Real Asymptomatic SARS-CoV-2 Infection Might Be Rare: Importance of Careful Interviews and Follow-up

Study design

This retrospective case series was conducted at UUH, the largest teaching hospital in Ulsan.

Study patients

All patients were Korean residents of Ulsan and were diagnosed with COVID-19 by real-time reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2. Among the 40 patients, 38 were confirmed at 10 screening centers in Ulsan and 2 at 2 screening centers in other cities and referred by the respective centers. The screening test for SARS-CoV2 was obligatory for families or those in close contacts with confirmed COVID-19 patients in Korea. Patients were admitted to UUH between February 22, 2020, and March 26, 2020. Clinical outcomes were monitored until May 19, 2020, the date when the last patient was discharged.

Data sources and variables

Demographic, clinical, and laboratory variables were collected from the clinical data warehouse platform in conjunction with the electronic medical records at the UUH Information of Clinical Ecosystem, and the authors manually reviewed these medical records. Additionally, we referred to epidemiological and clinical data identified by a preventive medicine specialist who interviewed the patients at the UUH and another source of epidemiological data for Ulsan. Transfers from UUH to a local hospital were merged and considered a single visit. Regarding patients who were readmitted during the study period, data from the first admission were considered. Data were collected on demographic characteristics (age, sex, occupation, education, and religion), epidemiological information, triage vitals (blood pressure, heart rate, temperature, respiratory rate, and peripheral oxygen saturation), comorbidities (hypertension, diabetes, dyslipidemia, cardiovascular disease, cancer, and hepatitis B infection), history of clinical signs and symptoms, laboratory and radiologic findings, medications (antiviral therapy and antimalarial therapy), treatments (continuous renal replacement therapy and invasive mechanical ventilation), outcomes (discharge, readmission, and mortality), and main durations (incubation period, symptom onset to hospital admission, viral shedding, and hospital stay). We calculated the Modified Early Warning Score (MEWS)8, 9 and CURB-6510, 11, 12 pneumonia severity score. MEWS is based on systolic blood pressure, heart rate, respiratory rate, temperature, and consciousness, whereas CURB-65 is based on confusion, urea levels, respiratory rate, blood pressure, and ≥ 65 years. Fever was defined as a temperature of ≥ 37.5°C or subjective fever before admission and a temperature of ≥ 37.5°C in axillary measurements obtained after admission. Laboratory and radiologic findings were considered from the first test results available, typically within 24 hours of admission. When all symptoms and signs, radiologic findings, and laboratory findings of COVID-19 subsided and two consecutive negative results for SARS-CoV-2 infection were reported, the patient was considered recovered from COVID-19 and was discharged. If a patient had persistent positive SARS-CoV-2 test results and the other parameters were normalized, the patient was referred to a local hospital specified for Ulsan and hospitalized until negative results were obtained in two consecutive SARS-CoV-2 tests.

Real-time RT-PCR for SARS-CoV-2

During hospitalization, respiratory tract specimens including sputum and nasopharyngeal or oropharyngeal swab samples were collected to detect SARS-CoV-2 on different dates. After viral RNA extraction with the NX-48 viral nucleic acid extraction kit (Genolution, Seoul, Korea) in conjunction with Nextractor NX-48 (Genolution), real-time RT-PCR was performed using the PowerChek™ 2019-nCoV Real-Time PCR Kit (KogeneBiotech, Seoul, Korea) with the Bio-Rad CFX96 Deep Well Real-Time PCR Detection System (Bio-Rad, Hercules, CA, USA). This assay targets two genes (E: for Sarbecovirus screening and RdRp for confirmation of SARS-CoV-2), as suggested by the Korea Centers for Disease Control and Prevention and WHO.13

Symptoms and signs

We created a list of symptoms from previous COVID-19 studies.4, 5, 6, 14, 15 Patients were classified as symptomatic if they had fever, cough, sputum production, sore throat, myalgia, headache, chills, rhinorrhea or nasal congestion, chest discomfort, shortness of breath, fatigue, anorexia, diarrhea, nausea or vomiting, or dry mouth for the duration from suspected exposure to SARS-CoV-2 to hospital admission. Presymptomatic patients were defined as those who had no symptoms before admission but developed symptoms during admission. Asymptomatic patients were those who had no symptoms at any time for the duration from suspected exposure to SARS-CoV-2 to hospital discharge.

Main durations

The incubation period was estimated based on the date of estimated exposure to SARS-CoV-2 to the date of symptom onset. Patients who were asymptomatic or symptomatic without the exact dates of exposure to SARS-CoV-2 or symptom onset known were excluded from this analysis. The duration from symptom onset to hospital admission was analyzed in symptomatic patients. Patients who were asymptomatic, presymptomatic, or symptomatic without the exact date of symptom onset known were excluded. To estimate the duration of viral shedding, we defined the date of nucleic acid conversion as the median of the date of the last positive real-time RT-PCR test result and the date of the first negative real-time RT-PCR test because real-time RT-PCR was not performed daily. The test intervals ranged from 1 to 7 days according to patient conditions. Therefore, the duration of viral shedding was calculated by subtracting the date of symptom onset from the median of the date of the last positive real-time RT-PCR test result and the date of the first negative real-time RT-PCR test result. Patients who were asymptomatic or symptomatic without the exact date of symptom onset known were also excluded. Duration of hospital stay was calculated by subtracting the date of admission from the date of discharge. Concerning patients who were readmitted, the durations of viral shedding and hospital stay were defined according to the real-time RT-PCR result at the first admission.

