Asymptomatic infection and atypical manifestations of COVID-19: Comparison of viral shedding duration.

Dear Editor,

Coronavirus disease 2019 (COVID-19) bears several challenging problems, including insidious symptom onset, subclinical manifestations and highly transmissible property during early stage of infection. In the recent study by Huang et al., SARS-CoV-2-infection presented strong infectivity during the incubation period with rapid transmission. Some patients with COVID-19 are asymptomatic, while others complain of atypical symptoms including loss of smell and taste sense. However, there is insufficient data on the prevalence of asymptomatic infection and atypical manifestations of COVID-19. In this study, we aimed to evaluate the prevalence of asymptomatic infection, anosmia (smell loss) and ageusia (taste loss) among patients with mild COVID-19 in a residential treatment center (RTC). We also compared the duration of SARS-CoV-2 viral shedding between groups with different clinical manifestations.

An observational cohort study was conducted for 199 patients with COVID-19 in a RTC at Gyeongju, Gyeongsangbuk province, Republic of Korea (ROK). The RTC was introduced to care patients with mild COVID-19 for the efficient distribution of limited medical resources during large epidemic in early March 2020. Data on demographic findings, symptoms, and duration of viral shedding were collected. The patients were interviewed about initial symptoms and their duration in detail. Real-time PCR (RT-PCR) to detect SARS-CoV-2 was performed every 2–7 days. Duration of viral shedding was considered as time from diagnosis date to the day before first negative conversion of two consecutive negative results of RT-PCR. RT-PCR was conducted using Allplex 2019-nCoV assay (Seegene, Seoul, South Korea). Statistical analyses were performed using SPSS 20.0 program. Mann-Whitney U test was performed to compare the duration of viral shedding between groups with different clinical manifestations. P-value < 0.05 was considered statistically significant. This study was approved by the Institutional Review Board of Korea University Guro Hospital (approval number: 2020GR0135).

Among 199 patients with COVID-19, male was 34.7% and mean age of the patients was 38.0 years (Table 1 ). Most patients (187, 94.0%) were healthy without chronic medical conditions. Among 199 patients, 26.6% were asymptomatic. In the early study, asymptomatic cases accounted for 10.7% (3/28) of COVID-19 cases in the ROK. Asymptomatic proportion of COVID-19 was estimated as 17.9% (95% credible interval, 15.5–20.2%) on the Diamond Princess cruise ship, Japan. Among clinical manifestations, cough (41.2%) was most common, followed by rhinorrhea and nasal stuffiness (30.2%). Of note, 26.1% (52/199) of patients presented anosmia, and 22.6% (45/199) complained of ageusia. Thirty-eight (19.1%) patients complained of both anosmia and ageusia. Duration of anosmia and ageusia ranged 2–28 days (median, 7 days) and 3 - 28 days (median, 7 days), respectively. Recently, substantial number of patients with COVID-19 were reported globally to have developed anosmia or hyposmia. , Among 59 hospitalized patients with COVID-19, 33.9% reported olfactory or taste disorder in Italy. This is consistent with current observations: among 146 symptomatic patients, 35.6% developed anosmia and 30.8% had ageusia in this study.

Table 1

Demographic and clinical characteristics of the patients with COVID-19 in a residential treatment center (n = 199).

Variable	Value
Sex - male, n (%)	69 (34.7)
Age, mean ± SD	38.0 ± 13.1
Chronic medical conditions	12 (6.0)
Diabetes mellitus	5 (2.5)
Hypertension	7 (3.5)
Cerebral infarction	2 (1.0)
Others*	2 (1.0)
Asymptomatic infection	53 (26.6)
Symptoms
Fever	38 (19.1)
Myalgia	34 (17.1)
Headache	7 (3.5)
Fatigue	8 (4.0)
Cough	82 (41.2)
Sputum	41 (20.6)
Sore throat	15 (7.5)
Rhinorrhea/nasal stuffiness	60 (30.2)
Anosmia	52 (26.1)
Duration, mean ± SD	8.4 ± 6.0
Ageusia	45 (22.6)
Duration, mean ± SD	7.5 ± 5.6
Anorexia	1 (0.5)
Diarrhea	9 (4.5)
Chest pain	7 (3.5)
Pneumonia	5 (2.5)
Duration of viral shedding, mean ± SD	24.5 ± 4.8

SD, standard deviation.

