1. Introduction
Globally, as of March 18, 2022, more than 420 million confirmed cases of COVID-19 and nearly 6 million deaths have been reported by the World Health Organization.[ 1 ] After experiencing several pandemic waves caused by wild-type, Alpha, Delta, and Omicron variants of concerns, novel recombination DeltaCron has just been reported,[ 2 ] alarming that the pandemic is “not over.” The Omicron variant continues to dominate the world, but its infection causes significantly less severe cases because of the global vaccination program.[ 3 ] Leaving medical resources for the most vulnerable individuals should be the top priority. Preparing affordable medical facilities is the key to saving more lives in the face of a pandemic.
The “dynamic clearing” policy for SARS-CoV-2 control and prevention in China has successfully contained viral spread. Under this policy, all imported SARS-CoV-2–infected individuals were admitted to a government-designated hospital for treatment. When viral RNA is consecutively negative at least twice more than a 24 hours apart, they are discharged and subjected to another 14-day isolated observation in hotels or hospitals before finally returning to normal life. Such measures, relying on a profound economic basis, have substantially prevented the virus from re-entering the country from imported cases.
2. Research presentation
This study was approved by Guangzhou Eighth People’s Hospital Ethics Committee (nos. 202001134 and 202115202). Two thousand two hundred twelve imported cases in Guangzhou from January to December 2021 retrospectively analyzed. All patients were required to receive the first in-hospital treatment period and were subjected to a subsequent isolation period in separate buildings for virus-safe quarantine [Figure 1 A]. We found that 695 cases of 2212 (31.4%) were viral RNA negative in both the hospitalization and isolation stages [Figure 1 B]. Despite their proportions varying month-by-month, such individuals were observed monthly [Figure 1 C], suggesting frequent occurrences. Notably, patients with obvious chest computed tomography abnormalities were defined as moderate, according to the essential criteria for COVID-19 diagnosis. Among the 695 all-negative viral RNA cases, the number of asymptomatic cases increased to 515 (74.1%). There were 147 (21.2%) and 33 (4.7%) moderate and mild cases, respectively [Figure 1 D]. Moderate patients with visible lung damage but undetectable viral RNA were in the recovery period when the virus was cleared and the lung damage was improving. Unfortunately, their symptoms were unavailable because of lack of convincing records before admission to our hospital. This high percentage of cases with undetectable viral RNA occupied precious medical beds and consumed a substantial amount of medical resources. Therefore, strategies to precisely identify and classify these individuals, and release them outside of the closed-loop patient management system will markedly relieve the medical burden.
Figure 1: The proportion and clinical classification of all-negative viral RNA cases in imported COVID-19 cases in Guangzhou, 2021. (A) Flow chart of admission and isolation management of patients with SARS-CoV-2 infection. (B, C) Proportion of all-negative cases for the whole year and each month in 2021. (D) Percentage of different clinical symptom classification in 695 all-negative cases.
Next, we investigated the relationship between all viral negative cases and length of hospitalization in every case. According to the Chinese Diagnosis and Treatment Protocol for COVID-19 Patients (Trial Version 8), suspected patients can be confirmed with a positive real-time polymerase chain reaction detection of the novel coronavirus nucleic acid and should be transferred to the hospital to receive treatment. All individuals who enter Guangzhou, China, from abroad were subjected to viral RNA detection. Patients who tested positive for viral RNA were transferred to Guangzhou Eighth People’s Hospital. In the hospital, all admitted patients had their first viral RNA detection immediately after admission (on day 0). Their nasopharyngeal samples were collected at 2- or 3-day intervals, depending on their viral titers, to monitor the viral load change in a timely manner. According to these criteria, patients with two consecutive viral RNA negative more than 24 hours apart can be discharged to leave the hospital.
We found that 1003 cases (of all 2212 imported cases, 45.3%) were discharged within 5 days (termed ultrashort hospitalization) [Figure 2 A and Table 1 ]. Six hundred one patients (59.9%) in this group tested negative on day 0, 2–3, and 3–5 for the first, second, and third viral detection [Figure 2 B]. In addition, 307 cases (30.6%) were retest positive during the isolated quarantine period. The other 95 cases (9.5%) had one or two viral RNA positive tests and two viral RNA negative tests during the hospitalization period.
