Health-related quality of life of COVID-19 survivors at 6 months after hospital discharge: a cohort study

Background: COVID-19 is a multi-systemic disease that is highly contagious and pathogenic. The long-term consequences of it are not yet clear, as is whether society and life can return to a healthy state. Long-term assessment of their health-related quality of life (HRQoL) is essential. This study aimed to investigate HRQoL and its risk factors in COVID-19 survivors at a follow-up of 6-month. Methods: A multicenter cross-sectional survey was conducted among 192 COVID-19 patients with con�rmed age ≥ 18 years who were discharged from various hospitals in Wuhan from January to April 2020. The demographic characteristics, clinical characteristics, and laboratory results of the study subjects were obtained from the hospital's medical records. Survivors' HRQoL was assessed using the Short Form 36 (SF-36), cognition was assessed using the ascertain dementia eight-item informant questionnaire (AD8), and survivors' pulmonary function were examined. All participants in this study completed the survey and testing at Hubei Provincial Hospital of Chinese and Western Medicine. SF-36 scores were compared with the Chinese norm, and logistic regression and multivariate analysis were used to investigate the factors affecting HRQoL in COVID-19 survivors. Results: SF-36 showed signi�cant differences in HRQoL between COVID-19 survivors and the general Chinese population ( P< 0.05).Multiple linear regression demonstrated that age was negatively correlated with physical functioning (PF), role-physical limitation (RP) and social functioning (SF) ( P <0.05). Bodily pain (BP), vitality (VT), SF and role-emotional limitation (RE) were negatively correlated with females ( P <0.05). Length from discharge to follow ‐ up was positively correlated with PF and RP ( P <0.05). Abnormal cognitive function was negatively correlated with PF, RP, general health (GH), VT, SF, RE and mental health (MH) ( P <0.05). Abnormal Carbon Monoxide Diffusing Capacity (DLCO%<80%) was signi�cantly negatively correlated with PF and SF ( P <0.05).In addition, there was a signi�cant negative correlation between Coronary heart disease and RP, GH, VT and RE ( P <0.05).Logistic regression analysis demonstrated that age(OR 1.032) and AD8 scores (OR 1.203)were risk factors associated with a low physical component summary (PCS) score. Length from discharge to follow ‐ up (OR 0.971) was the protective factor for PCS score. Abnormal cognitive function (OR 1.543) was a signi�cant determinant associated with a mental component summary (MCS)<50 in COVID-19 patients. Conclusions: The HRQoL of COVID-19 survivors remains to be improved at six-month follow-up. Future studies should track HRQoL in older adults, women, patients with abnormal DLCO


Abstract
Background: COVID-19 is a multi-systemic disease that is highly contagious and pathogenic.The long-term consequences of it are not yet clear, as is whether society and life can return to a healthy state.Long-term assessment of their health-related quality of life (HRQoL) is essential.This study aimed to investigate HRQoL and its risk factors in COVID-19 survivors at a follow-up of 6-month.Methods: A multicenter cross-sectional survey was conducted among 192 COVID-19 patients with con rmed age ≥ 18 years who were discharged from various hospitals in Wuhan from January to April 2020.The demographic characteristics, clinical characteristics, and laboratory results of the study subjects were obtained from the hospital's medical records.Survivors' HRQoL was assessed using the Short Form 36 (SF-36), cognition was assessed using the ascertain dementia eightitem informant questionnaire (AD8), and survivors' pulmonary function were examined.All participants in this study completed the survey and testing at Hubei Provincial Hospital of Chinese and Western Medicine.SF-36 scores were compared with the Chinese norm, and logistic regression and multivariate analysis were used to investigate the factors affecting HRQoL in COVID-19 survivors.Results: SF-36 showed signi cant differences in HRQoL between COVID-19 survivors and the general Chinese population ( P< 0.05).Multiple linear regression demonstrated that age was negatively correlated with physical functioning (PF), role-physical limitation (RP) and social functioning (SF) ( P <0.05).Bodily pain (BP), vitality (VT), SF and role-emotional limitation (RE) were negatively correlated with females ( P <0.05).Length from discharge to follow-up was positively correlated with PF and RP ( P <0.05).Abnormal cognitive function was negatively correlated with PF, RP, general health (GH), VT, SF, RE and mental health (MH) ( P <0.05).Abnormal Carbon Monoxide Diffusing Capacity (DLCO%<80%) was signi cantly negatively correlated with PF and SF ( P <0.05).In addition, there was a signi cant negative correlation between Coronary heart disease and RP, GH, VT and RE ( P <0.05).Logistic regression analysis demonstrated that age(OR 1.032) and AD8 scores (OR 1.203)were risk factors associated with a low physical component summary (PCS) score.Length from discharge to follow-up (OR 0.971) was the protective factor for PCS score.Abnormal cognitive function (OR 1.543) was a signi cant determinant associated with a mental component summary (MCS)<50 in COVID-19 patients.Conclusions: The HRQoL of COVID-19 survivors remains to be improved at six-month follow-up.Future studies should track HRQoL in older adults, women, patients with abnormal DLCO, and abnormal cognitive function for a long time and provide them with rehabilitation advice and guidance.

