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Downloaded Via UNIV of TORONTO on August 9, 2020 at 23:11:29 (UTC) This article is made available via the ACS COVID-19 subset 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 the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Review www.acsnano.org 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 B. Gubbay, and Warren C. W. Chan* Cite This: ACS Nano 2020, 14, 3822−3835 Read Online ACCESS Metrics & More Article Recommendations ABSTRACT: COVID-19 has spread globally since its discovery in Hubei province, China in December 2019. A combination of computed tomography imaging, whole genome sequencing, and electron microscopy were initially used to screen and identify SARS-CoV-2, the viral etiology of COVID-19. The aim of this review article is to inform the audience of diagnostic and surveillance technologies for SARS-CoV-2 and their performance characteristics. We describe point-of-care diagnostics that are on the horizon and encourage academics to advance their technologies beyond conception. Developing plug-and-play diag- nostics to manage the SARS-CoV-2 outbreak would be useful in preventing future epidemics. KEYWORDS: SARS-CoV-2, diagnostics, COVID-19, PCR, surveillance, pandemic oronavirus disease 2019 (COVID-19) was discovered study, an estimate of 17.9% of asymptomatic cases were in Hubei Province, China in December 2019.1 A reported. Asymptomatic individuals are as infectious as cluster of patients were admitted with fever, cough, symptomatic individuals and are therefore capable of further C 2 6 shortness of breath, and other symptoms. Patients were spreading the disease. scanned using computed tomography (CT), which revealed SARS-CoV-2 can be transmitted from human to human. Downloaded via UNIV OF TORONTO on August 9, 2020 at 23:11:29 (UTC). varied opacities (denser, more profuse, and confluent) in The current hypothesis is that the first transmission occurred comparison to images of healthy lungs.3 This finding led to the between bats and a yet-to-be-determined intermediate host 1 initial diagnosis of pneumonia. Additional nucleic acid analysis animal. It is estimated that a SARS-CoV-2-infected person will See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. infect approximately three new people (the reproductive using multiplex real-time polymerase chain reaction (PCR) of 7 known pathogen panels led to negative results, suggesting that number is averaged to be 3.28). The symptoms can vary, the cause of pneumonia was of unknown origin.1 By January with some patients remaining asymptomatic, while others 10, 2020, samples from patients’ bronchoalveolar lavage (BAL) present with fever, cough, fatigue, and a host of other fl symptoms. The symptoms may be similar to patients with uid were analyzed to reveal a pathogen with a similar genetic fl sequence to the betacoronavirus B lineage. It was discovered in uenza or the common cold. At this stage, the most likely ∼ ∼ ∼ mode of transmission is thought to be through direct contact that this new pathogen had 80%, 50%, and 96% similarity 8,9 to the genome of the severe acute respiratory syndrome virus and droplet spread. A recent study looking at aerosol and (SARS-CoV), Middle East respiratory syndrome virus (MERS- surface stability of SARS-CoV-2 showed that the virus may be 1,4 found in aerosols (<5 μm) for at least up to 3 h and may be CoV), and bat coronavirus RaTG13, respectively. The novel coronavirus was named SARS-CoV-2, the pathogen causing COVID-19. As of April 2, 2020, the disease has spread to at Received: March 27, 2020 least 202 countries, infected over 1 million people, and resulted Accepted: March 30, 2020 in at least 45,526 deaths globally. It is suspected that the total Published: March 30, 2020 number of reported COVID-19 infections is underestimated, as there are many mild or asymptomatic cases that go undetected.5 From the Diamond Princess cruise ship case © 2020 American Chemical Society https://dx.doi.org/10.1021/acsnano.0c02624 3822 ACS Nano 2020, 14, 3822−3835 ACS Nano www.acsnano.org Review Figure 1. Example of patient and sample workflow during the COVID-19 outbreak. Patients present at a healthcare facility for triage. The collected samples are tested on-site if possible or transported for molecular testing and sequencing. Patients are then managed appropriately. more stable on plastic and stainless steel than on copper