Figure 2: Analysis of viral RNA characteristics of imported COVID-19 cases discharged within 5 days in Guangzhou, 2021. (A) Distribution of hospitalization time of imported cases in 2021. (B) Classification of imported cases discharged within 5 days based on viral RNA test results. (C) Classification of 307 retest positive cases according to the frequency of positive viral RNA detection. (D) Peak viral load in retest positive period of 307 cases. Blue line, Ct = 33; interquartile rang is shown. (E) Dynamic changes of viral RNA levels during hospitalization and isolation in 95 positive test cases. Each individual is shown. Red, Ct number ≤ 30; blue, 30<Ct number ≤ 33, black, Ct number > 33. All_Neg: All-negative viral RNA cases; Retest_Pos: Cases of retest positiveness in isolation quarantine; InHospital_Pos: Cases of positive viral RNA during the In-Hospital period; 1_positive: Only positive at one time point during the isolation periods; >1 positive: Two or more viral RNA positive tests during the isolation stage.
Table 1 -
The distribution of hospitalization time of imported COVID-19 cases in each month in Guangzhou, China, 2021
Month
1–5 d
6–7 d
8–14 d
15–21 d
22–28 d
>28 d
Total
January
29
10
20
20
25
5
109
February
68
17
25
20
18
5
153
March
50
12
17
14
8
7
108
April
75
24
22
18
17
20
176
May
104
25
33
8
12
16
198
June
69
23
37
10
14
8
161
July
97
41
30
32
21
19
240
August
186
47
45
35
24
29
366
September
100
31
42
12
11
16
212
October
54
18
17
12
5
7
113
November
74
23
25
7
19
9
157
December
97
20
21
38
31
12
219
Total
1003
291
334
226
205
153
2212
Finally, we observed the viral titers among the different groups. Among the remaining 307 cases with viral RNA retest positivity, 148 (48.2%) were only positive at one time point during the isolation period, and 98.0% (145/148) of their peak viral RNA was over Ct = 33 cycles [Figure 2 C and 2D]. The remaining 159 cases (51.8%) showed two or more viral RNA positive tests during the isolation stage [Figure 2 C], and 95.0% of their peak viral RNA (151/159) was more than Ct = 33 cycles [Figure 2 D]. We analyzed dynamic viral RNA changes in 95 cases with detectable viral RNA during the in-hospital period [Figure 2 E]. Only two cases (red) had viral RNA levels less than Ct = 30 cycles, and only four cases (blue) had viral RNA levels between 30 and 33 cycles. Altogether, our results indicated that all cases had low levels of viral RNA .
3. Discussion
Our systemic analysis of all 2212 imported cases infected with SARS-CoV-2 over the entire year 2021 revealed that approximately 31.4% of patients (695/2212) were viral RNA test negative, suggesting that all those cases were inessential to subject to centralized treatment and isolation. During the infection life cycle, SARS-CoV-2 goes through incubation, increases, plateaus, declines, disappears, or sometimes retests positive. We postulate that all negative viral RNA test imported cases were already at the end of disappearing or retest positive when confirmed at the entry into the Chinese customs or retest positive in the isolated hotels. The sensitive PCR test caught their last viral RNA positive, and they were sent to the hospital to receive treatment.
Our study indicated that rigorous screening in customs and isolation hotels effectively identified individuals with low viral RNA levels.
Combining the initial three to four viral RNA tests provides a feasible strategy for identifying all negative viral RNA test patients if all consecutive tests are negative. The incubation period for Delta or Omicron has been shortened to less than 5 days.[ 4,5 ] In addition, the infectious viral particle has been found to persist for 2 weeks when the viral titer is greater than 10e5 copies/mL (equal to Ct = 29–32).[ 6–8 ] Therefore, in our study, 5 days and three viral RNA surveillance tests could confirm whether the viral concentration was in the early increase stage or the late disappearance. In the early stage, a significant viral increase occurs. Otherwise, if all three to four viral RNA tests are negative, the individual could be diagnosed with a late-stage infection, and they should be discharged in time.
