Do post-COVID-19 symptoms exist? A longitudinal study of COVID-19 sequelae in Wenzhou, China.

OBJECTIVE: We conducted a cohort of tracing discharge patients of COVID-19.
MATERIALS AND METHODS: We used the Mann-Whitney U test, χ2 test, or Fisher's exact test to compare differences between age groups and gender groups where appropriate.
RESULTS: Our study provides insights into the nature and severity of medical conditions specific to survivors of COVID-19.
CONCLUSIONS: It also highlights the potential mental health issues resulting from infectious disease outbreaks within communities.

Abbreviations

The novel Coronavirus

Post-traumatic stress disorder

PTSD checklist–civilian version

computed tomography

Introduction

The novel Coronavirus (COVID-19) outbreak occurred in Wuhan, China in December 2019 and spread to other countries. Most patients’ symptoms have been mild to moderate and have been resolved after receiving therapy.

The outbreak of COVID-19 in China has been defined by the World Health Organisation as a public health emergency of international concern. The epidemic not only causes social panic, but also causes physical and mental damage to people.

However, little is known about the patient's health status or disease prognosis when the COVID-19 patients are discharged from hospitals. Moreover, recurrence of positive SARS-CoV-2 RNA has been reported [1]. Of note, post-traumatic stress disorder (PTSD) had been reported in other fatal virus infectious diseases [2], [5], [6]. Most previous studies have focused on the effects of public health emergencies on post-traumatic stress disorder in medical staff (PTSD), but there are few studies on traumatic stress disorder in patients. To the best of our knowledge, there are no studies reporting on the status of discharged COVID-patients. Hence, we conducted a prospective study on the COVID-19 patients from Wenzhou.

Methods

Patients

Until February 14, there were 139 confirmed COVID-19 cases admitted in Wenzhou sixth people's hospital. Among them, 89 discharged patients were followed up during at least 3 weeks with a semi-structured questionnaire address on post-COVID-19 symptoms and health status. The surveys collected information on symptoms and diagnostic testing occurring any time during the recovery period. Mental health status was also assessed by administering the PTSD checklist–civilian version (PCL-C) [9]. The ethics commissions of Wenzhou central hospital medical group hospital approved the study.

The participants responded to the PLC-C, which includes 17 items on a 5-point scale, ranging from 1 (not at all) to 5 (extremely) in three areas: Intrusion, avoidance and numbing, and hyperarousal. A PTSD severity score was computed by summing up all symptom scores. Respondents indicated the extent to which they have been affected by symptoms over the past month. The PCL-C total score ranges from 17 to 85, with higher scores indicating greater PTSD symptom severity. It was recommended that, when the instrument was used as a continuous measure, a cut-off score of 50 is optimal for making the diagnosis of combat related PTSD. The scores that range from 38–49 suggest probable PTSD.

The protocol was approved by the review board at the Wenzhou central hospital. Written informed consent was obtained from all participants.

Discharge criteria

According to the national criteria, the discharge criteria were:

afebrility for at least 3 days;

obvious alleviation of respiratory symptoms;

improvement in radiological abnormalities on chest computed tomography (CT) or X-ray;

and two consecutive negative detections of SARS-CoV-2 at least 24 h apart [10].

Statistical analysis

Continuous and categorical variables were presented as median (IQR) and n (%), respectively. We used the Mann–Whitney U test, χ2 test, or Fisher's exact test to compare differences between age groups and gender groups where appropriate. The prevalence of the total prevalence of symptom or sign was estimated with 95% confidence intervals. All tests were 2-sided, and a P value less than 0.05 was considered statistically significant. All statistical analyses were performed by the SPSS software, version 19.0 (IBM Corp, Armonk, NY).

Results

Of 89 patients (median 43 years [IQR 31–52]), 43 were female (Table 1 ). Of note, six patients (6.7%) had a recurrence of positive RNA at the three-week follow-up. Several symptoms were reported by the discharged patients, e.g. mild (e.g., fatigue) to more severe complications requiring rehospitalisation or treatment. The most frequently reported symptoms were cough (46.1%), fatigue (36.0%), expectoration properties (24.7%) (coughing up or spitting up material from the respiratory track), chest tightness and insomnia (Table 1). Six patients (6.7%) had fever (oral temperature higher than 37.4̊C). Three patients (3.4%) complained of poor appetite, while two patients (2.2%) complained of myalgia, arthralgia, oral ulcers and eye discomfort respectively.

