1. Introduction
The continued spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a public health emergency of international community concern, causing a substantial global burden of disease. As of January 11, 2023, more than 660 million cases of coronavirus disease 2019 (COVID-19) have been confirmed worldwide, and nearly 6.7 million deaths have resulted from SARS-CoV-2 infection.[1] China has accumulated abundant knowledge and experience in its successful fight against COVID-19. Nevertheless, the long-term effects of SARS-CoV-2 infection in humans are still not completely clear, although studies on the follow-up of COVID-19 patients have been conducted. Given the large number of COVID-19 patients, exploring the long-term prognosis after discharge is urgently required. The main purpose of this study was to evaluate the quality of life (QoL) and sequelae of COVID-19 patients to understand the long-term health consequences of COVID-19, facilitate selective rehabilitation treatment after discharge, and improve the QoL of patients.
2. Subjects and methods
2.1. Ethical approval
This cross-sectional study was approved by the Medical Ethics Committee of the General Hospital of the Central Theater Command (review no. [2021] 026-01). Written informed consent was obtained from all participants.
2.2. Study subjects
All patients aged 18 to 80 years with laboratory-confirmed SARS-CoV-2 infection, who were discharged from Huoshenshan Hospital between February 15 and April 5, 2020, and who understood and signed informed consent were eligible for participation. The exclusion criteria were as follows: pregnant or breastfeeding women, patients with severe systemic or mental diseases unable to complete the follow-up, and patients who refused to provide informed consent. Participants who withdrew their informed consent or lost their ability to provide consent during follow-up could withdraw.
The diagnosis, clinical classification, and discharge criteria of COVID-19 were in line with the diagnosis and treatment protocol for COVID-19 issued by the National Health Commission of the People's Republic of China,[2] jointly issued by the General Office of the National Health Commission and the Office of the National Administration of Traditional Chinese Medicine. Patients who were neither severe nor critical were classified as nonsevere type of COVID-19.
2.3. Data collection
A total of 175 COVID-19 patients who met the inclusion criteria were followed up. At 3 follow-up visits at 6, 9, and 12 months after discharge, participants completed questionnaires on postdischarge QoL and sequelae under the guidance of medical staff with professional training [Figure 1].
;)
Figure 1: Flow chart of enrollment and follow-up visits for COVID-19 patients. COVID-19: Coronavirus diseases 2019; QoL: Quality of life.
2.4. Statistical analysis
The demographic and clinical characteristics of COVID-19 patients were analyzed using descriptive statistics, with continuous variables expressed as mean and standard deviation and categorical variables expressed as percentages of different categories. A generalized estimating equation model was used to analyze QoL-related factors. The χ2 test (or Fisher exact test) and multivariate logistic regression analysis were used to analyze the sequelae and influencing factors. All tests were 2-sided, and P < 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS software (IBM SPSS Statistics 26; IBM Corp, Armonk, NY) and GraphPad Prism 8 software (GraphPad Software Development, San Diego, CA).
3. Results
3.1. Demographic and clinical characteristics
A total of 175 COVID-19 patients discharged from Huoshenshan Hospital between February 15 and April 5, 2020, were recruited. The average age of the patients was (55 ± 13) years, and 87 were men (49.71%). The nonsevere type of COVID-19 was diagnosed in 128 patients (73.14%), and 47 patients (26.86%) had the severe or critical COVID-19 type. Twenty-three patients (13.14%) had a smoking history, and 45 (25.71%) had a history of alcohol intake. Fifty-four patients (30.86%) had hypertension; 29 (16.57%) had diabetes; 13 (7.43%) had hyperlipidemia; and 9 (5.14%) had hyperuricemia.
3.2. Quality of life and its influencing factors
Table 1 shows the results of the questionnaire on QoL. At the 3 follow-up visits after discharge, 6.67% (8/120), 5.83% (7/120), and 5.83% (7/120) of patients had a poor appetite, and 18.33% (22/120), 16.67% (20/120), and 20.83% (25/120) of patients had a poor mental condition, respectively. The proportion of patients with sleep disturbances, fatigue, and dyspnea ranged from 30% to 40%. Although some patients still had complaints, 89.17% had returned to their original work and life by the 12-month visit. Any differences in appetite, mental condition, sleep, fatigue, dyspnea, and return to original work and life were not statistically significant at the 3 follow-up visits.
