key: cord-261405-n05wjimk
authors: Lui, Grace; Ling, Lowell; Lai, Christopher KC; Tso, Eugene YK; Fung, Kitty SC; Chan, Veronica; Ho, Tracy HY; Luk, Fion; Chen, Zigui; Ng, Joyce KC; Chow, Kai-ming; Cheng, Peter KC; Chan, Rickjason CW; Tsang, Dominic NC; Gomersall, Charles; Hui, David SC; Chan, Paul KS
title: Viral dynamics of SARS-CoV-2 across a spectrum of disease severity in COVID-19
date: 2020-04-18
journal: J Infect
DOI: 10.1016/j.jinf.2020.04.014
sha: 
doc_id: 261405
cord_uid: n05wjimk

nan

Dear Editor, Fang et al. reported in this journal that viral shedding of SARS-CoV-2 in nasal swabs was longer in intensive care unit (ICU) patients compared with non-ICU patients with Coronavirus Disease 2019 (COVID-19). 1 COVID-19 encompasses a heterogeneous spectrum of illness, ranging from asymptomatic and mild infections, to severely ill cases in 4-16%. 2, 3 Here, we report the findings of a prospective cohort study to determine viral dynamics of SARS-CoV-2 in mild to critical severity of illness, and the temporal viral burden at different body sites.

We included the first eleven laboratory-confirmed COVID-19 patients hospitalized in two hospitals in Hong Kong in February 2020. Disease severity was categorized as previously defined. 3 We collected serial upper (pooled nasopharyngeal and throat swabs, N=75) and lower respiratory tract samples (sputum and tracheal aspirate, N=43), peripheral blood plasma (N=50), urine (N=43) and stool (N=43) samples from all participants, and monitored SARS-CoV-2 viral loads in these samples. 4

One participant had mild, 5 moderate, 3 severe, and 2 critical disease. All patients were discharged; no one died. Their clinical and epidemiological features are shown in Table 1. Viral loads for each sample   are shown in Supplementary Table 1. Nine participants, including 4 participants with mild-moderate disease, had viral shedding lasting longer than 14 days in the respiratory tract. In four (36%) participants, return to PCR positivity in the respiratory tract was observed after ≥1 negative test, without worsening of symptoms. In patient A, PCR positivity occurred in upper and lower respiratory tract samples after a 7-day "apparent clearance" where 3 upper and 3 lower respiratory samples were negative (Figure) .

2 Viral loads in respiratory tract samples did not correlate with disease severity. However, the timing of peak viral burden differed between participants with different severity. In all five participants with severe/critical and three with moderate disease, viral loads in respiratory tract samples continued to rise and peaked in the second week of illness (range 5.57-9.66 log copies/mL). In the remaining three with mild/moderate disease, viral load peaked in the first week of illness (range 3.25-6.40 log copies/mL) Table 2 ), but did not differ between mild-moderate and severe-critical diseases.

SARS-CoV-2 was not detected in any of the 43 urine samples. In particular, all 8 urine samples from patient B were negative despite the need for renal replacement therapy for acute kidney injury. His renal biopsy showed features of acute tubular injury; electron microscopy did not reveal viral particles in proximal tubules.

One patient with moderate and one with critical disease had transient viremia, lasting 1 and 5 days, with peak viral loads 4.00 and 3.65 log copies/mL respectively.

In this study of patients with COVID-19 across a wide spectrum of severity, we observed that viral shedding in the respiratory tract lasting longer than 14 days was common. Viral load peaked later in the second week of illness in more severe disease. Extrapulmonary detection of RT-PCR positivity other than the gut was uncommon.

We observe two patterns of viral dynamics trajectory in the respiratory tract. In more severe disease, viral load appeared to peak in the second week of illness in both upper and lower respiratory tract. A more heterogeneous pattern was seen in milder disease. Time to dyspnoea and intensive care was around 8-10 days after illness onset. 5 Therefore, continued viral replication in the respiratory tract, correlated with this timing of clinical deterioration, as observed in other studies. 6, 7 This observation implied that antiviral therapy, rather than immunomodulatory agents, might be more effective as treatment for severe disease. 7 Viral load was significantly higher and peaked later in lower than upper respiratory tract samples. In severe/critical disease, monitoring should be performed using lower respiratory tract samples. Firstly, viral shedding was more prolonged in lower than upper respiratory tract samples, thus serves as better guidance for the duration of infection prevention measures. 8 Secondly, viral loads in lower respiratory tract better reflected the temporal course of clinical progression in severe disease than upper respiratory tract samples. 6, 9 All patients demonstrated stool RT-PCR positivity at some stage of their disease, regardless of gastrointestinal symptoms. While other series had positivity rates of around 50%, 6, 9, 10 repeated testing in our study allowed detection of transient positivity lasting 1-2 days. There is widespread presence of ACE2 as cellular receptors and viral particles in epithelial cells along different parts of the gastrointestinal tract. 10 While the clinical role of testing SARS-CoV-2 from stool as monitoring or 4 discharge criteria remains uncertain, stool as an additional specimen to assist diagnosis, particularly in asymptomatic contacts of confirmed patients, is worth exploring.

Our study was limited by the small sample size. Asymptomatic patients were not studied, and the effect of antiviral therapy could not be determined. Viral dynamics at different sites should be further explored in larger populations of COVID-19 patients.

In conclusion, viral shedding in respiratory tract lasting longer than 14 days was common in all spectrum of COVID-19 severity. Clinical deterioration correlated temporally with viral replication in severe disease, especially in the lower respiratory tract, highlighting the importance of effective antiviral therapy.

Extrapulmonary detection of SARS-CoV-2 PCR other than the gut was uncommon. Death 0 (0%) 0 (0%) 0 (0%)

Comparisons of nucleic acid conversion time of SARS-CoV-2 of different samples in ICU and non-ICU patients

China Medical Treatment Expert Group for C. Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical Characteristics of Imported Cases of COVID-19 in Jiangsu Province: A Multicenter Descriptive Study

2019-Novel coronavirus (2019-nCoV) real-time rRT-PCR panel primers and probes

Clinical features of patients infected with 2019 novel coronavirus in

Viral load of SARS-CoV-2 in clinical samples. The Lancet Infectious diseases

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Duration of quarantine in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a question needing an answer

Singapore Novel Coronavirus Outbreak Research T. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore

Evidence for gastrointestinal infection of SARS-CoV-2

We would like to thank Ms Iris Wong, Ms Rity Wong and Ms Vickie Li for their clerical support in the preparation of the manuscript.

This research did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors.