Background
In January 2020, Chinese scientists identi ed a novel coronavirus, 2019-nCoV, which revealed the culprit of this infectious viral pneumonia that has attracted much attention in the world [1].COVID-19 is highly infectious and pathogenic, and as of November 19, 2020, it has caused 1,333,742 deaths worldwide [2].Some COVID-19 patients will experience lung injury, brain microstructural changes, olfactory and taste dysfunction, alopecia and psychosocial damage after rehabilitation and discharge [3][4][5].
Health-related quality of life(HRQoL) is a multidimensional concept in uenced by economic and social factors, life satisfaction, and the severity and stage of a disease [6,7].Studies have reported that COVID-19 survivors have decreased health-related quality of life at one-month follow-up[8, 9], but it is unknown whether COVID-19 has a longer-term effect on HRQoL.Long-term assessment of health-related quality of life in COVID-19 survivors is essential in order to develop strategies and interventions to improve their quality of life.Therefore, this study aimed to investigate HRQOL and its risk factors in COVID-19 survivors at six months after rehabilitation.

Study Design and Participants
Patients were recruited from September to October 2020 at the Physical Examination Center of Hubei Provincial Hospital of Chinese and Western Medicine after the eligibility evaluation.The study protocol followed the ethical principles of the Declaration of Helsinki and was approved by the Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (No. BF2020-205-01).All patients signed an informed consent.
The target subjects of this cross-sectional study were COVID-19 con rmed patients, aged ≥ 18 years, discharged from January -April 2020 in Wuhan, Hubei Province, China.The diagnosis was based on the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) published in China [10], A COVID-19 patient was identi ed through the SARS-CoV-2 virus infection by RT-PCR Viral gene sequencing or serum anti-SARS-CoV-2 IgM detection.The severity of COVID-19 infection was divided into mild the clinical symptoms were mild, and there was no sign of pneumonia on imaging , moderate showing fever and respiratory symptoms with radiological ndings of pneumonia , severe[adult cases meeting any of the following criteria: respiratory distress≥30 breaths/ min; oxygen saturation≦93% at rest; arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≦300 mmHg (l mmHg = 0.133 kPa)], and critical Cases meeting any of the following criteria: respiratory failure and requiring mechanical ventilation; shock; with other organ failure that requires ICU care .
According to their wishes,192 participants completed demographic and medical history data collection SF-36 questionnaire AD8 questionnaire and pulmonary function examination.

Questionnaires and Laboratory Tests
Demographic characteristics, co-morbidities, Clinical subtype of 192 subjects were obtained from their medical records.All participants in this study completed questionnaires and laboratory tests at Hubei Provincial Hospital of Chinese and Western Medicine.Questionnaires and laboratory tests are as follows: 1. Health-related quality of life HRQoL is evaluated using the SF-36 translated into Chinese, which is a common evaluation method for HRQoL [11].The measure consists of a health transition (HT) single item and 35 other items that are assessed in eight item categories: physical functioning, role-physical limitation, bodily pain, general health, vitality, social functioning, role-emotional limitation, and mental health with scores from 0 to 100, with 0 representing the most unfavorable functional status and 100 representing the most favorable functional status.Physical component summary score (PCS) and mental component summary score (MCS) were calculated using z-transformed scores as well as factor score coe cients, with low MCS or PCS (< 50) indicating poor HRQoL [12].
2. Ascertain Dementia 8-item Questionnaire (AD8) is one of the fast, simple, and sensitive screening methods for detecting both minor and major cognitive impairments [13].AD8 consists of a series of 8 statements, which are classi ed as "yes", "no", or "don't know" by the patient or informant, and the total score is given by the sum of the answers "yes" (range: 0 -8; higher scores are considered worse).Use speci ed boundaries (0-1: normal cognition; ≥ 2: possible cognitive impairment) [14].

