Some characteristics of clinical sequelae of COVID‐19 survivors from Wuhan, China: A multi‐center longitudinal study

Abstract Background The pandemic of COVID‐19 has a persistent impact on global health, yet its sequelae need to be addressed at a wide scale around the globe. This study aims to investigate the characteristics, prevalence, and risk factors for mid‐term (>6 months) clinical sequelae in a cohort of COVID‐19 survivors. Methods Totally 715 COVID‐19 survivors discharged before April 1, 2020, from three medical centers in Wuhan, China, were included. The longitudinal study was conducted by telephone interviews based on a questionnaire including the clinical sequelae of general, respiratory, and cardiovascular systems. Demographics and some characteristics of clinical sequelae of the survivors were recorded and analyzed. Multivariate logistic regression analysis was applied to explore the risk factors for the sequelae. Results The median time interval from discharge to telephone interview was 225.0 days. The COVID‐19 survivors' median ages were 69 years, and 51.3% were male. Among them, 29.9% had at least one clinical sequela. There were 19.2%, 22.7%, and 5.0% of the survivors reporting fatigue, respiratory symptoms, and cardiovascular symptoms, respectively. Comorbidities, disease severity, the application of mechanical ventilation and high‐flow oxygen therapy, and the history of re‐admission were associated with the presence of clinical sequelae. Conclusions Our study provides further evidence for the prevalence and characteristics of clinical sequelae of COVID‐19 survivors, suggesting long‐term monitoring and management is needed for their full recovery.

and were discharged from the hospital after approximately 1 month, 87.4% reported persistence of at least one symptom, particularly fatigue and dyspnea. 1 Previously, patients who recovered from severe acute respiratory syndrome (SARS) had radiological, functional, and psychological sequelae, both at short-term and long-term clinical follow-up. 2,3 Since the clinical features of COVID-19 and SARS are similar, and their pathogens both belong to beta coronaviruses, 4 COVID-19 survivors may also suffer from sequelae in different systems.
Clarifying the clinical sequelae of COVID-19 is crucial for its monitoring and management in the long run. Up till now, there have been a few relevant studies, and the follow-up time ranged from 1 to 6 months. [5][6][7][8][9][10] Being the first country stricken by COVID-19 since December 2019, China was supposed to have a large number of COVID-19 survivors with more prolonged convalescence than the others. 11,12 Therefore, we conducted this multi-center longitudinal questionnaire-based study to investigate the characteristics, prevalence, and risk factors for mid-term clinical sequelae in a cohort of COVID-19 survivors in China.

| Study design and participants
This study included participants from three cohorts of inpatients diagnosed with COVID-19 according to WHO interim guidance 13  (a) respiratory rate ≥30 breaths/min, or (b) oxygen saturation ≤93%, or (c) PaO 2 /FiO 2 ratio ≤300 mmHg. Critical cases were defined as those including one criterion as follows: shock, respiratory failure requiring mechanical ventilation, and organ failure requiring admission to ICU. Patients discharged before April 1, 2020, were considered as appropriate candidates for observing their clinical sequelae in mid-term convalescence from COVID-19, and telephone interview follow-ups were conducted from October 1 to November 1, 2020. Therefore, the interval time from discharge to the telephone follow-up initiation was more than 6 months. Patients with severe and complex comorbidities were excluded, including malignant tumors, mental disorders, severe anemia, cirrhosis, and chronic renal failure. The study was approved by the institutional board of each participating site. Verbal consents were obtained from all participants.

| Telephone interviews and data collection
Based on the previously reported clinical characteristics of COVID-19 patients and studies on the sequelae of SARS, 1,2,12 we conducted the telephone interviews according to a formal questionnaire about the clinical sequelae mainly on three aspects: (1) general symptoms: referring to fatigue or physical decline compared with the status before developing COVID-19, and the other symptoms not included in the questionnaire while self-reported by the interviewees; (2) respiratory symptoms: including cough, sputum, exertional or resting dyspnea, and chest tightness; (3) cardiovascular symptoms: including palpitation, orthopnea, and lower limb edema. All telephone interviews were conducted by experienced nurses by mobile phone.
All participants were instructed that only the remaining or newly occurring symptoms after developing COVID-19 were needed to report at the beginning of the interview, to avoid recording the possible long-standing symptoms unrelated to COVID-19 as much as possible. The demographics, categories of disease severity, the medical history including hypertension, diabetes, hyperlipidemia, stroke, and coronary heart disease as well as the history of the application of high-flow oxygen, admission to ICU, mechanical ventilation during hospitalization, and the history of re-admission to the hospital after discharge were also recorded. All data were carefully reviewed by the major investigators of this study.

| Data analysis
Continuous variables were shown as medians (interquartile ranges, IQR). Categorical variables were summarized as the counts and percentages for each category. To avoid selection bias, the differences in age, sex, disease severity, and comorbidity between the study population and the population lost to follow-up were compared using t test and chi-square test as appropriate. The univariate analysis of risk factors for the clinical sequelae was done by chi-square test. To further explore the risk factors associated with the clinical sequelae, multivariate logistic regression analysis was applied with the forward stepwise (conditional) method. The multicollinearity of all covariates was examined using the collinearity analysis and the variance inflation factor. All analyses were conducted with PASW version 18.0 for windows (SPSS, Inc., Chicago, IL). P < 0.05 was considered statistically significant.

