Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea | Infectious Diseases | JAMA Internal Medicine | JAMA Network
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Figure 1.  Proportion of Negative Conversion in Asymptomatic and Symptomatic (Including Presymptomatic) Patients
Proportion of Negative Conversion in Asymptomatic and Symptomatic (Including Presymptomatic) Patients

Kaplan-Meier curves for negative conversion ratio between asymptomatic and symptomatic (including presymptomatic) patients. Days since diagnosis means from diagnosis to the first negative conversion. There was no significant difference between the 2 groups (P = .07).

Figure 2.  The Cycle Threshold Value Dynamics of env, RdRp, and N Genes From Upper Respiratory Tract Specimens
The Cycle Threshold Value Dynamics of env, RdRp, and N Genes From Upper Respiratory Tract Specimens

Scatterplots for dynamics of cycle threshold values between asymptomatic and symptomatic (including presymptomatic) patients for the env gene (A), RdRp gene (B), and N gene (C). Beta value represents a slope of decline. There is a significant difference in the RdRp gene between the 2 groups (β = 0.040 [SE, 0.020]; P = .048).

Figure 3.  The Cycle Threshold Value Dynamics of env, RdRp, and N Genes From Lower Respiratory Tract Specimens
The Cycle Threshold Value Dynamics of env, RdRp, and N Genes From Lower Respiratory Tract Specimens

Scatterplots for dynamics of cycle threshold values between asymptomatic and symptomatic (including presymptomatic) patients for the env gene (A), RdRp gene (B), and N gene (C). Beta value represents a slope of decline. There is a significant difference in the env gene between the 2 groups (β = −0.065 [SE, 0.023]; P = .005).