Chinese Population Norm
The

Scores of SF-36 in the Study
The SF-36 mean score for eight speci c dimensions was measured(FIGURE 1).In these eight dimensions, PF RP BP GH VT SF RE and MH subgroup scores were signi cantly lower in patients than the Chinese population norm(P<0.05).

Correlates and predictors of health-related quality of life among survivors
There was a statistical signi cant correlation between the eight elds of the SF-36 and the assessed variables as shown in Table 2.Multiple linear regression analysis was performed with the eight elds of SF-36 as dependent variable and age, gender, clinical subtype ,length from discharge to follow-up, AD8 scores, DLCO% 80% and co-morbidities as independent variables (Table 3).Other variables were excluded from the model as they were non-signi cant on univariate analysis (Table 2).Age was negatively correlated with PF, RP and SF (P < 0.05).BP, VT, SF and RE were negatively correlated with females (P < 0.05).Followup time was positively correlated with PF and RP (P < 0.05).AD8 score was negatively correlated with PF, RP, GH, VT, SF, RE and MH (P < 0.05).Pulmonary function parameters (DLCO% < 80%) were signi cantly negatively correlated with PF and SF (P <0.05).In addition, there was a signi cant negative correlation between Coronary heart disease and RP, GH, VT and RE (P <0.05).We strati ed patients into two according to the PCS and MCS with a cut off point of 50 and then explored the relationship between the PCS, MCS, and potential risk factors(Tables 4 and 5).Logistic regression analysis demonstrated that age(OR 1.032,95% CI

Discussion
Previous evidence suggests that COVID-19 is a multi-system disease that causes impaired lung and physical function, reduced quality of life, and emotional distress [17].A recent study revealed the sequelae of COVID-19 patients at 6-month after infection, including fatigue or muscle weakness, sleep di culties,and anxiety or depression [18].However, it is unclear whether the society and life of COVID-19 survivors can be restored to a healthy state.Our study examines the HRQoL of COVID-19 survivors at six months of follow-up and reveals its in uencing factors and determinants, which provide potential guidance for improving the quality of life of COVID-19 discharged patients.
Comparing the results of this study with the Chinese norm, after six months in COVID-19 rehabilitation patients, the scores of the eight dimensions were signi cantly lower.This is different from the study by Chen KY [9], who found that the scores of BP,GH, VT, and MH were higher than the norm subjects after one month.Recently, studies have reported some sequelae in Covid-19 survivors,including headache, chest pain, and joint pain,among others.Ahmed H [19] found that lung function abnormalities, psychological impairment and reduced exercise capacity were common in SARS and MERS survivors.In this study, we also found that physical functioning, limitation due to physical problems, and general health remained poor in COVID-19 survivors.In addition, studies [20] [5]have reported that fatigue is the common symptom in COVID-19 survivors, which is consistent with our study.We found some decrease in the vitality of the patients.
In a study on SARS [21], people avoided contact with patients who had recovered because of fear of infection.
Coincidentally,Dong Liu [22] found that there was fear, stigmatization and discrimination against discharged patients with COVID-19 survivors in Wuhan.COVID-19 patients had poor psychiatric condition after one month of rehabilitation, and most of the patients had post-traumatic stress disorder, anxiety, depression, sleep disorders, and loneliness [23].Our study found that even after six months of rehabilitation, the social function, role limitation due to emotional problems, and mental health of patients were still lower than those of the general population, which shows that the mental rehabilitation of patients is a long process that requires the attention of family, society, and the scienti c community.Data reported in the scienti c literature has demonstrated that coronaviruses have neuroinvasive capacities since they can spread from the respiratory tract to the central nervous system [24].Blood-brain barrier deterioration in older adults leaves them more susceptible to neuroinvasion during SARS-CoV-2 infection [25].In addition, study[26] nded revealed possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting the long-term consequences of SARS-CoV-2.In the 6-month follow-up study,we found the AD8 is an independent predictor of MCS and PCS in this study,which may explain that the cognitive impairment and dementia was the independent predictor of COVID-19 survivors.
Abnormalities in DLCO indicated pulmonary brosis or a late phase in the course of recovery [27].According to a previous report, 9 patients (16.36%) had impaired DLCO at 3 months after recovered from COVID-19 [28].At 6-months after discharge, 110 patients (32.35%) were found to have DLCO impairment, and were negatively correlated with PF, RP, GH, and SF.This shows that long-term lung function impairment will reduce the quality of life.An early rehabilitation programme following AECOPD led to improvement in quality of life up to 6months [29].Pulmonary rehabilitation has also been shown to increase exercise capacity, muscle strength, and health-related quality of life in several populations with respiratory conditions [30].respiratory rehabilitation can improve respiratory function, QoL and anxiety of elderly patients with COVID-19 [31].
Oestrogens and progesterone exert a profound and broad effect on brain neurochemistry and brain function and interact with early life stress and genetic risk for depression among woman [32].In addition,a masculine gender identity, which includes personality traits of assertiveness, independence, and self-su ciency, was positively associated with improvements in participants' mental health [33].Due to gender differences, female survivors may experience a long time in the recovery of mental health, and we should pay more attention to female psychological recovery in future studies.
We acknowledge some of the limitations of our study.First,we were unable to compare the data we recruited for COVID-19 survivors in Wuhan with the general population in Wuhan during the same period, for objective reasons.Second, our study did not involve children.Finally, the design of our study is cross-sectional and should be followed up over time in future studies.

