ArticlePublisher preview available

Temporal dynamics in viral shedding and transmissibility of COVID-19

May 2020
Nature Medicine 26(5)

DOI:10.1038/s41591-020-0869-5

Authors:

Eric H Y Lau

The University of Hong Kong

Peng Wu

The University of Hong Kong

Show all 23 authorsHide

We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector–infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25–69%) of secondary cases were infected during the index cases’ presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission. Presymptomatic transmission of SARS-CoV-2 is estimated to account for a substantial proportion of COVID-19 cases.

Inferred infectiousness profile Infectiousness was assumed to start from 1 days (top left) to 7 days (bottom right) before symptom onset.

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Simulated serial intervals Simulated serial intervals assuming infectiousness started on the same day of symptom onset (top panel) and from 2 days before symptom onset (bottom panel) to about 10 days after symptom onset. Both scenarios assumed that infectiousness peaked on the first day of symptom onset.

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Simulated proportions of negative serial intervals Simulated proportions of negative serial intervals assuming start of infectiousness and peak infectiousness from 7 days before symptom onset to 3 days after symptom onset. From the estimated serial interval distribution based on infector-infectee pairs, 7.6% of the serial intervals were negative. Gray area represents the implausible range where the peak infectious is earlier than the start of infectiousness.

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Transmission of infectious diseases a, Schematic of the relation between different time periods in the transmission of infectious disease. b, Human-to-human transmission pairs of SAR-CoV-2 virus (N = 77). We assumed a maximum exposure window of 21 days prior to symptom onset of the secondary cases. Detailed information on the transmission pairs and the source of information is summarized in Supplementary Tables 2 and 3. c, Estimated serial interval distribution (top), inferred infectiousness profile (middle) and assumed incubation period (bottom) of COVID-19.

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Temporal patterns of viral shedding Viral load (threshold cycle (Ct) values) detected by RT–PCR (PCR with reverse transcription) in throat swabs from patients infected with SARS-CoV-2 (N = 94), overall and stratified by disease severity, sex, age group and link to Hubei province. The detection limit was Ct = 40, which was used to indicate negative samples. The thick lines show the trend in viral load, using smoothing splines. We added some noise to the data points to avoid overlaps.

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Brief CommuniCation

https://doi.org/10.1038/s41591-020-0869-5

1Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, China. 2World Health Organization Collaborating Centre for Infectious

Disease Epidemiology and Control, School of Public Health, University of Hong Kong, Hong Kong, SAR, China. 3These authors contributed equally: Xi He,

Eric H. Y. Lau. 4These authors jointly supervised this work: Benjamin J. Cowling, Fang Li, Gabriel M. Leung. ✉e-mail: ehylau@hku.hk

We report temporal patterns of viral shedding in 94 patients

with laboratory-confirmed COVID-19 and modeled COVID-19

infectiousness profiles from a separate sample of 77 infec-

tor–infectee transmission pairs. We observed the highest

viral load in throat swabs at the time of symptom onset, and

inferred that infectiousness peaked on or before symptom

onset. We estimated that 44% (95% confidence interval,

30–57%) of secondary cases were infected during the index

cases’ presymptomatic stage, in settings with substan-

tial household clustering, active case finding and quaran-

tine outside the home. Disease control measures should be

adjusted to account for probable substantial presymptomatic

transmission.

SARS-CoV-2, the causative agent of COVID-19, spreads effi-

ciently, with a basic reproductive number of 2.2 to 2.5 determined

in Wuhan1,2. The effectiveness of control measures depends on sev-

eral key epidemiological parameters (Fig. 1a), including the serial

interval (duration between symptom onsets of successive cases in

a transmission chain) and the incubation period (time between

infection and onset of symptoms). Variation between individuals

and transmission chains is summarized by the incubation period

distribution and the serial interval distribution, respectively. If the

observed mean serial interval is shorter than the observed mean

incubation period, this indicates that a significant portion of trans-

mission may have occurred before infected persons have developed

symptoms. Significant presymptomatic transmission would prob-

ably reduce the effectiveness of control measures that are initiated

by symptom onset, such as isolation, contact tracing and enhanced

hygiene or use of face masks for symptomatic persons.

SARS (severe acute respiratory syndrome) was notable, because

infectiousness increased around 7–10 days after symptom onset3,4.

