Comorbidities prolonged viral shedding of patients infected with SARS-CoV-2 omicron variant in Shanghai: A multi-center, retrospective, observational study

Abstract

Background

As the omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surges amid the coronavirus disease 2019 (COVID-19) pandemic, there is limited comorbidities data associated with viral shedding time (VST). We aimed to investigate the effect of comorbidities on VST in asymptomatic and mild patients with omicron.

Methods

A multi-center, retrospective, observational study was conducted from March 12, 2022 to May 24, 2022 in Shanghai. The analysis was adjusted for patients’ baseline demographic, using log-rank test and logistic regression model.

Results

The study enrolled 198,262 subjects. The median duration of viral shedding time (VST) was 8.29 days. The number of cumulative viral shedding events was significantly lower in the chronic obstructive pulmonary disease (COPD), hyperlipidemia, diabetes, urinary system disease, and cardiocerebrovascular disease than in the no corresponding comorbidities group. Patients with comorbidities had a lower incidence of viral shedding, and the most significant independent risk factor is COPD (aOR 1.78, 95% CI: 1.53–2.08, p < 0.001). Across different age ranges, the comorbidities affecting viral shedding also differ, with the greatest risk factors for viral shedding being hyperlipidemia (aOR 2.23, 95% CI: 1.50–3.31, p < 0.001) and COPD (aOR 1.85, 95% CI: 1.50–2.28, p < 0.001) between ages of 18–39 and 40–64, and thyroid dysfunction (aOR 2.36, 95% CI: 1.60–3.47, p < 0.001) above age 64.

Conclusions

Omicron-infected patients with comorbidities might prolong the VST. The independent risk factors also differ across age ranges, suggesting that providing targeted effective prevention and control guidance and allocating appropriate resources to different populations should be a crucial strategy.

Introduction

The unprecedented pandemic of coronavirus disease 2019 (COVID-19) started more than 2 years ago. So far, the alpha, beta, gamma, delta, and omicron variants of SARS-CoV-2 have emerged, and each later variant is more transmissible than the previous one [1]. After the omicron (B.1.1.529) variant of severe Acute respiratory syndrome coronavirus 2 (SARS-COV-2) was first identified in southern Africa [2], the virus has more than 30 mutations in its spike gene that made it more infectious, increasing the risk of reinfection and potentially escaping immunity [3], [4]. It was declared by the World Health Organization (WHO) to be a variant of concern on November 25, 2021. Currently, the omicron variant of SARS-CoV-2 has overtaken other variants to become the predominant circulating strain, sweeping the world [5]. Previous studies indicated that omicron infection was associated with significantly shorter hospital stays and lower severity and mortality than in previous variants [6], [7], [8]. Since the outbreak of the omicron variant in late February 2022, in Shanghai, the major omicron subline is BA.2. As of May 4, 2022, 593,336 cases have been identified, including 538,450 asymptomatic carriers [9]. In view of the alarming global spread and morbidity of omicron variant, the prolonged viral shedding time (VST) has attracted widespread attention, bringing greater challenges and difficulties to epidemic prevention and control. The VST is an important parameter to judge the discharge and termination of quarantine of infectious diseases and determines the transmission and duration of infectiousness.

More than half of patients with COVID-19 were reported to have at least one comorbidity on admission according to report [10]. Hypertension, diabetes, chronic obstructive pulmonary disease (COPD), and obesity were the most commonly reported. Comorbidities increase the prognosis of acute illness and the risk of exacerbating severe symptoms. However, there was insufficient evidence to prove any comorbidity had effects on VST in omicron variant infections. Most published studies on COVID-19 were retrospective and observational designs with inadequate sample sizes, making it difficult to evaluate how particular comorbidity affects viral shedding time [11]. To address this knowledge gap, we carried out a multi-center, retrospective, observational study to evaluate the effects of different comorbidities on clinical outcomes in asymptomatic carriers and mild cases infected with the omicron variant, with the hope that our study will provide updated information on the management of this variant.

