The natural history and transmission potential of asymptomatic SARS-CoV-2 infection

Background: Little is known about the natural history of asymptomatic SARS-CoV-2 infection or its contribution to infection transmission. Methods: We conducted a prospective study at a quarantine centre for COVID-19 in Ho Chi Minh City, Vietnam. We enrolled quarantined people with RT-PCR-confirmed SARS-CoV-2 infection, collecting clinical data, travel and contact history, and saliva at enrolment and daily nasopharyngeal throat swabs (NTS) for RT-PCR testing. We compared the natural history and transmission potential of asymptomatic and symptomatic individuals. Results: Between March 10th and April 4th, 2020, 14,000 quarantined people were tested for SARS-CoV-2; 49 were positive. Of these, 30 participated in the study: 13(43%) never had symptoms and 17(57%) were symptomatic. 17(57%) participants acquired their infection outside Vietnam. Compared with symptomatic individuals, asymptomatic people were less likely to have detectable SARS-CoV-2 in NTS samples collected at enrolment (8/13 (62%) vs. 17/17 (100%) P=0.02). SARS-CoV-2 RNA was detected in 20/27 (74%) available saliva; 7/11 (64%) in the asymptomatic and 13/16 (81%) in the symptomatic group (P=0.56). Analysis of the probability of RT-PCR positivity showed asymptomatic participants had faster viral clearance than symptomatic participants (P<0.001 for difference over first 19 days). This difference was most pronounced during the first week of follow-up. Two of the asymptomatic individuals appeared to transmit the infection to up to four contacts. Conclusions: Asymptomatic SARS-CoV-2 infection is common and can be detected by analysis of saliva or NTS. NTS viral loads fall faster in asymptomatic individuals, but they appear able to transmit the virus to others.


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measured Ct values between the two groups; for this we used a random effects model. Further  This clinical study received approvals from the Institutional Review Board of the HTD and the  CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020  Between March 10 th and April 4 th , 2020, approximately 14,000 people were referred to one of 1 4 5 nine designated quarantine centres deployed across HCMC, and were screened for SARS-CoV- Of the 30 study participants, 16 were imported cases (i.e. they acquired the infection outside of study period. Of the locally acquired infections, 7 (50%) were asymptomatic; while 6 (38%) of 1 5 5 the imported cases were asymptomatic. Those with locally acquired infection were more likely 1 5 6 to be male than those with infection acquired outside of Vietnam ( Table 2).  (Table 1 and 2). A small proportion of symptomatic patients presented with diarrhea 1 6 2 and/or lost their sense of smell. None of the 30 participants had abnormal findings on chest . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020 Compared with symptomatic patients, those with asymptomatic infection were less likely to 1 6 6 have detectable SARS-CoV-2 in NTS samples collected at enrolment (8/13 (62%) vs. 17/17 1 6 7 (100%) P=0.02). However, 4/5 patients whose NTS collected at enrolment were negative had 1 6 8 an NTS positive result in one of the subsequent sampling days, but with a high Ct value Of the 30 study participants, 27 (90%) had a saliva sample collected at enrollment with 1 7 2 sufficient volume for RT-PCR analysis. SARS-CoV-2 RNA was detected in 20/27 (74%) 1 7 3 available saliva, 7/11 (64%) in the asymptomatic and 13/16 (81%) in the symptomatic group 1 7 4 (P=0.56). There was one patient, whose NTS collected at enrolment was negative but saliva At enrolment, among those who were RT-PCR positive, the viral loads measured in NTS and 1 8 0 saliva were similar in asymptomatic and symptomatic patients ( Figure 3A). However, among 1 8 1 asymptomatic patients who had both saliva and NTS collected, higher viral load was observed 1 8 2 in NTS than in saliva (P=0.031) ( Figure 3B). A similar trend was observed for symptomatic During follow-up, Ct-values differed between the two groups (P=0.027 for difference over first CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020 patients. If restricted to RT-PCR positive samples, viral RNA abundance was similar to slightly Analysis of the probability of RT-PCR positivity showed asymptomatic participants had a 1 9 0 lower probability of having a positive RT-PCR result (i.e. a faster viral clearance) than 1 9 1 symptomatic participants (P<0.001 for difference over first 19 days, Figure 4B). This  Fourteen participants were identified to have an epidemiological link with two community-1 9 7 transmission clusters occurring in HCMC during the study period. Cluster #1 had three patients 1 9 8 participating in the present study. Of these three, 2 had contact with a confirmed case on March 1 9 9 2 nd , who was not enrolled in this study because this patient was admitted to a different hospital. CoV-2 on March 14, 2020. Two days later, a colleague of these two cases developed mild 2 0 4 respiratory symptoms, including runny nose and loss of sense of smell, and tested positive for  Cluster #2 included 11 study participants, including 7 with asymptomatic infection (Figure 5).

