Asymptomatic SARS-CoV-2 infection

Abstract

The pandemic spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of COVID-19, has placed lives and economies of many countries under unprecedented stress. Many countries have shut schools and workplaces and imposed physical distancing to reduce virus transmission, in an effort to prevent the number of COVID-19 cases from overwhelming health-care systems. Such measures, however, are not economically sustainable. Schools and workplaces will have to be reopened. An important challenge for returning to normality is the prevalence of asymptomatic infection and the question of whether such individuals could sustain community virus transmission. 1 As the health community debates and examines the epidemiological significance of asymptomatic individuals, such cases present unique opportunities to gain insight into COVID-19 pathogenesis. In The Lancet Infectious Diseases, two independent studies by Sakiko Tabata and colleagues 2 and Ivan Fan-Ngai Hung and colleagues 3 have focused on the COVID-19 outbreak on board the Diamond Princess cruise ship in February, 2020, to retrospectively and prospectively compare asymptomatic with presymptomatic infection. Screening for viral shedding of all individuals on board was done when the ship was docked in Japan and those who tested positive were hospitalised. Individuals who tested negative and who returned to their country of residence were further quarantined and monitored for infection. These control measures provided an opportunity for clinical studies of asymptomatic infection. A previous study found that half of the 634 passengers who screened positive for SARS-CoV-2 while on board the ship were asymptomatic, 4 although whether these individuals remained asymptomatic until infection resolution was not prospectively determined. Of the 43 individuals positive for SARS-CoV-2 on RT-PCR who were asymptomatic at admission to a hospital in Tokyo, Japan, ten developed COVID-19, including severe pulmonary disease. 2 Of the 215 asymptomatic individuals who returned to Hong Kong for further quarantine and were enrolled in the study by Hung and colleagues, 3 eight became RT-PCR positive and three of them eventually developed symptoms; a ninth individual was seropositive for SARS-CoV-2 and had abnormalities on chest CT scan but remained asymptomatic. The individuals in both studies were monitored until discharge from isolation. Neither of the studies, however, were able to identify the time of initial exposure to the virus that led to infection. Because RT-PCR positivity can persist for weeks and is subject to sampling error, 5 the comparison between asymptomatic and symptomatic cases could be confounded by the difference in time from virus exposure. Notwithstanding this limitation, these studies describe two remarkable features. First, the presence of comorbidities did not appear to increase susceptibility to symptomatic infection or even disease outcome in these studies. Instead, older age appeared to be the only demographic factor that differentiated symptomatic from asymptomatic outcome in the individuals in Hong Kong, 3 as well as differentiating severe from mild cases in the Japanese hospital. 2 Second, about 50% of asymptomatic individuals showed radiographic abnormalities, including ground-glass opacities on chest CT scans.2, 3 The Hong Kong group also observed that patients with CT scan abnormalities had higher concentrations of SARS-CoV-2 spike protein and nucleoprotein antibodies than those with normal CT scans, regardless of whether they were symptomatic or asymptomatic. 3 These findings suggest that the anatomy and extent of infection might not differentiate symptomatic from asymptomatic cases. A quantitative comparison of the extent of abnormalities in the chest radiographs or CT scans between those with symptomatic and presymptomatic infection would have been informative, but this analysis was not carried out in these studies. Nonetheless, these findings suggest that some individuals can tolerate a certain extent of lower respiratory tract infection without developing any symptoms. Besides the extent of pulmonary infection, differentiation between symptomatic and asymptomatic outcomes might be related to the type of host response to infection. In the Japanese study (but not in the Hong Kong study), significantly increased serum lactate dehydrogenase was observed in presymptomatic individuals compared with asymptomatic individuals. Lactate dehydrogenase is a marker of pyroptosis, an inflammatory form of programmed cell death. 6 Pyroptosis releases proinflammatory molecules, 6 including IL-1, which we found to be expressed before the nadir of respiratory function and peak expression of other cytokines in a previous study. 7 Pyroptosis could therefore be an initiator of pulmonary inflammation and symptomatic disease. In conclusion, outbreak investigations that are able to identify asymptomatic and presymptomatic infections have unique opportunities to gain clinical insights into COVID-19 pathogenesis. Such clinical insights will be pivotal for shaping future pathogenesis studies.