Methods

Study design and participants

This study was a multi-center, retrospective, observational study of adults (aged 18 years or older) with the omicron variant who were admitted to three Fangcang shelter hospitals from March 12, 2022 to May 24, 2022, during the omicron variants circulated in Shanghai. Eligible patients included asymptomatic carriers and mild cases diagnosed according to SARS-CoV-2 diagnosis and treatment guidance(ninth edition) of the National Health Commission of China. Laboratory confirmation of SARS-CoV-2 was defined as a positive result of real-time reverse transcriptase-polymerase chain reaction test with CT value< 35 of nasopharyngeal (NPS) or throat swab (TS). The outcome of the study was the viral shedding time among asymptomatic and mild symptomatic persons tested positive for SARS-CoV-2.

Data collection and definitions

Epidemiological, demographic, vaccine, comorbidities, and duration of viral RNA shedding, of all patients with a confirmed COVID-19 diagnosis were collected and recorded using a standardized electronic database. The time of the first positive RT-PCR test was recorded and defined as the date of diagnosis onset. The RT-PCR test was performed on the next day of admission. Patients were followed daily until two consecutive negative PCR tests were performed and the first viral test date was used to define the duration of shedding. Persons who had received at least two doses of the COVID-19 vaccine, irrespective of vaccine type, more than 7 days before the case diagnosis date were classified as vaccinated, whereas persons with an incomplete primary vaccination schedule (one dose or none) were considered unvaccinated.

Virological assessment and clinical management

For all included patients, the diagnosis of SARS-CoV-2 infection was confirmed on at least one respiratory specimen by the detection of SARS-CoV-2 RNA through real-time polymerase chain reaction (RT-PCR). During hospitalization, all patients underwent follow-up NPS and TS to assess viral shedding. The therapeutic management of patients was based on internal hospital protocol, national and international guidelines, and clinical judgment, according to the best evidence available at the time.

Statistical analysis

Continuous and categorical variables were expressed as medians with IQRs and as numbers (%), respectively. The cumulative probability of achieving viral shedding was estimated by Kaplan–Meier curves in people with different comorbidity. The differences between groups were compared by the log-rank statistic test. Multivariable logistic regression analysis to identify predictive factors of prolonged viral shedding. All statistical analyses were performed using R (version 4.2). A P -value< 0.05 indicated conventional statistical significance.

Ethical approvals

The ethics committee approved this study (Protocol Record SCAM2022). The ClinicalTrials.gov Identifier is NCT05375786. Patient information remained anonymous, and written consents were waived due to a major infectious disease outbreak.

Results

Baseline characteristics of all subjects infected with the omicron variant

In this study, 198,262 subjects infected with the omicron variant of SARS-CoV-2 were enrolled from March 12, 2022, to May 24, 2022 while the variants circulated in Shanghai. Their median age was 43.00 (IQR: 32.00–54.00), 59.06% were male, and the median duration time of VST was 8.29 days (IQR: 5.33–11.27). Among them, 20,504 (10.34%) were mildly infected patients and the rest were asymptomatic carriers (177,758 cases, 89.66%). We further analyzed the vaccination status of those patients: that is, one with incomplete vaccination (48,999 cases, 24.71%), one with full (two-dose) vaccination (59,745 patients, 30.13%), and one that received booster shots (i.e., three-dose vaccination) (89,518 cases, 45.15%). Then, the subjects were divided into two subgroups: no comorbidities (164,366 cases) or at least one comorbidity (33,896 cases, 17.09%). In the group with one or more comorbidities, the average VST was longer than in the group without comorbidities ( Table 1).

Table 1.

The characteristics of the total subjects included.