Statistical analysis

The study subjects were grouped by whether supplemental oxygen was required. We present continuous variables as median and interquartile range (IQR) and categorical variables as counts (%). The medians of continuous variables were compared using the Mann–Whitney U test. Proportions for categorical variables were compared using Fisher's exact test. We used Stata (version 13; StataCorp, College Station, TX, USA) for these analyses. For unadjusted comparisons, a two-sided α-value of < 0.05 was considered statistically significant. These analyses were not adjusted for multiple comparisons; given the potential for type I error, the findings should be interpreted as exploratory and descriptive.

Ethics statement

The UUH Institutional Review Board (IRB) approved this study as minimal-risk research because it used data collected for routine clinical practice and waived the requirement for informed consent (IRB File No. 2020-03-030).

Signs and symptoms

Table 2 and the Fig. 1 summarize patient signs and symptoms. Among the 40 patients, 33 (83%) were symptomatic, 5 (13%) were presymptomatic, and 2 (5%) were asymptomatic. The most common symptoms were cough (68%) and fever (55%). Sputum production, sore throat, headache, chills, chest discomfort, shortness of breath, fatigue, anorexia, dizziness, and dry mouth existed with cough or fever. Conversely, myalgia, rhinorrhea or nasal congestion, or diarrhea was the only symptom in five patients. Sputum production and chest discomfort were more common in patients requiring supplemental oxygen than in those not requiring supplemental oxygen (83% vs. 32% for sputum production and 50% vs. 3% for chest discomfort, respectively). More symptoms were present in patients requiring supplemental oxygen than in those not requiring supplement oxygen (7 [IQR, 3–7] vs. 3 [IQR, 1–5]).

Table 2
Patient symptoms for the entire duration from suspected exposure to SARS-CoV-2 to hospital discharge

• Click for larger image
• Click for full table
• Download as Excel file

Fig. 1
Symptoms of the 40 COVID-19 patients.
COVID-19 = coronavirus disease 2019, F = female, M = male.

• Click for larger image
• Download as PowerPoint slide

Laboratory and radiologic findings

Abnormal procalcitonin and C-reactive protein (CRP) levels were more commonly observed in patients requiring supplemental oxygen than in those not requiring supplemental oxygen (Table 3). The patient who died had the highest procalcitonin and CRP levels. Six (15%) patients had abnormal findings on chest X-ray or computed tomography, and patients requiring supplemental oxygen were more likely to have abnormal findings than those not requiring supplemental oxygen (5/6 [83%] vs. 1/34 [3%]).

Table 3
Laboratory and radiologic findings of the COVID-19 patients upon hospital admission

• Click for larger image
• Click for full table
• Download as Excel file

Treatments and clinical outcomes

Treatments and clinical outcomes of the 40 patients are summarized in Table 4. Thirty-nine (98%) patients (i.e., all except one pregnant female) received antiviral therapy (lopinavir/ritonavir). Further, eight (20%) patients received antimalarial therapy (hydroxychloroquine). Patients requiring supplemental oxygen were more likely to receive antimalarial therapy than those not requiring supplemental oxygen (4/6 [67%] vs. 2/34 [6%]). One patient received continuous renal replacement therapy and invasive mechanical ventilation but eventually died. Among the 40 patients, 39 were discharged after recovery and 1 died, corresponding to a mortality rate of 3% (1/40). Four patients (10%) were readmitted during the study period after receiving positive real-time RT-PCR test results again, including two patients with mild symptoms and two asymptomatic patients. The median duration from discharge to readmission was 25 days (IQR, 12–35).

Table 4
Treatment and clinical outcomes of the COVID-19 patients

• Click for larger image
• Click for full table
• Download as Excel file

The main durations related to COVID-19 are shown in Table 5. The median incubation period was 5 days (IQR, 4–6) for 25 patients in whom the exact dates of exposure to SARS-CoV-2 and symptom onset were known. The baseline characteristics of the two patient groups (included vs. excluded) evaluated for the estimation of the incubation period are shown in Supplementary Table 1. No imported patients knew the exact date of exposure to SARS-CoV-2 and thus were excluded from the estimation of incubation period.

Table 5
Main durations of COVID-19

• Click for larger image
• Click for full table
• Download as Excel file

The median duration from symptom onset to hospital admission was 5 days (IQR, 2–8). The median duration from symptom onset to undergoing PCR test was 3 days (IQR, 1–7) and that to obtaining PCR result was 1 day (IQR, 0–1) (Supplementary Table 2). Thirty-nine (98%) patients were admitted to the hospital within 1 day after receiving positive real-time RT-PCR results. The median duration of viral shedding was 21 days (IQR, 14–28), with the maximum duration being 51 days. The median duration of hospital stay was 22 days (IQR, 16–27).