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Virological assessment of hospitalized patients with COVID-2019
Open accessPublished version of a preprint
Abstract
Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 2019 1,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses 3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung 2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 2003 5. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission 6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 10 8 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.
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“It appears that peak viral loads can vary >100,000-fold between cases (Magleby et al., 2020; Wölfel et al., 2020)”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Wölfel et al., 2020
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“Clinical reports suggest that infection with CoV-2 is associated with high rates of disturbances in smell and taste perception, including anosmia (8-13).”
From Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia (2020) · cites this paper as [10]
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Self-citationEpithelial response to IFN‐γ promotes SARS‐CoV‐2 infection
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Implications of SARS‐CoV‐2 infection for neurogastroenterology
Marasco, G., Lenti, M. V., Cremon, C., Barbaro, M. R., Stanghellini, V., Sabatino, A. D., & Barbara, G. (2021) · Neurogastroenterology & Motility · doi:10.1111/nmo.14104 · Cited by 78
Doi, A., Iwata, K., Kuroda, H., Hasuike, T., Nasu, S., Kanda, A., Nagao, T., Nishioka, H., Tomii, K., Morimoto, T., et al. (2021) · Clinical Epidemiology and Global Health · doi:10.1016/j.cegh.2021.100747 · Cited by 77
Organ-specific genome diversity of replication-competent SARS-CoV-2
Cleemput, J. V., van Snippenberg, W., Lambrechts, L., Dendooven, A., D’Onofrio, V., Couck, L., Trypsteen, W., Vanrusselt, J., Theuns, S., Vereecke, N., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26884-7 · Cited by 77
COVID-19 myocarditis: quantitative analysis of the inflammatory infiltrate and a proposed mechanism
Fox, S., Falgout, L. M., & Heide, R. S. V. (2021) · Cardiovascular Pathology · doi:10.1016/j.carpath.2021.107361 · Cited by 80
“Initial published reports from China and Europe focused on the pulmonary pathology of COVID-19, yet data to suggest cardiovascular involvement was described early on as a potential source of significant morbidity and mortality [ 4 , 5 , 6] .”
Digital PCR Applications in the SARS-CoV-2/COVID-19 Era: a Roadmap for Future Outbreaks
Nyaruaba, R., Mwaliko, C., Dobnik, D., Neužil, P., Amoth, P., Mwau, M., Yu, J., Yang, H., & Wei, H. (2022) · Clinical Microbiology Reviews · doi:10.1128/cmr.00168-21 · Cited by 77
Atta, S., Zhao, Y., Li, J. Q., & Vo‐Dinh, T. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.3c04361 · Cited by 77
Early Viral Clearance and Antibody Kinetics of COVID-19 Among Asymptomatic Carriers
Xiao, T., Wang, Y., Yuan, J., Ye, H., Wei, L., Liao, X., Wang, H., Qian, S., Wang, Z., Liu, L., et al. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.595773 · Cited by 75
FOKAS, A. S., Δικαίος, Ν., & Kastis, G. A. (2020) · Journal of The Royal Society Interface · doi:10.1098/rsif.2020.0494 · Cited by 78
Zhou, Y., Ghassemi, P., Chen, M., McBride, D. R., Casamento, J. P., Pfefer, T. J., & Wang, Q. (2020) · Journal of Biomedical Optics · doi:10.1117/1.jbo.25.9.097002 · Cited by 77
Temporal landscape of human gut RNA and DNA virome in SARS-CoV-2 infection and severity
Zuo, T., Liu, Q., Zhang, F., Yeoh, Y. K., Wan, Y., Zhan, H., Lui, G. C.-Y., Chen, Z., Li, A. Y. L., Cheung, C. P., et al. (2021) · Microbiome · doi:10.1186/s40168-021-01008-x · Cited by 76
Yang, F., Pahlavan, A. A., Mendez, S., Abkarian, M., & Stone, H. A. (2020) · Physical Review Fluids · doi:10.1103/physrevfluids.5.122501 · Cited by 74
Engelmann, I., Alidjinou, E. K., Ogiez, J., Pagneux, Q., Miloudi, S., Benhalima, I., Ouafi, M., Sané, F., Hober, D., Roussel, A., et al. (2021) · ACS Omega · doi:10.1021/acsomega.1c00166 · Cited by 76
Ulytė, A., Radtke, T., Abela, I. A., Haile, S. R., Berger, C., Huber, M., Schanz, M. M., Schwarzmüller, M., Trkola, A., Fehr, J. S., et al. (2021) · BMJ · doi:10.1136/bmj.n616 · Cited by 76
“Because several days are required for seroconversion after SARS-CoV-2 infection, 35-38 recent infections could be missed.”