	Overall (n = 198,262)	Presence of comorbidity (n = 164,366)	Absence of comorbidity (n = 33,896)	p
Sex
Male (%)	117,095 (59.06)	97,232 (59.16)	19,863 (58.60)	0.059
Age (median [IQR])	43.0 [32.0, 54.0]	40.0 [31.0, 52.0]	56.000 [46.0, 64.0]	< 0.0001
Vaccination (%)				< 0.0001
0/1 dose (incomplete vaccination)	48,999 (24.71)	39,346 (23.94)	9653 (28.48)
2 dose	59,745 (30.13)	50,439 (30.69)	9306 (27.45)
3 dose	89,518 (45.15)	74,581 (45.37)	14,937 (44.07)
Viral Shedding Time (median [IQR])	8.290 [5.330, 11.270]	8.200 [5.320, 10.580]	9.290 [6.330, 12.280]	< 0.0001
Diagnosis				< 0.0001
Mild (%)	20,504 (10.34)	15,023 (9.14)	5481 (16.17)

Data are N (%), mean (SD) or median (IQR). SD: Standard Deviation; IQR: Interquartile Range.

Baseline characteristics of subjects with comorbidities

Then, demographic information and distribution of comorbidities were analyzed as shown in Table 2, and baseline characteristics of patients of different age groups were compared ( Fig. 1). Among 33,896 subjects with comorbidities, the median age was 56.00 (IQR: 46.00–64.00), and the median duration time of VST was 9.29 days (IQR: 6.33–12.28). The main complications of omicron infection were hypertension (65.24%), diabetes (28.39%), cardiocerebrovascular disease (9.01%), thyroid dysfunction (5.91%), and hyperlipidemia (3.94%). Among infected patients with underlying disease, 70.99% (12.14% of the total subjects) had at least one comorbidity (Table 2).

Table 2.

Baseline characteristics of subjects with comorbidities.

	Presence of comorbidity (n = 33,896)
Sex = Male (%)	19,863 (58.60)
Age (median [IQR])	56.0 [46.0, 64.0]
Vaccination (%)
0/1 dose (incomplete vaccination)	9653 (28.48)
2 dose	9306 (27.45)
3 dose	14,937 (44.07)
Viral shedding time (median, IQR)	9.29 [6.33, 12.28]
COPD	794 (2.34)
Hypertension	22,113 (65.24)
Hyperlipidemia	1335 (3.94)
Diabetes	9622 (28.39)
Thyroid dysfunction	2003 (5.91)
Chronic liver disease	160 (0.47)
Cardiocerebrovascular disease	3053 (9.01)
Gout	133 (0.39)
Urinary system diseases*	723 (2.13)
Other diseases	7219 (21.30)
Number of comorbidities
1	24,063 (70.99)
2	7132 (21.04)
3	2101 (6.20)
> 3	600 (1.77)
Diagnosis
Mild (%)	5481 (16.17)

Data are N (%), mean (SD) or median (IQR).

Abbreviations: SD: Standard deviation; IQR: Interquartile range; COPD: Chronic obstructive pulmonary disease.

*Urinary System Diseases: Chronic kidney disease and urinary system diseases were included.

Fig. 1.

The characteristics of subjects with comorbidities stratified by age.

The cumulative probability of viral shedding and associated risk factors

Over a median follow-up of 8.29 days (IQR 5.33–11.27). The shortest duration of viral shedding observed in our population was 3 days, while the longest was 30 days. After stratifying by different comorbidities, Kaplan-Meier estimates the cumulative probability of viral shedding from the upper respiratory tract (URT), as shown in Fig. 2. By log-rank test, the cumulative probability of viral shedding from URT in patients with different comorbidities during the observation was significantly higher than that in patients without comorbidities. The number of viral shedding events was significantly lower in the COPD (794 cases, p < 0.0001), hypertension (22,113 cases, p < 0.0001), hyperlipidemia (1335 cases, p < 0.0001), diabetes (9622 cases, p < 0.0001), urinary system disease (723 cases, p < 0.0001), cardiocerebrovascular disease (3053 cases, p < 0.0001), chronic liver disease (160, p < 0.005), and thyroid dysfunction (2003 cases, p < 0.0001) than in corresponding no comorbidities group.