Table 1 -
QoL questionnaire results of patients with coronavirus disease 2019 at different time points after discharge
| Time after discharge |
Poor appetite |
Poor mental condition |
Sleep disturbance |
Fatigue |
Dyspnea |
Difficulty to return to original work and life |
| 6 months |
8 (6.67) |
22 (18.33) |
43 (35.83) |
39 (32.50) |
48 (40.00) |
10 (8.33) |
| 9 months |
7 (5.83) |
20 (16.67) |
38 (31.67) |
48 (40.00) |
38 (31.67) |
11 (9.17) |
| 12 months |
7 (5.83) |
25 (20.83) |
40 (33.33) |
48 (40.00) |
37 (30.83) |
13 (10.83) |
|
χ
2
|
0.120 |
1.199 |
1.389 |
2.701 |
4.907 |
1.325 |
|
P valuea
|
0.942 |
0.549 |
0.499 |
0.259 |
0.086 |
0.516 |
Values are presented as n (%), unless specified otherwise.
aComparison of 3 follow-up groups.
QoL: Quality of life.
The results of the generalized estimating equations for QoL-related factors are presented in Table 2. Patients diagnosed with severe or critically ill COVID-19 had a worse mental condition than those with the nonsevere type (χ2 = 7.653, P = 0.022) and were also more prone to fatigue (χ2 = 4.836, P = 0.028). Women had more difficulty than men returning to their original work and life (χ2 = 8.922, P = 0.003) and showed a higher risk of sleep disturbance (χ2 = 10.026, P = 0.002) and dyspnea (χ2 = 5.672, P = 0.017). Patients with diabetes had a worse appetite (χ2 = 4.669, P = 0.031) and were more likely to experience sleep disturbance (χ2 = 4.417, P = 0.036) than those without diabetes.
Table 2 -
Factors affecting QoL of discharged patients with coronavirus disease 2019
| Variables |
Poor appetite |
Poor mental condition |
Sleep disturbance |
Fatigue |
Dyspnea |
Difficulty to return to original work and life |
|
χ
2
|
P value |
χ
2
|
P value |
χ
2
|
P value |
χ
2
|
P value |
χ
2
|
P value |
χ
2
|
P value |
| Time |
0.757 |
0.685 |
4.547 |
0.103 |
1.757 |
0.415 |
5.222 |
0.073 |
4.907 |
0.086 |
1.400 |
0.497 |
| Sex |
2.806 |
0.094 |
2.037 |
0.154 |
10.026 |
0.002 |
0.774 |
0.379 |
5.672 |
0.017 |
8.922 |
0.003 |
| Age |
0.694 |
0.707 |
1.317 |
0.518 |
3.192 |
0.203 |
0.043 |
0.979 |
4.826 |
0.063 |
— |
— |
| BMI |
0.421 |
0.810 |
0.112 |
0.946 |
0.380 |
0.827 |
1.451 |
0.484 |
0.995 |
0.608 |
3.368 |
0.186 |
| Clinical classification |
0.293 |
0.589 |
7.653 |
0.022 |
0.921 |
0.337 |
4.836 |
0.028 |
1.146 |
0.284 |
1.450 |
0.229 |
| Smoking history |
— |
— |
0.023 |
0.879 |
0.568 |
0.451 |
1.386 |
0.239 |
0.398 |
0.528 |
— |
— |
| History of alcohol intake |
0.557 |
0.456 |
0.853 |
0.356 |
— |
— |
0.375 |
0.540 |
2.982 |
0.076 |
0 |
1.000 |
| Hypertension |
0.003 |
0.960 |
0.002 |
0.961 |
3.443 |
0.064 |
0.010 |
0.919 |
1.006 |
0.316 |
1.583 |
0.208 |
| Diabetes |
4.669 |
0.031 |
2.731 |
0.098 |
4.417 |
0.036 |
2.677 |
0.102 |
0.670 |
0.413 |
2.432 |
0.119 |
| Hyperlipidemia |
1.408 |
0.235 |
1.220 |
0.269 |
0.149 |
0.699 |
2.246 |
0.134 |
1.298 |
0.255 |
0 |
0.996 |
| Hyperuricemia |
— |
— |
0 |
0.998 |
0.034 |
0.854 |
0.151 |
0.697 |
1.662 |
0.197 |
— |
— |
QoL: Quality of life; BMI: Body mass index; —: Not applicable.
