Asymptomatic infection and atypical manifestations of COVID-19: Comparison of viral shedding duration
Authors: Ji Yun Noh, Jin Gu Yoon, Hye Seong, Won Suk Choi, Jang Wook Sohn, Hee Jin Cheong, Woo Joo Kim, Joon Young Song
Journal: Journal of Infection (2020)

•More than 25% of patients with COVID-19 were asymptomatic.•Among patients with COVID-19, 26.1% presented anosmia, and 22.6% complained of ageusia with median duration of 7 days.•Mean duration of SARS-CoV-2 viral shedding was 24.5 days.•Irrespective of clinical manifestations, all patients with COVID-19 showed prolonged viral shedding. Coronavirus disease 2019 (COVID-19) bears several challenging problems, including insidious symptom onset, subclinical manifestations and highly transmissible property during early stage of infection.1Song J.Y. Yun J.G. Noh J.Y. Cheong H.J. Kim W.J Covid-19 in South Korea - challenges of subclinical manifestations.N Engl J Med. 2020; https://doi.org/10.1056/NEJMc2001801Crossref Scopus (92) Google Scholar In the recent study by Huang et al., SARS-CoV-2-infection presented strong infectivity during the incubation period with rapid transmission.2Huang L. Zhang X. Zhang X. et al.Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: a prospective contact-tracing study.J Infect. 2020; https://doi.org/10.1016/j.jinf.2020.03.006Abstract Full Text Full Text PDF Scopus (250) Google Scholar Some patients with COVID-19 are asymptomatic, while others complain of atypical symptoms including loss of smell and taste sense.3Giacomelli A. Pezzati L. Conti F. et al.Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study.Clin Infect Diseas Offic Publ Infect Diseases Soc Am. 2020; https://doi.org/10.1093/cid/ciaa330Crossref Scopus (898) Google Scholar 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.1Song J.Y. Yun J.G. Noh J.Y. Cheong H.J. Kim W.J Covid-19 in South Korea - challenges of subclinical manifestations.N Engl J Med. 2020; https://doi.org/10.1056/NEJMc2001801Crossref Scopus (92) Google Scholar Asymptomatic proportion of COVID-19 was estimated as 17.9% (95% credible interval, 15.5–20.2%) on the Diamond Princess cruise ship, Japan.4Mizumoto K. Kagaya K. Zarebski A. Chowell G Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan.Euro Surveill. 2020; 25https://doi.org/10.2807/1560-7917.es.2020.25.10.2000180Crossref PubMed Google Scholar 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.3Giacomelli A. Pezzati L. Conti F. et al.Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study.Clin Infect Diseas Offic Publ Infect Diseases Soc Am. 2020; https://doi.org/10.1093/cid/ciaa330Crossref Scopus (898) Google Scholar,5Luers J.C. Klussmann J.P. Guntinas-Lichius O The Covid-19 pandemic and otolaryngology: what it comes down to?.Laryngorhinootologie. 2020; https://doi.org/10.1055/a-1095-2344Crossref PubMed Scopus (73) Google Scholar Among 59 hospitalized patients with COVID-19, 33.9% reported olfactory or taste disorder in Italy3Giacomelli A. Pezzati L. Conti F. et al.Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study.Clin Infect Diseas Offic Publ Infect Diseases Soc Am. 2020; https://doi.org/10.1093/cid/ciaa330Crossref Scopus (898) Google Scholar. This is consistent with current observations: among 146 symptomatic patients, 35.6% developed anosmia and 30.8% had ageusia in this study.Table 1Demographic and clinical characteristics of the patients with COVID-19 in a residential treatment center (n = 199).VariableValueSex - male, n (%)69 (34.7)Age, mean ± SD38.0 ± 13.1Chronic medical conditions12 (6.0) Diabetes mellitus5 (2.5) Hypertension7 (3.5) Cerebral infarction2 (1.0) Others*1 arthritis, 1 migraine.2 (1.0)Asymptomatic infection53 (26.6)Symptoms Fever38 (19.1) Myalgia34 (17.1) Headache7 (3.5) Fatigue8 (4.0) Cough82 (41.2) Sputum41 (20.6) Sore throat15 (7.5) Rhinorrhea/nasal stuffiness60 (30.2) Anosmia52 (26.1) Duration, mean ± SD8.4 ± 6.0Ageusia45 (22.6) Duration, mean ± SD7.5 ± 5.6Anorexia1 (0.5) Diarrhea9 (4.5) Chest pain7 (3.5)Pneumonia5 (2.5)Duration of viral shedding, mean ± SD24.5 ± 4.8SD, standard deviation. 1 arthritis, 1 migraine. Open table in a new tab SD, standard deviation. 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.6Deems D.A. Doty R.L. Settle R.G. et al.Smell and taste disorders, a study of 750 patients from the University of pennsylvania smell and taste center.Arch. Otolaryngol. Head Neck Surg. 1991; 117: 519-528https://doi.org/10.1001/archotol.1991.01870170065015Crossref PubMed Scopus (848) Google Scholar Coronavirus 229E was detected in nasal discharge of a patient with post-viral olfactory dysfunction.7Suzuki M. Saito K. Min W.P. et al.Identification of viruses in patients with postviral olfactory dysfunction.Laryngoscope. 2007; 117: 272-277https://doi.org/10.1097/01.mlg.0000249922.37381.1eCrossref PubMed Scopus (296) Google Scholar SARS-CoV spread in the brain via the olfactory bulb in human angiotensin-converting enzyme 2 (ACE2) transgenic mice model.8Netland J. Meyerholz D.K. Moore S. Cassell M. Perlman S Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2.J. Virol. 2008; 82: 7264-7275https://doi.org/10.1128/jvi.00737-08Crossref PubMed Scopus (0) Google Scholar SARS-CoV-2 use ACE2 for cell entry and ACE2 is widely expressed in the oral tissues, especially in tongue epithelial cells.9Xu H. Zhong L. Deng J. et al.High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa.Int J Oral Sci. 2020; 12: 8https://doi.org/10.1038/s41368-020-0074-xCrossref PubMed Scopus (1866) Google Scholar Epithelial cells in salivary gland ducts were reported as early target cells of SARS-CoV in macaques model.10Liu L. Wei Q. Alvarez X. et al.Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques.J Virol. 2011; 85: 4025-4030https://doi.org/10.1128/jvi.02292-10Crossref PubMed Scopus (0) Google Scholar 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 2Comparison of the duration of viral shedding according to the clinical manifestations.Duration of viral shedding (days, mean ± SD)p valueAsymptomatic22.6 ± 4.0< 0.01*comparison of asymptomatic cases versus symptomatic cases.Symptomatic25.2 ± 4.9Fever Yes26.6 ± 5.40.08 No24.7 ± 4.6Myalgia Yes26.8 ± 5.40.15 No24.7 ± 4.6Headache Yes27.0 ± 4.50.15 No25.1 ± 4.9Fatigue Yes21.1 ± 4.70.02 No25.5 ± 4.8Cough Yes25.6 ± 5.10.18 No24.7 ± 4.5Sputum Yes26.8 ± 4.80.03 No24.6 ± 4.8Sore throat Yes27.1 ± 4.20.13 No25.0 ± 4.9Rhinorrhea/nasal stuffiness Yes25.9 ± 4.60.24 No24.7 ± 5.0Anosmia Yes25.6 ± 4.90.48 No25.0 ± 4.9Ageusia Yes25.0 ± 4.70.75 No25.3 ± 5.0Diarrhea Yes25.0 ± 6.80.98 No25.2 ± 4.8Chest pain Yes30.0 ± 4.70.01 No25.0 ± 4.8Pneumonia Yes27.8 ± 3.80.20 No25.1 ± 4.9 comparison of asymptomatic cases versus symptomatic cases. Open table in a new tab 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. 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. This work was supported by a Korea University Guro Hospital grant (O1905231). The authors declare no conflict of interest.