Our study had some limitations. First, this was a single-center retrospective study. Second, the cases in this study were mainly of the SARS-CoV-2 Delta variant. Nonetheless, the study has provided insight into the clinical characteristics of admitted patients who were all viral RNA test negative from admission to discharge to the final release from quarantine, and the retest positive cases had low levels of viral RNA .
In conclusion, a high percentage of imported COVID-19 cases (more than 1/3) admitted to Guangzhou Eighth People’s Hospital were viral RNA negative from the beginning to the final release after quarantine isolation, occupying precious medical resources for infectious diseases. We recommend that the hospital observation period for polymerase chain reaction–confirmed cases abroad be shortened to no more than 5 days to save medical resources, especially in dealing with large epidemics.
Acknowledgments
The authors thank all the patients and all the people involved in treating COVID-19, including all healthcare workers who provide care for patients with COVID-19 and are involved in the diagnosis and management of COVID-19 patients and those who trace and quarantine the contacts.
Author Contributions
Xilong Deng, Xiaoping Tang, Fengyu Hu, Feng Li, and Jinxin Liu developed the conceptual ideas and designed the study. Zhiwei Xie, Guofang Tang, and Lu Li performed the experiments and statistical analysis. Jingrong Shi provided the essential assistance through experiments. Qingxin Gan, Jingyan Tang, Xiaowen Zheng, Huimin Zeng, Chuyu Zhang, Sisi Chen, Jianping Cui, Zishi Lin, Lihua Lin, and Youxia Li were responsible for sample collection. All authors provided scientific expertise and the interpretation of data for the work. Feng Li drafted the manuscript. All authors contributed to critical revision of the manuscript for important intellectual content. All authors reviewed and approved the final version of the report.
Funding
This study was supported by the Emergency Key Program of Guangzhou Laboratory (EKPG21-29 and EKPG21-31), Zhongnanshan Medical Foundation of Guangdong Province (ZNSA-2021004), the Emergency Grants for SARS‐CoV‐2 Prevention and Control of Guangdong Province (Nos.2022A1111090002 and 2021A1111110001), and Guangzhou Science and Technology Plan Project (No.202201020338).
Conflicts of Interest
None.
Data Available Statement
The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
1. World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. Available from:
https://covid19.who.int/ . Accessed March 18, 2022.
2. Bolze A, Basler T, White S, et al. Evidence for SARS-CoV-2 Delta and Omicron co-infections and recombination. Med 2022;3(12):848–859.e4. doi: 10.1016/j.medj.2022.10.002.
3. Nyberg T, Ferguson NM, Nash SG, et al. Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study. Lancet 2022;399(10332):1303–1312. doi: 10.1016/S0140-6736(22) 00462-7.
4. Abbott S, Sherratt K, Gerstung M, et al. Estimation of the test to test distribution as a proxy for generation interval distribution for the Omicron variant in England. medRxiv 2022. doi: 10.1101/2022.01.08.22268920. Preprint.
5. Song JS, Lee J, Kim M, et al. Serial intervals and household transmission of SARS-CoV-2 Omicron variant, South Korea, 2021. Emerg Infect Dis 2022;28(3):756–759. doi: 10.3201/eid2803.212607.
6. Kim MC, Cui C, Shin KR, et al. Duration of culturable SARS-CoV-2 in hospitalized patients with COVID-19. N Engl J Med 2021;384(7):671–673. doi: 10.1056/NEJMc2027040.
7. Pekosz A, Parvu V, Li M, et al. Antigen-based testing but not real-time polymerase chain reaction correlates with severe acute respiratory syndrome coronavirus 2 viral culture. Clin Infect Dis 2021;73(9):e2861–e2866. doi: 10.1093/cid/ciaa1706.
8. van Kampen JJA, van de Vijver DAMC, Fraaij PLA, et al. Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19). Nat Commun 2021;12(1):267. doi: 10.1038/s41467-020-20568-4.