3.3. Sequelae and its influencing factors
Table 3 shows the number and proportion of patients with sequelae within 12 months of discharge. During the follow-up period, the most common symptoms were joint or muscle pain (34.86%), followed by pharyngeal discomfort or foreign body sensation (26.29%), eyesight decline (10.29%), memory decline (9.14%), chest tightness or chest pain (6.86%), hearing loss or tinnitus (4.00%), headache or dizziness (3.43%), palpitation or shortness of breath (2.86%), rash (1.14%), lipsotrichia (0.57%), and decreased sexual function (0.57%). The proportion of patients with at least 1 sequela increased from 29.76% (50/168) at 6 months to 51.11% (69/135) at 9 months (χ2 = 14.305, P < 0.001), whereas there was no significant difference between 9 and 12 months (χ2 = 0.518, P = 0.472). Similar trends were observed in the proportion of patients with joint or muscle pain and eyesight decline. The proportion of patients with joint or muscle pain increased from 13.10% (22/168) at 6 months to 29.63% (40/135) at 9 months (χ2 = 12.573, P < 0.001), and eyesight decline increased from 2.98% (5/168) at 6 months to 11.11% (15/135) at 9 months (χ2 = 8.035, P = 0.005). Although there was no significant difference between 6 and 9 months (χ2 = 0.166, P = 0.684), the proportion of patients with memory decline increased from 2.22% (3/135) at 9 months to 10.07% (14/139) at 12 months (χ2 = 7.251, P = 0.007). The proportion of patients with hearing loss or tinnitus increased from 0 at 6 months and 0.74% (1/135) at 9 months to 5.04% (7/139) at 12 months (χ2 = 10.101, P = 0.002). No significant decrease in the proportion of patients with sequelae was observed over time in the total follow-up period.
Further multivariate logistic regression analysis for risk factors with sequelae within 1 year after discharge is shown in Figure 2 and Figure 3. The associations of sex, hyperuricemia, and hypertension with joint or muscle pain and the association of clinical classification with memory decline were statistically significant. Compared with male patients, female patients had an odds ratio (OR) of 4.632 (95% confidence interval [CI], 1.716–12.501) for joint or muscle pain (P = 0.002). Hypertension increased the risk of joint or muscle pain (OR, 3.014; 95% CI, 1.193–7.615; P = 0.020). Hyperuricemia seemed to decrease the risk of joint or muscle pain (OR, 0.102; 95% CI, 0.018–0.566; P = 0.009), but additional telephone follow-up revealed that patients with hyperuricemia irregularly took ibuprofen, celecoxib, or other nonsteroidal anti-inflammatory drugs; thus, we considered that nonsteroidal anti-inflammatory drugs may mask the symptoms of joint or muscle pain. Patients diagnosed with severe and critical COVID-19 had an OR of 4.325 (95% CI, 1.215–15.401) for memory decline compared with those with the nonsevere type (P = 0.024).
Figure 2: Risk factors associated with joint or muscle pain. Multivariate logistic regression analysis was performed on the risk factors of joint or muscle pain in 175 patients with coronavirus disease 2019 within 1 year after discharge. *P < 0.05. BMI: Body mass index; OR: Odds ratio.
Figure 3: Risk factors associated with memory decline. Multivariate logistic regression analysis was performed on the risk factors of memory decline in 175 patients with coronavirus disease 2019 within 1 year after discharge. *P < 0.05. BMI: Body mass index; OR: Odds ratio.
3.4. Chronological order of occurrence of the sequelae
All 3 follow-up visits were completed by 120 patients, 38 (31.67%) of whom had no sequelae at any of the follow-up visits, whereas more patients (82/120 [68.33%]) had sequelae after discharge (χ2 = 32.267; P < 0.001). The chronological order of occurrence of the sequelae at the 3 follow-up visits is shown in Table 4. At 6 months, 50 of 120 patients (41.67%) had no sequelae but did have sequelae at 9 or 12 months. The number of patients with sequelae showed no significant difference between 6 and 9 months but decreased at 12 months (χ2 = 22.867; P < 0.001). There was no significant association between the chronological order of occurrence of sequelae and demographic factors and underlying diseases (Supplemental Table 1, https://links.lww.com/IDI/A25).
