Diagnosing COVID-19: the Disease and Tools for Detection Buddhisha Udugama, Pranav Kadhiresan, Hannah N

Subscriber access provided by University of Minnesota Libraries Review Diagnosing COVID-19: The Disease and Tools for Detection Buddhisha Udugama, Pranav Kadhiresan, Hannah N. Kozlowski, Ayden Malekjahani, Matthew Osborne, Vanessa Y.C. Li, Hongmin Chen, Samira Mubareka, Jonathan Gubbay, and Warren C.W. Chan ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.0c02624 • Publication Date (Web): 30 Mar 2020 Downloaded from pubs.acs.org on April 4, 2020 Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. 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ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts. is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties. Page 1 of 28 ACS Nano 1 2 3 4 Diagnosing COVID-19: The Disease and Tools for Detection 5 6 7 8 9 Buddhisha Udugama,1,2, 9 Pranav Kadhiresan,1,2,9 Hannah N. Kozlowski, 1,2,9 Ayden Malekjahani, 10 1,2,9 Matthew Osborne, 1,2,9 Vanessa Y. C. Li, 1,2,9 Hongmin Chen, 1,2,9 Samira Mubareka,3,4 11 Jonathan B. Gubbay,3,5,6 and Warren C. W. Chan1,2,7,8* 12 13 14 15 1. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON 16 M5S 3G9, Canada 17 2. Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, 18 Toronto, ON M5S 3E1, Canada 19 3. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of 20 21 Toronto, Toronto, Ontario, Canada 4. 22 Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada 23 5. Public Health Ontario, Toronto, ON M5G 1V2, Canada 24 6. Hospital for Sick Children, Toronto, ON M5G 1V2, Canada 25 7. Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6 26 8. Materials Science and Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada 27 28 29 9. These authors contributed equally to the manuscript 30 31 32 *Corresponding author: [email protected] 33 34 35 Abstract 36 37 COVID-19 has spread globally since its discovery in Hubei province, China in December 2019. A 38 combination of computed tomography imaging, whole genome sequencing, and electron 39 40 microscopy were initially used to screen and identify SARS-CoV-2, the viral etiology of COVID- 41 19. The aim of this review article is to inform the audience of diagnostic and surveillance 42 technologies for SARS-CoV-2 and their performance characteristics. We describe point-of-care 43 diagnostics that are on the horizon and encourage academics to advance their technologies beyond 44 conception. Developing plug-and-play diagnostics to manage the SARS-CoV-2 outbreak would 45 also be useful in preventing future epidemics. 46 47 48 49 50 51 52 53 54 55 56 57 58 1 59 60 ACS Paragon Plus Environment ACS Nano Page 2 of 28 1 2 3 TOC image 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 2 59 60 ACS Paragon Plus Environment Page 3 of 28 ACS Nano 1 2 3 Coronavirus disease 2019 (COVID-19) was discovered in Hubei Province, China in December 4 2019.1 A cluster of patients were admitted with fever, cough, shortness of breath, and other 5 2 6 symptoms. Patients were scanned using computed tomography (CT), which revealed varied 3 7 opacities (denser, more profuse, and confluent) in comparison to images of healthy lung. This 8 finding led to the initial diagnosis of pneumonia. Additional nucleic acid analysis using multiplex 9 real-time polymerase chain reaction (PCR) of known pathogen panels led to negative results, 10 suggesting that the cause of pneumonia was of unknown origin.1 By January 10, 2020, samples 11 from patients’ bronchoalveolar lavage (BAL) fluid were sequenced to reveal a pathogen with a 12 similar genetic sequence to the betacoronavirus B lineage. It was discovered that this new pathogen 13 14 had ~80%, ~ 50%, and ~96% similarity to the genome of the severe acute respiratory syndrome 15 virus (SARS-CoV), Middle East respiratory syndrome virus (MERS-CoV), and bat coronavirus 16 RaTG13, respectively.1,4 The novel coronavirus was named SARS-CoV-2, the pathogen causing 17 COVID-19. As of March 28, 2020, the disease has spread to at least 202 countries, infected at least 18 575,444 people, and has resulted in at least 26,654 deaths globally. It is suspected that the total 19 number of reported COVID-19 infections is underestimated as there are many mild or 20 5 21 asymptomatic cases that go undetected . From the Diamond Princess cruise ship case study, an 22 estimate of 17.9% of asymptomatic cases were reported. Asymptomatic individuals are as 23 infectious as symptomatic individuals and are therefore capable of contributing to further 24 spreading the disease. 6 25 26 SARS-CoV-2 can be transmitted from human to human. The current hypothesis is that the first 27 transmission occurred between bats and a yet-to-be-determined intermediate host animal.1 It is 28 29 estimated that a SARS-CoV-2-infected person will infect approximately three new people (the 7 30 reproductive number is averaged to be 3.28). The symptoms can vary, with some patients 31 remaining asymptomatic while others present with fever, cough, fatigue, and a host of other 32 symptoms. The symptoms may be similar to patients with influenza or common cold. At this stage, 33 the most likely mode of transmission is thought to be through direct contact and droplet-spread.8,9 34 A recent study looking at aerosol and surface stability of SARS-CoV-2 showed that the virus may 35 be found in aerosols (< 5 µm) at least up to 3 h and may be more stable on plastic and stainless 36 10 37 steel than on copper and cardboard. 38 39 Development of therapeutics and vaccines is underway but there are currently no United States 40 Food and Drug Administration (FDA) approved therapeutics or vaccines for the treatment of 41 COVID-19 patients.11,12 Diagnostics can play an important role in the containment of COVID-19, 42 enabling the rapid implementation of control measures that limit the spread through case 43 44 identification, isolation, and contact tracing (i.e., identifying people that may have come in contact 45 with an infected patient). The current diagnostic workflow for COVID-19 is described in Figure 46 1. In this review article, we aim to summarize the current known biological properties of SARS- 47 CoV-2, diagnostic tools and clinical results for detecting SARS-CoV-2, emerging diagnostics, and 48 surveillance technology to curb the spread. This is a rapidly moving topic of research and a review 49 article that encompasses the current findings may be useful for guiding strategies to deal with a 50 potential COVID-19 pandemic. 51 52 53 54 55 56 57 58 3 59 60 ACS Paragon Plus Environment ACS Nano Page 4 of 28 1 2 3 Biological Properties of SARS-CoV-2 4 5 6 SARS-CoV-2 was first identified from patient samples in Wuhan. Human airway epithelial cells 7 were cultured with the virus from BAL fluid isolated from patients. Supernatant was collected 8 from cells that were damaged or killed and analyzed by negative-stained transmission electron 9 microscopy (Figure 2).13 The images revealed that the virus has a diameter ranging from 60 to 10 140 nm, has an envelope with protein spikes, and has genetic material.14 The overall structure 11 looks similar to other viruses from the Coronaviridae family. 12 13 14 SARS-CoV-2 has a single-stranded positive sense RNA genome that is ~30,000 nucleotides in 15 length.1,15 The genome encodes 27 proteins including an RNA-dependent RNA polymerase 16 (RdRP) and four structural proteins.15,16 RdRP acts in conjunction with nonstructural proteins to 17 maintain genome fidelity. A region of the RdRP gene in SARS-CoV-2 was shown to be highly 18 similar to a region of the RdRP gene found in bat coronavirus RaTG13 and 96% similar to the 19 RaTG13 overall genome sequence.1 Of 104 strains sequenced between December 2019 and mid- 20 21 February 2020, 99.9% sequence homology was observed but, more recently, changes in the viral 2,17 22 genome have been catalogued, showing higher sequence diversity.

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