Table 1

Selected signs and symptoms reported by COVID-19 patients 3 weeks after discharge.

Symptoms or signs	Total (n = 89)No. (% [95% CI])	Age, No. (%)			Gender, No. (%)
		< 45y(n = 47)	≥ 45y(n = 42)	P value	Female(n = 43)	Male(n = 46)	P value
Fever	6 (6.7 [1.4–12.1])	3 (6.4)	3 (7.1)	1.000	4 (9.3)	2 (4.3)	0.424
Cough	41 (46.1 [35.5–56.6])	20 (42.6)	21 (50)	0.528	20 (46.5)	21 (45.7)	1.000
Expectoration	22 (24.7 [15.6–33.9])	9 (19.1)	13 (31.0)	0.418	11 (25.6)	11 (23.9)	0.706
Fatigue	32 (36.0 [25.8–46.1])	14 (29.8)	18 (42.9)	0.269	18 (41.9)	14 (30.4)	0.279
Diarrhea	16 (18.0 [9.8–26.1])	9 (19.1)	7 (16.7)	0.790	7 (16.3)	9 (19.6)	0.786
Chest tightness	22 (24.7 [15.6–33.9])	10 (21.3)	12 (28.6)	0.468	13 (30.2)	9 (19.6)	0.634
Poor appetite	3 (3.4 [0–7.2])	0 (0.0)	3 (7.1)	0.101	4 (9.3)	0 (0.0)	0.051
Insomnia	22 (24.7 [15.6–33.9])	9 (19.1)	13 (31.0)	0.226	13 (30.2)	9 (19.6)	0.326
Recurrence of positive SARS-CoV-2 RNA	6 (6.7 [1.4–12.1])	4 (8.5)	2 (4.8)	0.680	3 (7.0)	3 (6.5)	1.000
General recovery				1.000			1.000
Complete improvement	38 (42.7 [32.2–53.2])	25 (53.2)	13 (31.0)		19 (44.2)	19 (41.3)
Much improvement	42 (47.2 [36.6–57.8])	21 (44.7)	21 (50)		16 (37.2)	26 (56.5)
Slight improvement	7 (7.9 [2.2–13.6])	1 (2.1)	6 (14.3)		6 (14.0)	1 (2.2)
No improvement	1 (1.1 [0–3.4])	0 (0.0)	1 (2.4)		1 (2.3)	0 (0.0)
Worse	1 (1.1 [0–3.4])	0 (0.0)	1 (2.4)		1 (2.3)	0 (0.0)

Altogether, thirty-eight of the patients (42.7%) felt completely improved, and forty-two patients (47.2%) felt much improved, with one patient feeling no improvement and another patient feeling even worse. There was no significant difference in symptoms, signs or RT-PCR conversion between the age and sex groups (P  > 0.05).

Only 73 patients were assessed for psychological stress by administering the PTSD checklist–civilian version (PCL-C) (Table 2 ). There were sixteen patients, more likely to be females aged over 45 years, who did not participate in the mental health assessment. Eleven percent of the survivors had probable post-traumatic stress disorder (PTSD) and 13.7% of the survivors, who manifested high distress and with trauma exposure, had PTSD. Females had higher scores of PTSD than males (P  = 0.001), but there was no significant difference between age groups.

Table 2

PTSD checklist–civilian version (PCL-C) by COVID-19 patients after discharge.