Evidence For and Against Direct Kidney Infection by SARS-CoV-2 in Patients with COVID-19
Hassler, L., Reyes, F., Sparks, M. A., Welling, P. A., & BATLLE, D. C. (2021) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.04560421 · Cited by 76
Soares, R. R. G., Akhtar, A. S., Pinto, I. F., Lapins, N., Barrett, D., Sandh, G., Yin, X., Pelechano, V., & Russom, A. (2021) · Lab on a Chip · doi:10.1039/d1lc00266j · Cited by 80
Shinkai, M., Tsushima, K., Tanaka, S., Hagiwara, E., Tarumoto, N., Kawada, I., Hirai, Y., Fujiwara, S., Komase, Y., Saraya, T., et al. (2021) · Infectious Diseases and Therapy · doi:10.1007/s40121-021-00517-4 · Cited by 79
Li, S., Yang, S., Zhou, Y., Disoma, C., Dong, Z., Du, A., Zhang, Y., Chen, Y., Huang, W., Chen, J., et al. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.712081 · Cited by 80
Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape
Mast, F. D., Fridy, P. C., Ketaren, N. E., Wang, J., Jacobs, E. Y., Olivier, J. P., Sanyal, T., Molloy, K. R., Schmidt, F., Rutkowska, M., et al. (2021) · eLife · doi:10.7554/elife.73027 · Cited by 69
“Beyond typical administration methods, a major advantage of nanobodies is their potential for direct delivery by nebulization deep into the lungs (Wölfel et al., 2020; Nambulli et al., 2021).”
MethodSARS-CoV-2 Virologic Rebound With Nirmatrelvir–Ritonavir Therapy
Edelstein, G. E., Boucau, J., Uddin, R., Marino, C., Liew, M. Y., Barry, M., Choudhary, M. C., Gilbert, R. F., Reynolds, Z., Li, Y., et al. (2023) · Annals of Internal Medicine · doi:10.7326/m23-1756 · Cited by 74
Green, H., Wilder, M. L., Middleton, F. A., Collins, M. B., Fenty, A., Gentile, K. L., Kmush, B. L., Zeng, T., & Larsen, D. A. (2020) · medRxiv · doi:10.1101/2020.05.21.20109181 · Cited by 76
A model for COVID-19 with isolation, quarantine and testing as control measures
Aronna, M. S., Guglielmi, R., & Moschen, L. M. (2021) · Epidemics · doi:10.1016/j.epidem.2021.100437 · Cited by 75
Hu, X. L., Deng, Q., Li, J., Chen, J., Wang, Z., Zhang, X., Fang, Z., Li, H., Zhao, Y., Pan, Y., et al. (2020) · mSphere · doi:10.1128/msphere.00808-20 · Cited by 75
Effective control of SARS-CoV-2 transmission in Wanzhou, China
Shi, Q., Hu, Y., Peng, B., Tang, X.-J., Wang, W., Su, K., Luo, C., Wu, B., Zhang, F., Zhang, Y., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-01178-5 · Cited by 73
The impact of school reopening on the spread of COVID-19 in England
Keeling, M. J., Tildesley, M. J., Atkins, B. D., Penman, B. S., Southall, E., Guyver‐Fletcher, G., Holmes, A., McKimm, H., Gorsich, E. E., Hill, E. M., et al. (2021) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2020.0261 · Cited by 78
Multi-kingdom gut microbiota analyses define COVID-19 severity and post-acute COVID-19 syndrome
Liu, Q., Su, Q., Zhang, F., Tun, H. M., Mak, J. W. Y., Lui, G. C.-Y., Ng, S. S., Ching, J. Y. L., Lu, W., Lu, W., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34535-8 · Cited by 74
“Briefly, contigs were required to fulfill one of the following criteria; 1) Categories 1–6 from VirSorter when run with default parameters and Refseqdb (–db) (1)(37) positive, (2) circular, (3) greater than 3 kb with no BLASTn alignments to the NT database (January ‘19) (evalue threshold: 1e-10), (4) a minimum of 2 pV…”
BackgroundMethodPrevalence of SARS-CoV-2 infection in the Luxembourgish population: the CON-VINCE study.Preprint
Snoeck, C. J., Vaillant, M., Abdelrahman, T., Satagopam, V., Turner, J. D., Beaumont, K., Gomes, C. P. C., Fritz, J. V., Schröder, V. E., Kaysen, A., et al. (2020) · medRxiv · doi:10.1101/2020.05.11.20092916 · Cited by 75
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The Impact of COVID-19 on Radiation Oncology Clinics and Patients With Cancer in the United States
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COVID-19: Pandemic surgery guidance
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SARS‐CoV‐2 environmental contamination associated with persistently infected COVID‐19 patients
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Molecular diagnostic assays for COVID-19: an overview
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“RNA load of less than 106 copies/mL [104].”