Fig. 2.

Kaplan-Meier curves estimating the cumulative probability of viral shedding (VS) in total population with different comorbidities.

Risk factors associated with prolonged viral shedding

In this study, prolonged viral shedding time was defined as detecting SARS-CoV-2 RNA on respiratory specimens for> 8.29 days (the median duration of VST in our population). As shown in Fig. 3, when having more than three comorbidities, the risk of prolonged viral shedding increased to 2.09 times (aOR 2.09, 95% CI: 1.74–2.50, p < 0.001) (supplementary Table 1). In the included subjects, had COPD (aOR 1.78, 95% CI: 1.53–2.08, p < 0.001), hypertension (aOR 1.21, 95% CI: 1.18–1.25, p < 0.001), hyperlipidemia (aOR 1.32, 95% CI: 1.18–1.49, p < 0.001), diabetes (aOR 1.21, 95% CI: 1.15–1.26, p < 0.001) and thyroid dysfunction (aOR 1.27, 95% CI: 1.15–1.41, p < 0.001) during hospitalization were significantly associated to increased odds of slower viral shedding as shown in Fig. 4 (supplementary Table 2). Among different age ranges, the comorbidities affecting viral shedding also differ, with the greatest risk factors for viral shedding in 18–39 years, 40–64 years, and older than 64 years being hyperlipidemia (aOR 2.23, 95% CI: 1.50–3.31, p < 0.001, Fig. 5A, supplementary Table 3), COPD (aOR 1.85, 95% CI: 1.50–2.28, p < 0.001, Fig. 5B, supplementary Table 4), thyroid dysfunction (aOR 2.36, 95% CI: 1.60–3.47, p < 0.001, supplementary Table 5), respectively.

Fig. 3.

Predictive factors (based on number of comorbidities) of viral shedding time (>8.29 days) by Logistic regression analysis (on 198,262 patients).

Fig. 4.

Predictive factors (based on different comorbidities) of viral shedding time (>8.29 days) by Logistic regression analysis (on 198,262 patients).

Fig. 5.

Predictive factors of viral shedding time (>8.3 days) by Logistic regression analysis. A. Age of 18–39. B. Age of 40–64. C. Above age of 64.

Discussion

This retrospective study focused on the duration of viral shedding from the URT and the association with both comorbidities and prolonged viral shedding.

In our cohort, the median duration of viral shedding, from PCR positive onset to viral shedding, was 8.29 days. While concerning the presence of comorbidity, the median time was 9.29 days. Advanced age, presence of symptoms, and underlying comorbidities were considered independent risk factors of delayed viral shedding in our study. Although comorbidities have been identified as one of the main prognostic factors for COVID-19 severity, only a few studies have reported an association with the duration of viral shedding among people infected with the omicron variants [12]. Our study observed that patients with underlying comorbidities were more likely to have both slower viral shedding and prolonged viral detection with an increased risk for each additional comorbidity. Additionally, there were significant relations between specific comorbidities and the persistence of viral RNA, including hypertension, hyperlipidemia, diabetes, COPD, thyroid dysfunction, and so on. The comorbidities affecting viral shedding also differ across age ranges, with the greatest risk factors for viral shedding being hyperlipidemia and COPD in 18–39 years and 40–64 years, and thyroid dysfunction in the elderly group (≥ 65 years), respectively. It would be instructive for the health professionals and the community regarding the precautionary measures, comprehending the risk of comorbidities in COVID-19, and establishing management strategies to combat the pandemic situation. However, the mechanisms and pathophysiology of some comorbidities in COVID-19 patients yet need further understanding.

During this pandemic in Shanghai, only a rare proportion of critically ill or deceased patients were reported due to the omicron infection directly [9]. Patients infected with the omicron variant of SARS-CoV-2 included in this study, similar to other studies reported from other countries [8], [13], [14], demonstrated reduced clinical severity and patients were mainly asymptomatic and mild. This result further mirrors the attenuated pathogenicity of the omicron variant compared to that induced by the wild-type strain or other variant.