Table 3 -
Sequelae of discharged patients with
COVID-19 at different time points
| Time after discharge |
Joint or muscle pain |
Pharyngeal discomfort or foreign body sensation |
Eyesight decline |
Memory decline |
Chest tightness or chest pain |
Hearing loss or tinnitus |
Headache or dizziness |
Palpitation or shortness of breath |
Rash |
Lipsotrichia |
Decreased sexual function |
Patients with at least 1 sequela |
Total patients surveyed |
| 6 months |
22 (13.10) |
24 (14.29) |
5 (2.98) |
5 (2.98) |
6 (3.57) |
0 (0) |
2 (1.19) |
3 (1.79) |
0 (0) |
1 (0.60) |
0 (0) |
50 (29.76) |
168 |
| 9 months |
40 (29.63) |
30 (22.22) |
15 (11.11) |
3 (2.22) |
7 (5.19) |
1 (0.74) |
4 (2.96) |
1 (0.74) |
2 (1.48) |
1 (0.74) |
0 (0) |
69 (51.11) |
135 |
| 12 months |
34 (24.46) |
18 (12.95) |
16 (11.51) |
14 (10.07) |
6 (4.32) |
7 (5.04) |
2 (1.44) |
2 (1.44) |
1 (0.72) |
1 (0.72) |
1 (0.72) |
65 (46.76) |
139 |
| Total a
|
61 (34.86) |
46 (26.29) |
18 (10.29) |
16 (9.14) |
12 (6.86) |
7 (4.00) |
6 (3.43) |
5 (2.86) |
2 (1.14) |
1 (0.57) |
1 (0.57) |
102 (58.29) |
175 |
|
χ
2
|
12.932 |
5.116 |
9.692 |
11.217 |
0.474 |
10.101 |
1.405 |
0.675 |
2.313 |
0.474 |
1.953 |
16.239 |
— |
|
P valueb
|
0.002 |
0.077 |
0.008 |
0.004 |
0.789 |
0.002 |
0.505 |
0.877 |
0.193 |
1.000 |
0.627 |
<0.001 |
— |
Values are presented as n (%), unless specified otherwise. Differences in the incidence of sequelae at 3 follow-up visits were determined by the χ2 test or Fisher exact test.
aDischarged patients with COVID-19 may report more than 1 sequela.
bComparison of 3 follow-up groups.
COVID-19: Coronavirus disease 2019; —: Not applicable.
Table 4 -
Chronological order of
sequelae occurrence in discharged patients with
COVID-19 at 3
follow-up visits
| Time after discharge |
Joint or muscle pain |
Pharyngeal discomfort or foreign body sensation |
Eyesight decline |
Memory decline |
Chest tightness or chest pain |
Hearing loss or tinnitus |
Headache or dizziness |
Palpitation or shortness of breath |
Rash |
Lipsotrichia |
Decreased sexual function |
Totala
|
| 6 months |
21 |
12 |
2 |
3 |
3 |
0 |
1 |
3 |
0 |
1 |
0 |
32 |
| 9 months |
27 |
25 |
10 |
3 |
3 |
1 |
2 |
0 |
1 |
0 |
0 |
40 |
| 12 months |
8 |
0 |
4 |
11 |
0 |
4 |
0 |
2 |
0 |
0 |
1 |
10 |
|
χ
2
|
11.969 |
28.255 |
6.802 |
7.903 |
3.051 |
5.273 |
2.017 |
2.839 |
2.006 |
1.187 |
2.006 |
22.867 |
|
P value |
0.003 |
<0.001 |
0.033 |
0.019 |
0.218 |
0.072 |
0.365 |
0.242 |
0.367 |
1.000 |
0.367 |
<0.001 |
Differences in the incidence of sequelae at 3 follow-up visits were determined by the χ2 test or Fisher exact test.
aDischarged patients with COVID-19 may report more than 1 sequela.
COVID-19: Coronavirus disease 2019.
4. Discussion
The long-term prognosis of COVID-19 patients, especially in terms of physical and functional recovery, urgently needs to be elucidated. Therefore, we established a longitudinal cohort study to better understand the impact of SARS-CoV-2 infection on patients. Through follow-up at 3 time points within 1 year, we found that most of the COVID-19 patients had returned to their original work and life by the 12-month follow-up after discharge, but some patients still had varying degrees of decline in QoL and various sequelae. These results are similar to those of previous longitudinal cohort studies conducted in the United States, China, Brazil, and other countries.[3–7] However, our study also showed that the proportion of patients with at least 1 sequela symptom increased from 6 months to 9 months. Moreover, some patients developed novel symptoms at 9 or 12 months, such as hearing loss and decreased sexual function. The influencing factors related to QoL and sequelae after discharge included sex, clinical classification of COVID-19, and some underlying diseases.
