.117
Years of education 0.098 0.004 2.580 0.013*
tive function in COVID-19 survivors even at 15 months after recovery.
Isolation time 0.000 0.013 0.056 0.956 This study provides evidence of long-term cognitive function impair­
Length of hospital stay -0.006 0.015 -0.465 0.644 ments in patients with COVID-19, and its relationship with inflamma­
Duration of nucleic acid positivity 0.014 0.279 0.920 0.362 tory profiles.
Self-perceived disease severity 0.149 0.542 0.534 0.596
(general)
Self-perceived disease severity -1.522 0.632 -2.809 0.007 * * Funding
(Somewhat severe)b
Self-perceived disease severity 1.197 1.099 1.893 0.065 This work was supported by China National Key Research and
(severe) Development Program (2020AAA0105005), Department of Science and
Ostracized by family members -0.809 0.379 -0.736 0.466
Technology of Sichuan Province (Grant numbers 2020YFS0582,
(somewhat)
Insulted by others (somewhat) 0.241 0.469 0.636 0.528 2020YFS0231), 1⋅3⋅5 Project for Disciplines of excellence, West China
Insulted by others (moderate) 0.225 0.293 0.479 0.634 Hospital, Sichuan University (Grant number ZYJC21004), the National
Ostracized by neighbors and 0.181 0.585 0.617 0.541 Natural Science Foundation of China (Grant numbers 81871061), and
community (somewhat)
by Postdoctoral Foundation of West China Hospital (Grant number
Ostracized by neighbors and 0.453 0.651 0.774 0.443
community (moderate) 2020HXBH041 to M.Y.).
Ostracized by neighbors and -0.343 0.529 -0.526 0.601
community (severe) Declaration of Interest
PHQ-9 score 0.397 0.110 0.749 0.458
GAD-7 score -0.092 0.628 -0.836 0.407
The authors declare that the research was conducted in the absence
Signif. codes: 0 ‘* ** ’ 0.001 ‘* *’ 0.01 ‘* ’ 0.05 ‘.’ 0.1 ‘ ’ 1 of any commercial or financial relationships that could be construed as a
Residual standard error: 0.8504 on 45 degrees of freedom potential conflict of interest.
Multiple R-squared: 0.5345, Adjusted R-squared: 0.3276
F-statistic: 2.584 on 20 and 38 DF, p-value: 0.004166 Acknowledgements
a
: The reference variable is experience of ICU stays (NO)
b
: Self-perceived disease severity (mild)
The authors would like to thank all the participants, as well as all
facilitators that contributed to this research and especially Minlan Yuan.

6
D. He et al. Asian Journal of Psychiatry 80 (2023) 103409

Ethics Approval and Consent to Participate González-Hermosillo, J.A., Martínez-López, J.P., Carrillo-Lampón, S.A., Ruiz-Ojeda, D.,
Herrera-Ramírez, S., Amezcua-Guerra, L.M., Martínez-Alvarado, M.D.R., 2021. Post-
Acute COVID-19 symptoms, a potential link with myalgic encephalomyelitis/chronic
The research processes adhered to the Declaration of Helsinki (2008) fatigue syndrome: a 6-month survey in a mexican cohort. Brain Sci. 11.
Ethical Principles for Medical Research Involving Human Subjects and Gorelick, P.B., 2010. Role of inflammation in cognitive impairment: results of
were approved by the Medical Ethics Committee of West China Hospital, observational epidemiological studies and clinical trials. Ann. N. Y. Acad. Sci. 1207,
155–162.
Sichuan University. Besides, all the voluntary subjects gave written Guo, P., Benito Ballesteros, A., Yeung, S.P., Liu, R., Saha, A., Curtis, L., Kaser, M.,
consents and were informed they were at liberty to withdraw from the Haggard, M.P., Cheke, L.G., 2022. COVCOG 2: cognitive and memory deficits in long
study at any time, with an additional examination. COVID: a second publication from the COVID and cognition study. Front. Aging
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Hampshire, A., Trender, W., Chamberlain, S.R., Jolly, A.E., Grant, J.E., Patrick, F.,
Mazibuko, N., Williams, S.C., Barnby, J.M., Hellyer, P., Mehta, M.A., 2021. Cognitive
Consent for Publication deficits in people who have recovered from COVID-19. EClinicalMedicine 39,
101044.
Han, Q., Zheng, B., Daines, L., Sheikh, A., 2022. Long-term sequelae of COVID-19: a
Not applicable.
systematic review and meta-analysis of one-year follow-up studies on post-COVID
symptoms. Pathogens 11.
Harrison, J.E., Barry, H., Baune, B.T., Best, M.W., Bowie, C.R., Cha, D.S., Culpepper, L.,
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MLY designed this research and the revised the draft critically for
Heneka, M.T., Golenbock, D., Latz, E., Morgan, D., Brown, R., 2020. Immediate and long-
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