Conclusion
Our study revealed the in uencing factors and determinants of HRQoL for COVID-19 survivors at the sixth month of follow-up, including age, sex, length from discharge to follow-up, AD8 score, and DLCO.AD8 scores was common predictors of PCS and MCS, and predicted poorer physical and psychological quality of life.Chinese patients with COVID-19 have signi cant HRQoL impairment, and we recommend long-term monitoring in future studies.

Figure 1 Mean
Figure 1

TABLE 1 |
Chinese population norm was based on the study done by Wang and his colleagues who used a Mandarin version of the SF-36 to evaluate adults in mainland China through a randomly-strati ed multistage sampling design[16].Sample Demographic and Clinical FeaturesA total of 192 subjects from Hubei Provincial Hospital of Traditional Chinese and Western Medicine, Hankou Hospital of Wuhan ,and Leishenshan Hospital of Wuhan were recruited.Most of the patients were moderate cases(70.83%),withPhysicalComponent Summary (PCS) < 50 of 103 (53.65%) and Mental Component Summary (MCS) < 50 of 162 (84.38%) evaluated by SF-36.The more prevalent comorbidities were hypertension (20.31%) and diabetes (11.98%).A comparison between patients with PCS ≥ 50 and those with PCS < 50 showed statistically signi cant differences for age, BMI, subgroup, AD8 scores, Length from discharge to follow-up, and Coronary heart diseases.Compared with the 89 survivors in the PCS ≥ 50 group, patients in the PCS <50 group were signi cantly older(59.86±10.10 vs. 56.47±10.96,P=0.027)andwith higher AD8 scores (3.11±2.18 vs. 2.2±2.19P=0.005).Moreover, the PCS of mild moderate and severe or critical cases were different.Besides, patients with MCS ≥ 50 showed lower AD8 scores compared with those with MCS < 50.These data are shown in Table1.Demographic, clinical and laboratory data of all recovers and two groups of recovers with PCS and MCS scores of 50 as cut-off points laboratory characteristics were analyzed by t-Student tests, one-way ANOVA tests, or non-parametric Mann-Whitney U tests; correlations were analyzed by Pearson's or Spearman's correlation coe cients.If there were signi cant correlations, a stepwise multiple linear regression model was constructed to determine the factors related to the SF-36 scores among the independent variables.Multivariate analyses associated with decreased PCS scores and MCS scores were performed using logistic regression analyses, with odds ratios (ORs) as the basis for evaluating the degree of impact.P-values < 0.05 were considered statistically signi cant.Results

TABLE 2| Statistical
Signi cant Correlations between the eight elds of SF-36 and Variables Evaluated.
TABLE 3|Factors associated with Short-Form 36-item questionnaire (SF-36) among patients in the multivariate analysis.