Table.  Baseline Characteristics of Patients Infected With Severe Acute Respiratory Syndrome Coronavirus 2
Baseline Characteristics of Patients Infected With Severe Acute Respiratory Syndrome Coronavirus 2
1.
Zhu  N, Zhang  D, Wang  W,  et al; China Novel Coronavirus Investigating and Research Team.  A novel coronavirus from patients with pneumonia in China, 2019.   N Engl J Med. 2020;382(8):727-733. doi:10.1056/NEJMoa2001017 PubMedGoogle ScholarCrossref
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World Health Organization. Coronavirus disease (COVID-19) pandemic. Accessed May 20, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
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Park  PG, Kim  CH, Heo  Y, Kim  TS, Park  CW, Kim  CH.  Out-of-hospital cohort treatment of coronavirus disease 2019 patients with mild symptoms in Korea: an experience from a single community treatment center.   J Korean Med Sci. 2020;35(13):e140. doi:10.3346/jkms.2020.35.e140 PubMedGoogle Scholar
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Li  R, Pei  S, Chen  B,  et al.  Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2).   Science. 2020;368(6490):489-493. doi:10.1126/science.abb3221 PubMedGoogle ScholarCrossref
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Kimball  A, Hatfield  KM, Arons  M,  et al; Public Health – Seattle & King County; CDC COVID-19 Investigation Team.  Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled nursing facility—King County, Washington, March 2020.   MMWR Morb Mortal Wkly Rep. 2020;69(13):377-381. doi:10.15585/mmwr.mm6913e1 PubMedGoogle ScholarCrossref
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Mizumoto  K, Kagaya  K, Zarebski  A, Chowell  G.  Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020.   Euro Surveill. 2020;25(10). doi:10.2807/1560-7917.ES.2020.25.10.2000180 PubMedGoogle Scholar
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Gudbjartsson  DF, Helgason  A, Jonsson  H,  et al.  Spread of SARS-CoV-2 in the Icelandic population.   N Engl J Med. 2020;382(24):2302-2315. doi:10.1056/NEJMoa2006100 PubMedGoogle ScholarCrossref
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Bai  Y, Yao  L, Wei  T,  et al.  Presumed asymptomatic carrier transmission of COVID-19.   JAMA. 2020;323(14):1406-1407. doi:10.1001/jama.2020.2565PubMedGoogle ScholarCrossref
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Zou  L, Ruan  F, Huang  M,  et al.  SARS-CoV-2 viral load in upper respiratory specimens of infected patients.   N Engl J Med. 2020;382(12):1177-1179. doi:10.1056/NEJMc2001737 PubMedGoogle ScholarCrossref
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Rawlins  EL, Hogan  BL.  Ciliated epithelial cell lifespan in the mouse trachea and lung.   Am J Physiol Lung Cell Mol Physiol. 2008;295(1):L231-L234. doi:10.1152/ajplung.90209.2008 PubMedGoogle ScholarCrossref
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Wölfel  R, Corman  VM, Guggemos  W,  et al.  Virological assessment of hospitalized patients with COVID-2019.   Nature. 2020;581(7809):465-469. doi:10.1038/s41586-020-2196-x PubMedGoogle ScholarCrossref
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    4 Comments for this article
    EXPAND ALL
    Saliva sampling as the gold standard method of RT-PCR test for transmissibility among pre-symptomatic or asymptomatic people
    Yasuharu Tokuda, MD, MPH | Muribushi Okinawa Center for Teaching Hospitals
    We read with interest the results by Lee S et al about reverse transcription–polymerase chain reaction (RT-PCR) assay from upper respiratory tract specimens (nasopharynx and oropharynx swab) and lower respiratory tract specimens (sputum) for SARS-CoV-2 in both asymptomatic and symptomatic patients.1 One of the key issues to tackle COVID-19 is how best to test, trace and isolate asymptomatic or pre-symptomatic infections. In majority of these symptomless cases, sputum is absent, but predominant mode of transmission includes talking, shouting, and singing. In these circumstances, sampling among respiratory tract specimen should be used and saliva could likely to be a choice of sampling because it can be obtained by patients themselves and it can reduce infectious risk to a sampling personnel. When we deal with infected asymptomatic or pre-symptomatic infections, assessing instant transmissibility or infectiousness should be a major purpose of testing rather than clinically diagnosing COVID-19.2,3 A clinical gold standard testing for this purpose among asymptomatic or pre-symptomatic people should continue to be RT-PCR test using samples of nasopharyngeal, oropharyngeal or saliva and viral shedding on saliva should be compared in both asymptomatic and symptomatic patients.

    Yasuharu Tokuda, MD, MPH
    Muribushi Okinawa for Teaching Hospitals, Okinawa, Japan
    Kenji Shibuya, MD, DrPH
    King’s College London, London, UK
    Taro Kondo, MD
    Kondo Clinic, Tokyo, Japan

    References

    1. Lee Sea. Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea. JAMA Internal Medicine. 2020.
    2. He X, Lau EH, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nature medicine. 2020;26(5):672-675.
    3. Larremore DB, Wilder B, Lester E, et al. Test sensitivity is secondary to frequency and turnaround time for COVID-19 surveillance. medRxiv. 2020.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    regarding study interptation
    dheer singh meena, md resident doctor | rml hospital delhi
    In this article, differential negative conversion is compared with respect to three genes in asymptomatic and symptomatic patients so which gene should be used for diagnosis?  In upper respiratory tract samples, rdrp gene has low ct value and delayed clearing in symptomatic patients. In sputum sample, env gene has low ct value in asymptomatic patients.  So what is the net interpretation of this study? Which patients recover early?
    CONFLICT OF INTEREST: None Reported
    Good in theory, Difficult to put into practice!
    Arvind Joshi, MBBS MD; FCGP FAMS FICP. | Our Own Discussion Group
    Isolating an asymptomatic person who indeed is infected with SARS-CoV-2 may be difficult, nay IMPOSSIBLE!
    Simply because there may be no way, even to guess which apperently asymptomatic person my be infected.
    It may be practically impossible to trace all the people who might have come in contact with a proven SARS-CoV-2 infected person.
    All the same I greatly appreciate and value the research, the thought, the efforts and knowledge it has generated!