	Total (n = 73)No. (% [95% CI])	Age, No. (%)			Gender, No. (%)
		< 45y(n = 42)	≥ 45y(n = 31)	P value	Female(n = 33)	Male(n = 40)	P value
Median (IQR)	28.0 (20.0–40.0)	27.5 (18.8–44.3)	28.0 (22.0–37.0)	0.942	31.0 (27.5–43.0)	23.0 (17.0–34.0)	0.001
Normal score = 0∼37	55 (75.3 [65.2–85.5])	30 (71.4)	25 (80.6)	1.000	22 (66.7)	33 (82.5)	1.000
Probable PTSD score = 38∼49	8 (11.0 [3.6–18.3])	4 (9.5)	4 (12.9)		5 (15.2)	3 (7.5)
PTSD score ≥ 50	10 (13.7 [5.6–21.8])	8 (19.0)	2 (6.4)		6 (18.2)	4 (10.0)

Discussion

Post-COVID-19 symptoms include, but are not restricted to, musculoskeletal pain, headache, and ocular problems. Our results are consistent with previous studies of similar infectious diseases, such as Ebola, SARS, and MERS that result in emergency conditions [4], [7], [8]. Most symptoms reported in the present study are not specific, which could be due to previous chronic disease conditions patients already suffer from, or it could be temporary symptoms related to COVID-19. It might resolve in the future. However, long-term follow-up is needed.

Recurrence of positive SARS-CoV-2 RNA is a unique phenomenon. It is different from coronaviruses, such as SARS and MERS, which do not similarly reported relapses in the literature resulting among discharged patients. In the present study, there were 6 cases among 89 discharge patients (6.7% with 95% CI [1.4–12.1]). The mechanism is still unclear until now. The potential explanation is that health systems are being overwhelmed and are not able to adequately follow up with patient's post-discharge. The hospitals are often forced to discharge these patients, even if they haven’t fully recovered, as the need for beds is immense. Future studies on the clinical symptoms of those patients and pathology are warrant.

COVID-19 pandemic has been associated with increases in mental health issues among COVID-19 patients. Typically, PTSD is triggered by a terrifying or traumatic event, which could result from either experiencing it or witnessing it. As for COVID-19, the emergency environmental conditions that have been induced with this infectious disease might produce unique characteristics that are resulting in PTSD among COVID-19 survivors. Of note, most COVID-19 patients are more likely to be infected by close contact from family members, for example. As a result, those patients might be experiencing the impacts of both COVID-19 exposure in themselves as well as witnessing it in their family member. This could result in a double exposure effect and could have a more severe impact. Also, our results confirm that gender difference exists in PTSD [3]. It could be due to the hormone and neurosteroid/peptide differences from both pre-clinical and clinical research [3].

Limitations

Our study has several limitations. Dysfunctional information related to complained symptoms was not accessed. Most symptoms were self-reported and were not crosschecked against medical charts. Also, follow-up time since hospital discharge was short, and PTSD symptoms can manifest years after the traumatic situation has occurred. The pathogenesis of the symptoms reported by survivors of COVID-19 is unclear and requires further study.

Implications

Our study provides insights into the nature and severity of medical conditions specific to survivors of COVID-19. It also highlights the potential mental health issues resulting from infectious disease outbreaks within communities. The long-term consequences may not just be physical symptoms, which could necessitate comprehensive and coordinated mental health responses. Lastly, this study has underscored the importance of better understanding the conditions that lead to reinfection and what this means for measures that are undertaken to decrease disease transmission.

Conclusion

Long-term psychological support could be a crucial element aiding in reducing mortality and morbidity, and promoting overall effectiveness of efforts to halt COVID-19 transmission. This study provides a reference for improving people's mental health and psychological adaptability during any future COVID-19-like pandemic.

Funding

This work was supported by Zhejiang Health Science and Technology Program Project (innovative Talent Project) in 2021 (Grant No. 2021RC125) and the Basic Public Welfare Research Project of Zhejiang Province (LGF20H010003).

Disclosure of interest

The authors declare that they have no competing interest.

Ethics approval

The ethics commissions of Wenzhou central hospital medical group hospital approved the study.

Statement of informed consent

Written informed consent was obtained from a legally authorised representative(s) for anonymised patient information to be published in this article.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Authors’ contributions

Min Zhou, Jing Cai and Wenjie Sun designed the study, and supervised the data collection; Jing Wu, Yidong Wang and Michelle Gamber analysed and interpreted the data; Lingyan Fan and Guiqing He prepared the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.