BackgroundCatching, A., Capponi, S., Yeh, M. T., Bianco, S., & Andino, R. (2021) · Scientific Reports · doi:10.1038/s41598-021-94960-5 · Cited by 76
SARS-CoV-2 new variants: Characteristic features and impact on the efficacy of different vaccines
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“Variable symptoms such as loss of smell, fatigue, fever, breathing hitches, cough, and loss of taste and asymptomatic cases have been reported [44,45].”
Virologic Features of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children
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Unconventional CD147‐dependent platelet activation elicited by SARS‐CoV‐2 in COVID‐19
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Breadth of SARS-CoV-2 neutralization and protection induced by a nanoparticle vaccine
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Expiratory Aerosol pH: The Overlooked Driver of Airborne Virus Inactivation
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“SARS-CoV-2 strain BetaCoV/Germany/BavPat1/2020 was obtained from the European Virus Archive GLOBAL (EVA-GLOBAL; Ref-SKU: 026V-03883)(2) and propagated in VeroE6 cells (kindly provided by Volker Thiel, University of Bern).”
Method
Metadata
- Authors
- Wölfel, R., Corman, V. M., Guggemos, W., Seilmaier, M., Zange, S., Müller, M. A., Niemeyer, D., Jones, T. C., Vollmar, P., Rothe, C., Hoelscher, M., Bleicker, T., Brünink, S., Schneider, J., Ehmann, R., Zwirglmaier, K., Drosten, C., & Wendtner, C.
- Affiliations
- Institut für Mikrobiologie der Bundeswehr (DE)
- Charité – Universitätsmedizin Berlin (DE)
- München Klinik Schwabing (DE)
- University of Cambridge (GB)
- LMU Klinikum (DE)
- Corresponding author
- Drosten, Christian
- Wendtner, Clemens
- ORCID
- Venue
- Nature
- Published
- 2020-04-01
- Volume
- 581
- Issue
- 7809
- Pages
- 465-469
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3013893137
- Cited by
- 6,661
- References
- 37
- Citations by year
- 2026: 92 · 2025: 165 · 2024: 328 · 2023: 526 · 2022: 1091 · 2021: 2228 · 2020: 2219
- FWCI
- 199.03
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-12-11)
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- European Commission (602525)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Keywords
- COVID-19 pandemic, SARS-CoV-2, upper respiratory tract, viral replication, seroconversion, viral load, hospitalized patients
- MeSH terms
- Seroconversion, Betacoronavirus, COVID-19, SARS-CoV-2, COVID-19 Testing, Coronavirus Envelope Proteins, Antibodies, Viral, Base Sequence, Blood, Feces, Hospitalization, Humans, Immunoglobulin G, Immunoglobulin M, Lung, Pharynx, Pneumonia, Viral, RNA, Viral, Sputum, Urine, Viral Envelope Proteins, Virus Replication, Virus Shedding, Coronavirus Infections, Clinical Laboratory Techniques, Viral Load, Polymorphism, Single Nucleotide, Pandemics
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