    -Arvind Joshi;
    MBBS, MD; FCGP, FAMS, FICP;
    Founder Convener and President:
    Our Own Discussion Group;
    602-C, Megh Apartments; Ganesh Peth Lane Dadar West; Mumbai Maharashtra State
    INDIA; PIN 400028;
    and Consulting Physician at:
    Ruchi Diagnostic Centre/Ruchi Clinical Laboratory,
    Sector 21, Kharghar, Maharashtra State INDIA PIN 410210.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    PCR Data Reliability and Clarification
    Tae-Ho Hwang, PhD | Pusan National University
    According to Park et al. (reference 3 of this paper), CTC (community treatment center) housing was designated for out-of-hospital cohort treatment of COVID-19 infected patients with mild symptoms in Korea as a resource-saving strategy.

    In this paper, PCR assay was conducted in a population of 303 SARS-CoV-2 infected patients isolated in a CTC.  The authors suggest that addressing asymptomatic patients may be necessary to control the spread of SARS-CoV-2. However the WHO update "Transmission of COVID19 by asymptomatic cases (June 11, 2020)" states that “asymptomatically infected patients are much less likely to transmit the virus”.
    /> We raise questions regarding confirmed infection in asymptomatic patients measured by PCR in this study, focusing on figure 2 and 3. PCR assays were scheduled to be conducted on day 8, 9, 15 and 16 post-diagnosis, but there seems to be no corresponding data shown for day 8, and no positive cases in day 9 monitoring. Furthermore, under the assumption that initial isolation was determined by a preliminary PCR positive (Ct value < 40) test (laboratory-confirmed COVID-19), these baseline viral load data are also absent.
    The higher incidence of positive PCR tests appear in the time frame following the few tests on day 9 and 10, so taken with the lack of initial PCR test results in this paper, we would ask if there were any possibility for community infection, as all patients were living in the same CTC after being designated for isolation. It is notable that some patients in the same CTC had substantially high loads of SARS-CoV-2 virus (< 25 in Ct value). In addition, viral load level speculated by linear regression suggests there are values higher than Ct 40 which aren’t included in the figures. Care should be taken when PCR data is considered as a positive signal in > 35 Ct value, as reliability may be low especially in asymptomatic patients (https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.32.2001483).

    Ct value may be the only parameter to confirm SARS-CoV-2 infection in these 303 patients. Accordingly, can housing asymptomatic PCR-positive patients and other patients showing high viral load (< 25 in Ct) in the same CTC be justified?
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    August 6, 2020

    Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea

    Author Affiliations
    • 1Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea
    • 2Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
    • 3Department of Surgery, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
    • 4Department of Emergency Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
    • 5Department of Family Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
    • 6Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea
    • 7Department of Biostatistics, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
    • 8Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
    JAMA Intern Med. Published online August 6, 2020. doi:10.1001/jamainternmed.2020.3862
    Key Points

    Question  Are there viral load differences between asymptomatic and symptomatic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection?

    Findings  In this cohort study that included 303 patients with SARS-CoV-2 infection isolated in a community treatment center in the Republic of Korea, 110 (36.3%) were asymptomatic at the time of isolation and 21 of these (19.1%) developed symptoms during isolation. The cycle threshold values of reverse transcription–polymerase chain reaction for SARS-CoV-2 in asymptomatic patients were similar to those in symptomatic patients.

    Meaning  Many individuals with SARS-CoV-2 infection remained asymptomatic for a prolonged period, and viral load was similar to that in symptomatic patients; therefore, isolation of infected persons should be performed regardless of symptoms.

    Abstract

    Importance  There is limited information about the clinical course and viral load in asymptomatic patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

    Objective  To quantitatively describe SARS-CoV-2 molecular viral shedding in asymptomatic and symptomatic patients.

    Design, Setting, and Participants  A retrospective evaluation was conducted for a cohort of 303 symptomatic and asymptomatic patients with SARS-CoV-2 infection between March 6 and March 26, 2020. Participants were isolated in a community treatment center in Cheonan, Republic of Korea.

