Viable SARS-CoV-2 shedding under remdesivir and dexamethasone treatment.

Dear Editor,

In a recent systemic literature review, Walsh et al. reported that viral load of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) peaks around symptom onset, and becomes undetectable about two weeks after symptom onset. However, some studies have revealed that infectious SARS-CoV-2 shedding was detectable up to 20 days of symptom onset. , In patients with severe coronavirus disease 2019 (COVID-19), the duration of SARS-CoV-2 shedding is an issue in infection control and isolation strategies. The current standard treatment (remdesivir and dexamethasone) might influence the duration of infectious viral shedding. However, there have been scarce studies which investigated the duration of viable virus shedding in severe COVID-19 patients, who received anti-inflammatory and antiviral therapy with dexamethasone and remdesivir.

This study analyzed the duration of viable virus shedding in COVID-19 intensive care units of two university hospitals from March 1 to December 31, 2021. We enrolled hospitalized patients with COVID-19 pneumonia who required high-flow oxygen therapy or had a high probability of progression to severe disease due to underlying medical conditions. COVID-19 severity was classified using an ordinal scale proposed by the World Health Organization. Paired nasopharyngeal swab samples were collected on the day of enrollment and every other day after that. Real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and plaque assays were conducted to detect viable SARS-CoV-2 using the cell culture method (supplementary appendix). In addition, the SARS-CoV-2 rapid antigen test, STANDARDTM Q COVID-19 Ag Test (SD Biosensor, Inc.) was used to evaluate the association between the results of the rapid kit and infectious virus shedding. Serum samples were collected on 7th and 14th day after symptom onset to detect the anti-S immunoglobulin G antibody levels using the Elecsys® Anti-SARS-CoV-2 S assay (Roche, Rotkreuz, Switzerland). The study protocol was approved by the Institutional Review Boards of Korea University Guro Hospital (2021GR0096) and Ajou University Hospital (AJIRB-BMR-SMP-21-030). Informed consent was obtained from the patients or their immediate family members.

Among the 48 enrolled patients with COVID-19 pneumonia, 50% (n = 24) were men with a median age of 60 years, while 20 patients (41.7%) had comorbidities (Table 1 ). High-flow oxygen therapy was required in 85.4% of the patients (n = 41). Mechanical ventilation was required in 31.3% of the patients (n = 15), while 16.7% (n = 8) were supported by extracorporeal membrane oxygenation. Eight patients died during hospitalization. All patients received more than 6 mg/day of dexamethasone, and 46 patients (95.8%) were treated with remdesivir for five days or more. Among the 160 nasopharyngeal specimens, 17 yielded a positive culture result from days 3 to 18 after symptom onset (Fig. 1 A). Infectious virus samples were not detected after the third dose of remdesivir (200 mg intravenously (IV) on day 1, then 100 mg IV daily from day 2) despite high-dose dexamethasone treatment (Fig. 1B). Rapid antigen test (RAT) was positive in 80% (4/5) of culture-positive samples and in 15.6% (10/64) of culture-negative samples (Fig. S1). The positive and negative predictive values of RAT for detecting viable viruses were 28.6% and 98.2%, respectively. The geometric mean titer of immunoglobulin-G anti-S antibody on days 7 and 14 after symptom onset were 28.6 U/mL and 217.8 U/mL, respectively (Fig. S2).

Table 1

Clinical characteristics and treatment outcomes of patients with COVID-19 pneumonia.

Clinical characteristics and treatment outcomes (N=48)	No. (%)
Sex (men), n (%)	24 (50.0%)
Age, median (IQR)	63 (51-71)
Length of hospital stay, mean days (SD)	20.2 (11.5)
Underlying disease, n (%)	20 (41.7%)
Diabetes, n (%)	15 (31.3%)
Cardiovascular diseases, n (%)	4 (8.3%)
Solid cancer, n (%)	3 (6.3%)
COVID-19 vaccination (any dose), n (%)	12 (25.0%)
WHO COVID-19 ordinal scale at enrollment, n (%)
Score 4, Oxygen by mask or nasal prongs, n (%)	7 (14.6%)
Score 5, Non-invasive ventilation or high-flow oxygen, n (%)	39 (81.3%)
Score 6, Intubation and mechanical ventilation, n (%)	2 (4.2%)
Mechanical ventilation, n (%)	15 (31.3%)
ECMO, n (%)	8 (16.7%)
Death, n (%)	8 (16.7%)
Dexamethasone treatment, n (%)	48 (100%)
Dexamethasone dose
6-10 mg/day, n (%)	42 (87.5%)
>10 mg/day, n (%)	6 (12.5%)
Dexamethasone treatment duration
1-10 days, n (%)	21 (43.8%)
11-20 days, n (%)	19 (39.6%)
>20 days, n (%)	8 (16.7%)
Remdesivir treatment, n (%)	46 (95.8%)
Duration of remdesivir treatment, mean days (SD)	5.5 (1.5)
Interval from symptom onset to remdesivir treatment, mean days (SD)	6.2 (3.3)
†Monoclonal antibody treatment, n (%)	1 (2.1%)

Abbreviations; IQR, interquartile range; SD, standard deviation; COVID-19, coronavirus disease 2019; WHO, World Health Organization; ECMO, extracorporeal membrane oxygenation

Regdanvimab (RegkironaTM), manufactured by Celltrion, Inc.

Fig. 1

Correlation between viable severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) shedding and cycle-threshold (Ct) values according to time from symptom onset (A) and start of remdesivir treatment (B).

Based on a clinical trial, the cycle threshold (Ct) value of RT-PCR was not significantly reduced by remdesivir. However, this study showed that SARS-CoV-2 shedding significantly decreased after remdesivir treatment, regardless of the Ct value. Early de-isolation can be done after remdesivir treatment, even in patients with severe COVID-19. RAT is a viable adjunctive tool that guides the decision to terminate the isolation period.

Financial support

This work was supported by the National Research Foundation of Korea [grant number NRF-2021R1I1A1A01050952].

CRediT authorship contribution statement

Jin Gu Yoon: Formal analysis, Writing – original draft, Conceptualization, Visualization, Writing – review & editing. Jin Sae Yoo: Conceptualization, Visualization, Writing – review & editing. Jungmin Lee: Conceptualization, Visualization, Writing – review & editing. Hak-Jun Hyun: Conceptualization, Visualization, Writing – review & editing. Hye Seong: Conceptualization, Visualization, Writing – review & editing. Ji Yun Noh: Conceptualization, Visualization, Writing – review & editing. Hee Jin Cheong: Conceptualization, Visualization, Writing – review & editing. Woo Joo Kim: Conceptualization, Visualization, Writing – review & editing. Young Rong Kim: Conceptualization, Visualization, Writing – review & editing. Jung Yeon Heo: Conceptualization, Visualization, Writing – review & editing. Joon-Yong Bae: Conceptualization, Visualization, Writing – review & editing. Chunguang Cui: Conceptualization, Visualization, Writing – review & editing. Sohyun Lee: Conceptualization, Visualization, Writing – review & editing. Man-Seong Park: Formal analysis, Writing – original draft, Conceptualization, Visualization, Writing – review & editing. Joon Young Song: Formal analysis, Writing – original draft, Conceptualization, Visualization, Writing – review & editing.

Declaration of Competing Interest

The authors declare no conflicts of interest.