1 arthritis, 1 migraine.

Mechanism of anosmia and ageusia induced by SARS-CoV-2 infection was not elucidated. Upper respiratory infection is one of the most common causes of olfactory dysfunction. Coronavirus 229E was detected in nasal discharge of a patient with post-viral olfactory dysfunction. SARS-CoV spread in the brain via the olfactory bulb in human angiotensin-converting enzyme 2 (ACE2) transgenic mice model. SARS-CoV-2 use ACE2 for cell entry and ACE2 is widely expressed in the oral tissues, especially in tongue epithelial cells. Epithelial cells in salivary gland ducts were reported as early target cells of SARS-CoV in macaques model. It may be possible that viral tropism and distribution of ACE2 contribute to the development of anosmia and ageusia in patients with SARS-CoV-2 infection. Further research would be required on the mechanism of post-SARS-CoV-2 infection olfactory and taste dysfunction.

Among the study population, mean duration of viral shedding was 24.5 days. Duration of viral shedding was longer in symptomatic patients than in asymptomatic patients (25.2 days versus 22.6 days, p < 0.01) (Table 2 ). Particularly among symptomatic patients, those with chest pain released the virus significantly longer (30.0 days versus 25.0 days, p = 0.01). Prolonged viral shedding was also found in patients who complained of sputum (26.8 days versus 24.6 days, p = 0.03).

Table 2

Comparison of the duration of viral shedding according to the clinical manifestations.

	Duration of viral shedding (days, mean ± SD)	p value
Asymptomatic	22.6 ± 4.0	< 0.01*
Symptomatic	25.2 ± 4.9
Fever
Yes	26.6 ± 5.4	0.08
No	24.7 ± 4.6
Myalgia
Yes	26.8 ± 5.4	0.15
No	24.7 ± 4.6
Headache
Yes	27.0 ± 4.5	0.15
No	25.1 ± 4.9
Fatigue
Yes	21.1 ± 4.7	0.02
No	25.5 ± 4.8
Cough
Yes	25.6 ± 5.1	0.18
No	24.7 ± 4.5
Sputum
Yes	26.8 ± 4.8	0.03
No	24.6 ± 4.8
Sore throat
Yes	27.1 ± 4.2	0.13
No	25.0 ± 4.9
Rhinorrhea/nasal stuffiness
Yes	25.9 ± 4.6	0.24
No	24.7 ± 5.0
Anosmia
Yes	25.6 ± 4.9	0.48
No	25.0 ± 4.9
Ageusia
Yes	25.0 ± 4.7	0.75
No	25.3 ± 5.0
Diarrhea
Yes	25.0 ± 6.8	0.98
No	25.2 ± 4.8
Chest pain
Yes	30.0 ± 4.7	0.01
No	25.0 ± 4.8
Pneumonia
Yes	27.8 ± 3.8	0.20
No	25.1 ± 4.9

comparison of asymptomatic cases versus symptomatic cases.

This study has some limitations. Anosmia and ageusia were subjective symptoms. Olfactory test was not performed, and quantitative scale of olfactory dysfunction was not measured. In addition, viability of SARS-CoV-2 detected by PCR was not proven using viral culture. However, this study is valuable in that it can provide detailed information about asymptomatic infections and atypical manifestations such as smell or taste dysfunction in patients with COVID-19.

In conclusion, all patients with COVID-19 showed prolonged viral shedding irrespective of clinical manifestations. Asymptomatic patients have potential to spread SARS-CoV-2 without recognition. Thus, mask wearing, hand hygiene and social distancing would be important to control the viral transmission.

Author contributions

JYN and JYS analyzed the data with responsibility for its integrity and prepared the manuscript. All authors contributed to the conception and design of the study and to the interpretation of data. All authors critically revised the manuscript for intellectual content and approved the final draft for submission.

Financial support

This work was supported by a Korea University Guro Hospital grant (O1905231).

Declaration of Competing Interest

The authors declare no conflict of interest.