    Main Outcomes and Measures  Epidemiologic, demographic, and laboratory data were collected and analyzed. Attending health care personnel carefully identified patients’ symptoms during isolation. The decision to release an individual from isolation was based on the results of reverse transcription–polymerase chain reaction (RT-PCR) assay from upper respiratory tract specimens (nasopharynx and oropharynx swab) and lower respiratory tract specimens (sputum) for SARS-CoV-2. This testing was performed on days 8, 9, 15, and 16 of isolation. On days 10, 17, 18, and 19, RT-PCR assays from the upper or lower respiratory tract were performed at physician discretion. Cycle threshold (Ct) values in RT-PCR for SARS-CoV-2 detection were determined in both asymptomatic and symptomatic patients.

    Results  Of the 303 patients with SARS-CoV-2 infection, the median (interquartile range) age was 25 (22-36) years, and 201 (66.3%) were women. Only 12 (3.9%) patients had comorbidities (10 had hypertension, 1 had cancer, and 1 had asthma). Among the 303 patients with SARS-CoV-2 infection, 193 (63.7%) were symptomatic at the time of isolation. Of the 110 (36.3%) asymptomatic patients, 21 (19.1%) developed symptoms during isolation. The median (interquartile range) interval of time from detection of SARS-CoV-2 to symptom onset in presymptomatic patients was 15 (13-20) days. The proportions of participants with a negative conversion at day 14 and day 21 from diagnosis were 33.7% and 75.2%, respectively, in asymptomatic patients and 29.6% and 69.9%, respectively, in symptomatic patients (including presymptomatic patients). The median (SE) time from diagnosis to the first negative conversion was 17 (1.07) days for asymptomatic patients and 19.5 (0.63) days for symptomatic (including presymptomatic) patients (P = .07). The Ct values for the envelope (env) gene from lower respiratory tract specimens showed that viral loads in asymptomatic patients from diagnosis to discharge tended to decrease more slowly in the time interaction trend than those in symptomatic (including presymptomatic) patients (β = −0.065 [SE, 0.023]; P = .005).

    Conclusions and Relevance  In this cohort study of symptomatic and asymptomatic patients with SARS-CoV-2 infection who were isolated in a community treatment center in Cheonan, Republic of Korea, the Ct values in asymptomatic patients were similar to those in symptomatic patients. Isolation of asymptomatic patients may be necessary to control the spread of SARS-CoV-2.

    Introduction

    Since the first cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were detected in Wuhan, China, in December 2019,1 a total of 4 789 205 laboratory-confirmed cases and 318 789 deaths have been documented globally as of May 20, 2020.2 An explosive outbreak among a religious group in Daegu, Republic of Korea (ROK), in February 2020 led to a vigorous containment strategy, including massive testing and active contact tracing. As the number of cases surpassed the capacity of the health care system, the Ministry of Health and Welfare of Korea decided to isolate asymptomatic and pauci-symptomatic patients in community treatment centers (CTCs),3 temporary facilities. The potential for transmission from asymptomatic people has been cited as an important factor in controlling the spread of novel coronavirus disease 2019 (COVID-19),4 but there is limited information about the clinical course and viral loads of asymptomatic people with SARS-CoV-2 infection. Using an asymptomatic patient cohort in a CTC, we describe the clinical course of asymptomatic infection and quantitatively compare the molecular viral load of SARS-CoV-2 between asymptomatic and symptomatic patients.