Early studies reported by South African researchers suggested that the pathogenicity was greatly attenuated during the spread of the omicron variant [6], [7], [15]. The vaccination rate in Shanghai, a city of 25 million people, is now more than 90%, with immunity to the SARS-CoV-2 mainly from effective vaccinations [9]. Reduced effectiveness of fully vaccinated individuals when fighting omicron infection compared to the Delta variant has been reported [16], [17]. In our study, it is evident that timely vaccination (with a booster shot) did not provide a significant protective effect against viral shedding, possibly due to a series of mutations in the omicron genome spike protein involved in immune evasion [18], [19]. Reduced neutralization of the omicron variant has been reported in studies [20], [21], [22] using plasma specimens from individuals with complete (two or three doses) mRNA vaccine series, and from patients with prior SARS-CoV-2 infection, which further demonstrates that there might be a limited effect of the vaccine on clearance of the omicron variant among asymptomatic and mild patients.

Although severity is alleviated with the emergence of the BA.2 subtype of omicron variant, higher transmissibility of omicron variant infections and immune evasion from previous infection and vaccination remains a concern. The high rate of infection in the community has overwhelmed healthcare systems in Shanghai and elsewhere and has translated to high absolute numbers of hospitalizations with lower severity of infections associated with the omicron variant. Observations in Hong Kong with low immunity previously caused by infection [23] highlight the risk of severe and fatal illness due to omicron variants, although the risk of severe clinical outcomes in cases tends to be lower than with Delta variants. Underlying diseases, such as hypertension, cardiovascular disease, diabetes, and COPD, have been reported as risk factors for severe disease and also increased the mortality rate, therefore better management with special consideration must be given to these patients. Such patients need to be accurately evaluated on admission and different guidelines should be designed for these patients.

As the situation is rapidly evolving, future studies with larger sample sizes will likely contribute to identifying additional comorbidities. The prevalence of chronic diseases is increasing year by year, and targeted public health interventions must be adopted to better protect people with chronic diseases from infection with SARS-CoV-2 and other respiratory viruses. Knowledge of populations at risk is critical for providing effective guidance and allocating appropriate resources.

Limitations and strength

Our study has several limitations. First, the study could be prone to bias related to unmeasured confounders due to its observational nature. Such as drugs used to treat comorbidities or health care resources that could influence viral shedding. Given the recent escalation of omicron outbreaks and the increasing number of patients with no symptoms or no need for hospitalization, clinical data became less available, which further reduces the data of patients in different subgroups. Second, the estimated duration of viral shedding could have been influenced by heterogeneity in the frequency of specimen collection and the type of respiratory specimen used. Additionally, the lack of any quantitative determination of viral load such as cycle threshold prevents us from drawing conclusions about the potential infectivity of long-term shedding. Finally, there was no severe or deceased patient in our study, so we could not have access to analyze the possible risk factors associated with the severity or mortality of COVID-19 infection by the omicron variant. However, the study's main strength is its large sample size. To our knowledge, this is one of the largest cohorts in which the duration of viral shedding in patients with omicron variant has been investigated. Thus, this study provides significant information on the correlation between prolonged viral shedding and comorbidities.

Conclusion

Asymptomatic and mild omicron infected patients with comorbidities such as COPD, hypertension, hyperlipidemia, diabetes, and thyroid dysfunction might prolong the viral RNA shedding time. The independent risk factors also differ across age ranges, suggesting that appropriate action to protect those most at risk will therefore be integral to limiting the number of severe and fatal cases and mitigating the burden on health systems.

Funding

This work was supported by the Program for Outstanding Medical Academic Leader, Shanghai Shenkang Hospital Development Center of China (Grant numbers SHDC2020CR1028B, SHDC22021304).

Conflicts of interest

No competing financial interests exist.

Appendix A. Supplementary material

Supplementary material

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