Recent studies have shown that a range of symptoms can persist after discharge in patients with COVID-19.[8–11] The range of symptoms is known as long COVID.[12,13] The sequelae described by patients in our longitudinal cohort covered most of the known sequelae of COVID-19, including joint or muscle pain, pharyngeal discomfort or foreign body sensation, eyesight decline, memory decline, chest tightness or chest pain, hearing loss or tinnitus, headache or dizziness, palpitation or shortness of breath, rash, lipsotrichia, and decreased sexual function. Some of the symptoms we observed are rare and currently less reported, such as eyesight decline, hearing loss, and lipsotrichia.
Several studies have reported the risk factors associated with COVID-19 sequelae.[14–16] Ramos-Casals and colleagues[17] reviewed the symptoms of COVID-19 patients that had been reported worldwide, including more than 70 different systemic and organ-specific diseases and abnormal inflammatory responses involving extrapulmonary tissues, and their review indicated that the clinical manifestations seem to be influenced by demographic factors such as age, sex, and ethnicity.[18–20] Our study showed that patients diagnosed with severe and critical COVID-19 had worse mental conditions and were more likely to feel fatigued. Female patients had a higher risk of sleep disturbance and dyspnea and had more difficulty returning to their original work and life. Patients with diabetes had a worse appetite and were more prone to sleep disturbances after discharge. Female sex and hypertension were risk factors for joint or muscle pain. The diagnosis of severe or critical COVID-19 was a risk factor for joint or muscle pain and memory decline.
Although there have been some basic experimental studies on the sequelae of COVID-19,[21] the pathogenesis of the sequelae of COVID-19 remains unclear. Disser and colleagues[22] reported the musculoskeletal consequences of COVID-19, [22] and Ramani and colleagues[23] provided musculoskeletal manifestations of COVID-19 with a review of imaging, but there was no evidence of SARS-CoV-2 directly infecting the joints and muscles. Dewanjee and colleagues[24] shed light on the pathological crosstalk between COVID-19 and rheumatoid arthritis. We speculated that post-COVID-19 joint or muscle pain may be associated with a rheumatoid arthritis–like chronic inflammatory response caused by SARS-CoV-2 infection. Similar findings have been reported for other sequelae. Chronic inflammatory responses and post-COVID-19 autoimmune dysfunction are thought to be the main causes.[17,24] Furthermore, some studies showed the sequelae might be a result of complex and dynamic interactions between biological, psychological, and social factors.[25]
Our study had some limitations. First, this was a single-center study with an insufficient sample size, which focused on COVID-19 patients who were hospitalized early in the pandemic, limiting the representativeness of this cohort, especially in the current situation in which SARS-CoV-2 has undergone multiple mutations. Second, our study did not address the mechanisms of the sequelae associated with SARS-CoV-2 infection, and basic experimental studies on the COVID-19 sequelae are needed for our next step.
One year after discharge, most COVID-19 patients had returned to their original work and life; however, the impact of SARS-CoV-2 infection on health of some people persisted. The QoL of some patients declined by varying degrees. Some patients had sequelae, including newly occurring symptoms after discharge. Continuous longitudinal follow-up is needed to better characterize the long-term prognosis of COVID-19, and further mechanistic research on the etiology of sequelae is also needed to better understand the long-term impact of SARS-CoV-2 infection on human health.
Acknowledgments
The authors acknowledge all health care workers involved in the management of the patients and thank Cheng Zhen and Xiaoyong Sai for their statistical and epidemiological advice.
Funding
This work was supported by grants from the National Key R&D Program of China (2020YFC0860900) and Military Logistics Research Project (BLB19J017).
Author Contributions
Bo Zhang, Lei Huang and Fu-Sheng Wang worked on the design of the study. Nan Guo and Ya-Ping Yao collected and analyzed data and drafted the manuscript. Le Song, Guan-Zhen Wang, Jun-Li He, Ning Zheng, Qiong Mo and Wen-Xu Ni. were involved in the follow-up of patients and acquired the data. All authors critically revised the manuscript and approved the final manuscript.
Conflicts of Interest
None.
Editor note: Fu-Sheng Wang is the editor of Infectious Diseases & Immunity. The article was subject to the journal's standard procedures, with peer review handled independently by this editor and his research group.
Data Availability Statement
The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
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