    Methods
    Study Design and Participants

    A retrospective cohort study was conducted at a CTC in Cheonan, ROK, between March 6 and March 26, 2020. In total, 303 patients with SARS-CoV-2 infection were included from Daegu. The CTC was previously a dormitory building for public officials owned by the government. Patients with confirmed infection were isolated in solitary (92%) or shared spaces with separate rooms (8%). Health care personnel included 8 physicians, 12 nurses, and 8 nurse assistants. Physicians took charge of symptom monitoring via daily telephone calls and collection of specimens from patients. Body temperature was monitored twice daily. Patients could be seen by a physician on demand. The clean zone, where health care workers worked, was separated from the patient zone. One negative-pressure container for a portable radiograph imaging facility was located next to the entrance. The Korea Centers for Disease Control and Prevention has recommended the end of isolation after consecutive negative results 24 hours apart after 1 to 2 weeks from isolation. Reverse transcription–polymerase chain reaction (RT-PCR) assay from upper respiratory tract (URT) specimens (nasopharynx and oropharynx swab) and lower respiratory tract (LRT) specimens (sputum) for SARS-CoV-2 were tested on days 8, 9, 15, and 16 of isolation. On days 10, 17, 18, and 19, RT-PCR assays from URT or LRT samples were performed at the discretion of the physician. A negative conversion of RT-PCR assay for SARS-CoV-2 was defined as negative results from both URT and LRT specimens, and the median time of first negative conversion was calculated from the date of diagnosis. Data on demographic characteristics, comorbidities, symptoms, and signs and the results of RT-PCR assay for SARS-CoV-2 were investigated. Asymptomatic patients were defined as those with no symptoms or signs of infection with SARS-CoV-2 during the study period from the date of diagnosis. Presymptomatic patients were defined as asymptomatic from diagnosis to isolation placement with subsequent development of symptoms during observation. This study was approved by the Institutional Review Board (IRB) of Soonchunhyang University, Seoul Hospital (IRB No. 2020-04-007). The IRB waived the requirement for patient informed consent owing to the retrospective nature of the study and its impracticability. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    Specimen Collection and RT-PCR for SARS-CoV-2

    The URT specimens were collected from both nasopharyngeal and oropharyngeal swabs obtained by trained medical staffs (physicians and nurses). For LRT specimens, participants were given instructions the night before to collect a first morning sputum (after gargling) in a specimen cup; RT-PCR assays for SARS-CoV-2 were performed using Allplex 2020-nCoV assay (Seegene, Seoul, ROK) to determine the presence of virus through the identification of 3 genetic markers: envelope (env) gene, RNA-dependent RNA polymerase (RdRp) gene, and nucleocapsid protein (N) gene. The cycle threshold (Ct) during RT-PCR testing refers to when the detection of viral amplicons occurs, it is inversely correlated with the amount of RNA present. A lower Ct value indicates large quantities of viral RNA. It was considered positive when the Ct values of all genes were less than 40 cycles.

    Statistical Analyses

    Categorical variables were expressed as counts and frequencies, and continuous variables were expressed as medians and interquartile ranges (IQRs) or means and SDs or SEs. Proportions for categorical variables were compared using χ2 or Fisher exact test. Continuous variables were analyzed using the Mann-Whitney U test method. The proportions of negative conversion were estimated using survival analysis, Kaplan-Meier plot, and log-rank test to determine the difference in median time of the first negative conversion from diagnosis between asymptomatic and symptomatic (including presymptomatic) patients. To estimate marginal effects and linear time interaction by group, generalized estimating equations were used to compare appropriacy of dynamics of Ct values between asymptomatic and symptomatic (including presymptomatic) patients. All statistical analyses were performed using SPSS software, version 26.0 (IBM Corporation). Statistical significance was set as P < .05.