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We identified a transmission chain involving an asymptomatic participant (patient #19) who  Subsequently, a contact of this case (patient #22) was positive for SARS-CoV-2 on March 23 rd 2 1 0 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted April 29, 2020. . 1 0 (Ct value of NTS: 23, and saliva: 34), although this contact did not develop symptoms.

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Furthermore, on March 27 th , a contact of both patient #19 and #22 (patient #27) presented with 2 1 2 cough and sore throat, with positive NTS for SARS-COV-2. Additionally, patient #26, contact 2 1 3 of patient #22, who was also a contact of patient #19, was confirmed with SARS-CoV-2 on 2 1 4 March 20 th , also without any symptoms. An additional transmission chain from cluster #2 was 2 1 5 recorded between patient #24 and #29, both of whom were asymptomatic ( Figure 5). including 170 imported cases and 100 cases acquired locally [2,19]. During the same period, 2 2 1 the number of confirmed cases worldwide increased from 582 to more than 2.7 million.

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Social distancing, school closure, isolation of confirmed cases and their contacts, and airport quarantine of large numbers of contacts has offered a unique opportunity to study the natural 2 2 6 history of SARS-CoV-2 infection, especially in those without symptoms.

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Using data from 30 patients, representing 56% of the reported case in HCMC since the 2 2 8 beginning of the epidemic, we provide important insights into the natural history of SARS- CoV-2 infection. We found that 43% of SARS-CoV-2 positive cases were asymptomatic, with . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted April 29, 2020. . 1 1 despite these data suggesting faster viral clearance from the respiratory tract, we found good 2 3 4 evidence these asymptomatic individuals transmitted the virus to others. demonstrating the utility potential of easy-to-collect saliva samples for the diagnosis of in the saliva is also consistent with the known high infectiousness of SARS-CoV-2 and its 2 4 2 ready ability to spread through droplet transmission even without respiratory symptoms.

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Although the viral loads at enrolment were similar between the asymptomatic and symptomatic infection include pre-existing cross-immunity as a consequence of previous exposure to 2 5 0 common human coronavirus, which may enhance immunity and control of the infection in  Nevertheless, despite faster viral clearance in asymptomatic individuals, we found good 2 5 3 evidence that they were still able to transmit the infection. Two of the asymptomatic 2 5 4 participants were the highly likely origin of at least 2, and possible 4 further infections.

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Transmission from asymptomatic and especially pre-symptomatic individuals has been 2 5 6 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10. 1101/2020 suggested previously [4-6, 8, 9] and may explain why the virus is so hard to control. The 2 5 7 finding supports the Vietnam approach of vigorous case-finding, quarantining, and testing and 2 5 8 suggests they are essential of the infection is to be controlled.

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The strengths of our study include the inclusion of the majority of asymptomatic and 2 6 0 symptomatic cases reported in southern Vietnam over 4 weeks, without selection bias based on 2 6 1 symptoms or disease severity. In so doing, we were able to study prospectively the full 2 6 2 spectrum of SARS-CoV-2 infection. Our study also has some limitations. We did not perform although through contact history, we identified at least two transmission events from 2 6 5 completely asymptomatic individuals. Additionally, we did not perform chest computerized 2 6 6 tomography scans [24], which are more sensitive than chest radiographs for the detection of  To summarize, we demonstrate that a high proportion (43%) of quarantined people who were 2 7 2 RT-PCR positive for SARS-CoV-2 were asymptomatic. These individuals carried SARS-CoV- for SARS-CoV-2 among isolated people in controlling the ongoing pandemic. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted April 29, 2020. . Nguyen Than Ha Quyen, for their support. Singapore for their guidance in the development of diagnostic reagents in this study.

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We thank the patients for their participations in this study and the doctors and nurses of Cu Chi Hospital, who cared for the patients and provided the logistic support with the study. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint *Extrapolated from data extracted from the HTD database system. During this period, HTD tested a total of 11,052 cases, accounting for 80% of isolated people in HCMC. **The remaining cases were either treated at the main campus of HTD in HCMC or at the other designated isolation center (Can Gio Hospital).

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One was transferred to the main campus of HTD 10 hours after admission and two were transferred from the main campus of HTD after 5 and 6 days of hospitalization and were not enrolled because of enrolment competition. Maps were obtained from https://mapchart.net/. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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