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      Asymptomatic SARS-CoV-2 infection

      a , b , c , a , b , c

      The Lancet. Infectious Diseases

      Elsevier Ltd.

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          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.

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          SARS-CoV-2 shedding and seroconversion among passengers quarantined after disembarking a cruise ship: a case series

          Summary Background A cruise ship is a closed-off environment that simulates the basic functioning of a city in terms of living conditions and interpersonal interactions. Thus, the Diamond Princess cruise ship, which was quarantined because of an onboard outbreak of COVID-19 in February, 2020, provides an opportunity to define the shedding pattern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patient antibody responses before and after the onset of symptoms. Methods We recruited adult (≥18 years) passengers from Hong Kong who had been on board the Diamond Princess cruise ship docked in Yokohama, Japan in February, 2020. All participants had been found to be negative for SARS-CoV-2 by RT-PCR 4 days before disembarking and were transferred to further quarantine in a public estate in Hong Kong, where they were recruited. Participants were prospectively screened by quantitative RT-PCR (RT-qPCR) of nasopharyngeal and throat swabs, and serum IgG and IgM against internal nucleoprotein and the surface spike receptor-binding protein (RBD) of SARS-CoV-2 at baseline (upon entering quarantine) and on days 4, 8, and 12 of quarantine. Findings On Feb 22, 2020, 215 adults were recruited, of whom nine (4%; 95% CI 2–8) were positive for SARS-CoV-2 by RT-qPCR or serology and were hospitalised. Of these nine patients, nasopharyngeal swab RT-qPCR was positive in eight patients (89%; 57–99) at baseline. All nine patients were positive for anti-RBD IgG by day 8. Eight (89%; 57–99) were simultaneously positive for nasopharyngeal swab RT-PCR and anti-RBD IgG. One patient who was positive for anti-RBD IgG and had a negative viral load had multifocal peripheral ground-glass changes on high-resolution CT that were typical of COVID-19. Five patients (56%; 27–81) with ground-glass changes on high-resolution CT were found to have higher anti-nucleoprotein-IgG OD values on day 8 and 12 and anti-RBD IgG OD value on day 12 than patients without ground-glass changes. Six (67%; 35–88) patients remained asymptomatic throughout the 14-day quarantine period. Interpretation Patients with COVID-19 can develop asymptomatic lung infection with viral shedding and those with evidence of pneumonia on imaging tend to have an increased antibody response. Positive IgG or IgM confirmed infection of COVID-19 in both symptomatic and asymptomatic patients. A combination of RT-PCR and serology should be implemented for case finding and contact tracing to facilitate early diagnosis, prompt isolation, and treatment. Funding Shaw Foundation Hong Kong; Sanming-Project of Medicine (Shenzhen); High Level-Hospital Program (Guangdong Health Commission).
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            Author and article information

            Contributors
            Journal
            Lancet Infect Dis
            Lancet Infect Dis
            The Lancet. Infectious Diseases
            Elsevier Ltd.
            1473-3099
            1474-4457
            12 June 2020
            12 June 2020
            Affiliations
            [a ]Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore
            [b ]Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore
            [c ]Department in Infectious Diseases, Singapore General Hospital, Singapore
            Article
            S1473-3099(20)30460-6
            10.1016/S1473-3099(20)30460-6
            7292578
            © 2020 Elsevier Ltd. All rights reserved.

            Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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            Infectious disease & Microbiology

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