    Results
    Clinical Characteristics and Prognosis of Asymptomatic Patients

    As shown in the Table, the median (IQR) age of patients was 25 (22-36) years, and 201 (66.3%) were women. Only 12 (3.9%) patients had comorbidities (10 had hypertension, 1 had cancer, and 1 had asthma). The median (IQR) time from diagnosis to date of isolation was 6 (6-9) days. Of 303 enrolled patients, 110 (36.3%) were asymptomatic at the time of isolation. Of asymptomatic patients, 21 (19.1%) developed symptoms during isolation. The median (IQR) interval time from diagnosis to symptom onset in presymptomatic patients was 15 (13-20) days. The most common symptoms among 193 symptomatic patients at the time of isolation were cough (108 [56.0%]), rhinorrhea/nasal congestion (88 [45.6%]), and sputum production (53 [27.5%]), followed by sore throat (52 [26.9%]), dysosmia (20 10.4%), diarrhea (10 [5.2%]), dysgeusia (7, [3.6%]), abdominal pain (4 [2.1%]), and vomiting (1 [0.5%]). On March 10, 2020, one symptomatic patient was transferred to the hospital because of severe vomiting. From March 15 to March 16, 2020, a total of 26 asymptomatic patients and 58 symptomatic patients were released from isolation based on the results of RT-PCR from March 13, 14, and 15.

    Comparison of Ct Values of RT-PCR Assay for SARS-CoV-2 Between Asymptomatic and Symptomatic Patients

    In total, 1886 RT-PCR assays for SARS-CoV-2 were performed. There were 567 (30.1%) tests performed for asymptomatic patients and 1319 (69.9%) tests performed for symptomatic (including presymptomatic) patients. The mean (SD) number of tests was 6.4 (2.1) per person for the 89 asymptomatic patients and 6.2 (2.3) tests for the 214 symptomatic patients. According to the Kaplan-Meier plot, the proportions of participants with a negative conversion at days 14 and 21 from diagnosis were 33.7% and 75.2% in asymptomatic patients and 29.6% and 69.9% in symptomatic (including presymptomatic) patients, respectively (Figure 1). The median (SE) time from diagnosis to first negative conversion was 17 (1.07) days in asymptomatic patients and 19.5 (0.63) days in symptomatic (including presymptomatic) patients (P = .07) (Figure 1).

    The Ct value dynamics of the RdRp gene from URT specimens showed that viral loads of symptomatic (including presymptomatic) patients tended to decrease more slowly in the time interaction trend than those of asymptomatic patients (β = 0.040 [SE, 0.020]; P = .048) (Figure 2). As shown in Figure 3, the Ct value dynamics of env genes from LRT specimens showed that viral loads of asymptomatic patients tended to decrease more slowly in the time interaction trend than those of symptomatic (including presymptomatic) patients (β = −0.065 [SE, 0.023]; P = .005). There were no significant differences in Ct values of env (β = −0.012 [SE, 0.035]; P = .73) and N genes (β = 0.011 [SE, 0.016]; P = .49), from URT specimens and RdRp (β = −0.015 [SE, 0.026]; P = .57) and N genes (β = −0.006 [SE, 0.018]; P = .75), from LRT specimens between asymptomatic and symptomatic (including presymptomatic) patients.

    Discussion

    The findings demonstrate that 80.9% (95% CI, 77.2%-84.6%) of patients with SARS-CoV-2 who were asymptomatic at the time of detection of a positive RT-PCR remained asymptomatic during a median (IQR) of 24 (20-26) days from diagnosis, and the Ct values in asymptomatic patients were similar to those in symptomatic patients. A previous study in a long-term care facility showed that 56.5% of patients with SARS-CoV-2 infection were asymptomatic at the time of diagnosis, and 23.1% remained asymptomatic during 7 days.5 As mathematically estimated in Diamond Princess cruise ship patients, the proportion of asymptomatic cases was 17.9%.6 In a population-based study in Iceland, 43% of 1221 participants who tested positive were asymptomatic initially, although symptoms developed later.7 In these previous reports, presymptomatic patients were also considered asymptomatic cases because the clinical course of asymptomatic cases was not observed. In our study, asymptomatic patients who were required to be isolated in a CTC according to government policy were fully observed by health care personnel. An important implication of our findings is that there may be substantial underreporting of infected patients using the current symptom-based surveillance and screening.