Onward transmission can be substantially reduced by contain-

ment measures such as isolation and quarantine (Fig. 1a)5. In con-

trast, influenza is characterized by increased infectiousness shortly

around or even before symptom onset6.

In this study, we compared clinical data on virus shedding with

separate epidemiologic data on incubation periods and serial inter-

vals between cases in transmission chains, to draw inferences on

infectiousness profiles.

Among 94 patients with laboratory-confirmed COVID-19

admitted to Guangzhou Eighth People’s Hospital, 47/94 (50%) were

male, the median age was 47 years and 61/93 (66%) were moderately

ill (with fever and/or respiratory symptoms and radiographic evi-

dence of pneumonia), but none were classified as ‘severe’ or ‘critical’

on hospital admission (Supplementary Table 1).

A total of 414 throat swabs were collected from these 94 patients,

from symptom onset up to 32 days after onset. We detected high

viral loads soon after symptom onset, which then gradually

decreased towards the detection limit at about day 21. There was no

obvious difference in viral loads across sex, age groups and disease

severity (Fig. 2).

Separately, based on 77 transmission pairs obtained from pub-

licly available sources within and outside mainland China (Fig. 1b

and Supplementary Table 2), the serial interval was estimated to have

a mean of 5.8 days (95% confidence interval (CI), 4.8–6.8 days) and

a median of 5.2 days (95% CI, 4.1–6.4 days) based on a fitted gamma

distribution, with 7.6% negative serial intervals (Fig. 1c). Assuming

an incubation period distribution of mean 5.2 days from a separate

study of early COVID-19 cases1, we inferred that infectiousness

started from 12.3 days (95% CI, 5.9–17.0 days) before symptom onset

and peaked at symptom onset (95% CI, –0.9–0.9 days) (Fig. 1c). We

further observed that only <0.1% of transmission would occur before

7 days, 1% of transmission would occur before 5 days and 9% of

transmission would occur before 3 days prior to symptom onset. The

estimated proportion of presymptomatic transmission (area under

the curve) was 44% (95% CI, 30–57%). Infectiousness was estimated

to decline quickly within 7 days. Viral load data were not used in the

estimation but showed a similar monotonic decreasing pattern.

In sensitivity analysis, using the same estimating procedure but

holding constant the start of infectiousness from 5, 8 and 11 days

before symptom onset, infectiousness was shown to peak at 2 days

before to 1 day after symptom onset, and the proportion of pres-

ymptomatic transmission ranged from 37% to 48% (Extended Data

Fig. 1).

Finally, simulation showed that the proportion of short serial

intervals (for example, <2 days) would be larger if infectiousness

were assumed to start before symptom onset (Extended Data Fig. 2).

Given the 7.6% negative serial intervals estimated from the infec-

tor–infectee paired data, start of infectiousness at least 2 days before

onset and peak infectiousness at 2 days before to 1 day after onset

would be most consistent with this observed proportion (Extended

Data Fig. 3).

Here, we used detailed information on the timing of symptom

onsets in transmission pairs to infer the infectiousness profile of

Temporal dynamics in viral shedding and

transmissibility of COVID-19

Xi He1,3, Eric H. Y. Lau 2,3 ✉ , Peng Wu2, Xilong Deng1, Jian Wang1, Xinxin Hao2, Yiu Chung Lau2,

Jessica Y. Wong2, Yujuan Guan1, Xinghua Tan1, Xiaoneng Mo1, Yanqing Chen1, Baolin Liao1,

Weilie Chen1, Fengyu Hu1, Qing Zhang1, Mingqiu Zhong1, Yanrong Wu1, Lingzhai Zhao1,

Fuchun Zhang1, Benjamin J. Cowling 2,4, Fang Li1,4 and Gabriel M. Leung 2,4

NATURE MEDICINE | VOL 26 | MAY 2020 | 672–675 | www.nature.com/naturemedicine

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Background Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses. Methods We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection. Findings Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37–75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log10 copies per mL (IQR 4·1–7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope −0·15, 95% CI −0·19 to −0·11; R²=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074–0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R²>0·9). No genome mutations were detected on serial samples. Interpretation Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for high-risk individuals. Serological assay can complement RT-qPCR for diagnosis. Funding Richard and Carol Yu, May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, and Sanming Project of Medicine.

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Mar 2020

Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/L (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/L could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

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