| Demographics and characteristics of the participants
A total of 964 adult COVID-19 patients discharged from three hospitals in Wuhan from our previous study were firstly screened. 14 Of these, 13 patients (1.4% of the total survivors) were excluded because of chronic renal failure who needed routine hemodialysis (n = 11) or cirrhosis due to hepatitis B infection (n = 2), considering they were likely to report unspecific symptoms which may confound the results.
Then 951 patients discharged before April 1, 2020, were considered as the candidate participants. During the telephone follow-ups, 236 cases did not complete the interview, of whom 54 could not be contacted by the recorded telephone numbers and 182 refused to participate in our study. Finally, 715 COVID-19 survivors accomplished the complete telephone interview follow-up. The flow chart of the study sample is shown in Figure S1. There were no differences in age, sex, disease severity, and comorbidity between the study population (n = 715) and the population lost to follow-up (n = 236) (see Table S1).
The time interval from discharge to telephone interview was 225.0 days (IQR 222.0-228.0). The survivors' median ages were 69 years (IQR 67-73), and 51.3% (367/715) were male. The detailed demographics, categories of disease severity, medical history including hypertension, diabetes, hyperlipidemia, stroke, and coronary heart disease, as well as the history of the application of high-flow oxygen or mechanical ventilation, admission to ICU during hospitalization, and re-admission to the hospital after discharge are shown in Table 1.  Table 2.

| Risk factors for clinical sequelae of the COVID-19 survivors
The results of univariate analysis of risk factors for the common clinical sequelae, including fatigue, respiratory and cardiovascular symptoms, are shown in Table S2. And the risk factors were further analyzed via multivariate logistic regression. The collinearity analysis showed no multicollinearity of all covariates, including age, sex, comorbidities, disease severity, the application of high-flow oxygen, admission to ICU, mechanical ventilation during hospitalization, and the history of re-admission after discharge (see Table S3). Therefore, they were all included in the regression analysis. It is shown in Table 3 that disease severity (moderate vs. mild, OR = 2.14, 95% CI 1.

| DISCUSSION
To the best of our knowledge, the follow-up time of this study is by patients who needed mechanical ventilation during hospitalization was usually worse than those who did not. Therefore, the recovery of pulmonary function for these patients is supposed to be longer and more difficult. 10  function examinations are warranted to assess their pulmonary function decline. The comorbidity of hypertension was another risk factor for the presence of fatigue and respiratory sequelae. In a recent study including over 44,000 patients with COVID-19, hypertension, chronic respiratory disease, diabetes mellitus, cardiovascular disease, and cancer emerged as the most common comorbidities. 16 Besides, hypertension was rendered to be a risk factor for disease progression and unfavorable outcomes. 14,17 Our study further provided evidence that hypertension could also be the risk factor for clinical sequelae.
Angiotensin-converting enzyme type 2 (ACE2) may link hypertension and disease susceptibility, disease progression, and possibly clinical sequelae of COVID-19, 18,19 yet the underlying mechanism needs to be further explored.
It has been well documented that cardiac injury is a common condition among hospitalized COVID-19 patients. 20,21 COVID-19 patients with cardiac injury and pre-existing cardiovascular disease are also associated with a higher risk of admission to ICU and inhospital mortality. 20,22 Therefore, the cardiovascular sequelae of COVID-19 ought to be monitored. According to our findings, only 5% of COVID-19 survivors had at least one cardiovascular symptom, which was much lower than the prevalence of respiratory sequelae.
Interestingly, the application of high-flow oxygen therapy during hospitalization seems to show a protective effect on cardiovascular sequelae. The high-flow oxygen therapy has been proved to be bene- First, the case-fatality rate (CFR) of COVID-19 is reported to be 2.3%, which is much lower than those of SARS (9.6%) and the Middle East respiratory syndrome (MERS, 34.4%), 16 which indicates that the toxicity of SARS-COV-2 might be milder than SARS-COV and MERS-COV, and its damage to the respiratory and other systems may not be profound. This is supported by the evidence that, unlike SARS, the hospitalized patients with mild-to-moderate COVID-19 were not at risk of developing pulmonary fibrosis. 27 Consistently, in a 4-month followedup study for 25 children convalescing from COVID-19, mid-term sequelae were also rarely observed. 28

| CONCLUSION
Clinical sequelae of general, respiratory and cardiovascular symptoms are common in COVID-19 survivors, of which fatigue, exertional or resting dyspnea, and palpitation were the most prominent in this study. Comorbidities, degrees of disease severity, the application of mechanical ventilation during hospitalization, and the history of readmission after discharge may be associated with these sequelae. Our study provides evidence for the characteristics and prevalence of midterm (>6 months) clinical sequelae in COVID-19 survivors, indicating that long-term monitoring and proactive management are needed for their full recovery.

ACKNOWLEDGMENTS
The authors would like to thank all the participants in this study for their contributions to the scientific research of COVID-19.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.12943.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.