    Little is known about the infectiveness of asymptomatic patients. Our findings, given a recent report of SARS-CoV-2 transmission from an asymptomatic person to 4 family members,8 nevertheless offer biological plausibility to such reports of transmission by asymptomatic people. A previous study9 analyzing a small number of patients also reported that viral load of asymptomatic SARS-CoV-2 patients was as high as that of symptomatic patients. Although the high viral load we observed in asymptomatic patients raises a distinct possibility of a risk for transmission, our study was not designed to determine this. In this study, Ct values of env genes from LRT specimens in asymptomatic patients tended to decrease more gradually than those of symptomatic patients. It appears that the env target signal was aberrant owing to fragmented or degraded genomes. The genetic material of dead viral particles remaining within epithelial cells can be detected as epithelial cells are desquamated.10 In a recent study, viral shedding from sputum has been shown to extend beyond symptom duration.11 It is important to note that detection of viral RNA does not equate infectious virus being present and transmissible. For a better understanding of the viral shedding and potential transmissibility of asymptomatic infection, large rigorous epidemiologic and experimental studies are needed.

    Limitations

    This study has limitations. First, it is possible that the asymptomatic patients in our cohort were not representative of all asymptomatic patients in the community because false negatives would not have been included in our sample. This may have been in contrast to symptomatic patients, where the false-negative rate was lower. Unfortunately, without widespread testing in the community with different methods, we have no way of knowing if this was the case. Second, we did not determine the role that molecular viral shedding played in transmission from asymptomatic patients. An epidemiologic investigation with this objective was not conducted, and we did not obtain information about the date of exposure and symptom onset prior to isolation. However, had we obtained this information, inferences would still be uncertain because of difficulty validating exposures and determining which exposure was a causal relationship. Third, our findings cannot be generalized to the entire population, because our cohort consisted of young, healthy patients. Fourth, we could not evaluate the adequacy of sputum specimens because of biosafety issues and equipment availability.

    Conclusions

    In this cohort study of symptomatic and asymptomatic patients with SARS-CoV-2 infection who were isolated in a community treatment center in Cheonan, ROK, the Ct values in asymptomatic patients were similar to those in symptomatic patients. Viral molecular shedding was prolonged. Because transmission by asymptomatic patients with SARS-CoV-2 may be a key factor in community spread, population-based surveillance and isolation of asymptomatic patients may be required.

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    Article Information

    Accepted for Publication: June 29, 2020.

    Corresponding Author: Eunjung Lee, MD, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, 59, Daesagan-ro, Yongsan-gu, Seoul 14401, Republic of Korea (shegets@schmc.ac.kr).

    Published Online: August 6, 2020. doi:10.1001/jamainternmed.2020.3862

    Author Contributions: Dr E. Lee had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs S. Lee and T. Kim are joint first authors and contributed equally to the work.

    Study concept and design: S. Lee, Tark Kim, E. Lee, H. Kim, J. Park, Choo.

    Acquisition, analysis, or interpretation of data: S. Lee, Tark Kim, E. Lee, C. Lee, Rhee, Se Yoon Park, Son, Yu, Suyeon Park, Loeb, Tae Hyong Kim.

    Drafting of the manuscript: S. Lee, Tark Kim, E. Lee, H. Kim.

    Critical revision of the manuscript for important intellectual content: S. Lee, Tark Kim, E. Lee, C. Lee, Rhee, Se Yoon Park, Son, Yu, J. Park, Choo, Suyeon Park, Loeb, Tae Hyong Kim.

    Statistical analysis: S. Lee, E. Lee, Suyeon Park.

    Obtained funding: E. Lee.

    Administrative, technical, or material support: S. Lee, E. Lee, C. Lee, H. Kim, J. Park.

    Study supervision: S. Lee, Tark Kim, E. Lee, C. Lee, Rhee, Se Yoon Park, Son, Choo, Tae Hyong Kim.

    Conflict of Interest Disclosures: Dr Loeb reported receiving grants and personal fees from Seqirus, personal fees and nonfinancial support from Sanofi, and personal fees from the World Health Organization and Pfizer outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was supported by the Soonchunhyang University Research Fund.

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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