and research, and a review article that encompasses the current cardboard.10 findings may be useful for guiding strategies to deal with the Development of therapeutics and vaccines is underway, but current COVID-19 pandemic. there are currently no United States Food and Drug Biological Properties of SARS-CoV-2. SARS-CoV-2 was Administration (FDA) approved therapeutics or vaccines for first identified from patient samples in Wuhan, China. Human the treatment of COVID-19 patients.11,12 Diagnostics can play airway epithelial cells were cultured with the virus from BAL an important role in the containment of COVID-19, enabling fluid isolated from patients. Supernatant was collected from the rapid implementation of control measures that limit the cells that were damaged or killed and analyzed by negative- spread through case identification, isolation, and contact stained transmission electron microscopy (Figure 2).13 The tracing (i.e., identifying people that may have come in contact images revealed that the virus has a diameter ranging from 60 with an infected patient). The current diagnostic workflow for to 140 nm, has an envelope with protein spikes, and has COVID-19 is described in Figure 1. In this review article, we genetic material.14 The overall structure looks similar to other aim to summarize the current known biological properties of viruses from the Coronaviridae family. SARS-CoV-2, diagnostic tools and clinical results for detecting SARS-CoV-2 has a single-stranded positive sense RNA SARS-CoV-2, emerging diagnostics, and surveillance technol- genome that is ∼30,000 nucleotides in length.1,15 The genome ogy to curb the spread. This is a rapidly moving topic of encodes 27 proteins including an RNA-dependent RNA 3823 https://dx.doi.org/10.1021/acsnano.0c02624 ACS Nano 2020, 14, 3822−3835 ACS Nano www.acsnano.org Review fluorescently stained viruses with cells that express the ACE2 receptor from Chinese horseshoe bats, pigs, humans, and civets, but not from mice. The ACE2 mRNA is present in almost all human organs. ACE2 is present in arterial and venous endothelial cells and arterial smooth muscle cells in the lungs, stomach, small intestine, colon, skin, lymph nodes, liver bile ducts, kidney parietal epithelial cells, and the brain. It is also expressed on the surface of lung alveolar epithelial cells and enterocytes of the small intestine that allows them to be infected. Tissues of the upper respiratory tract (i.e., oral and nasal mucosa and nasopharynx) did not show surface expression of ACE2 on epithelial cells and therefore are unlikely the primary site of SARS-CoV-2 infection.22 CT scans may show higher opacity in the lower lungs because cells in that region express more ACE2. SARS-CoV-2 has been isolated from oral swabs, BAL fluid, and stool.1,23 Higher viral loads have been recorded in the nose versus the throat, with similar viral loads seen in asymptomatic and symptomatic patients.24 Understanding the biological properties of SARS- CoV-2 enabled researchers to develop diagnostics for detection. Current Diagnostic Tests for COVID-19. The symptoms expressed by COVID-19 patients are nonspecific and cannot be used for an accurate diagnosis. Guan et al. reported that 44% of 1099 COVID-19 patients from China had a fever when they entered the hospital and that 89% developed a fever while in hospital.25 They further found that patients had a cough (68%), fatigue (38%), sputum production (34%), and Figure 2. SARS-CoV-2 morphology. Transmission electron micro- shortness of breath (19%). Many of these symptoms could 13 scope image of SARS-CoV-2 spherical viral particles in a cell. be associated with other respiratory infections. Nucleic acid The virus is colorized in blue (adapted from the US Centers for testing and CT scans have been used for diagnosing and Disease Control). Representation of the viral structure is screening COVID-19. illustrated with its structural viral proteins. Molecular techniques are more suitable than syndromic testing and CT scans for accurate diagnoses because they can polymerase (RdRP) and four structural proteins.15,16 RdRP acts target and identify specific pathogens. The development of in conjunction with nonstructural proteins to maintain genome molecular techniques is dependent upon understanding (1) fidelity. A region of the RdRP gene in SARS-CoV-2 was shown the proteomic and genomic composition of the pathogen or to be highly similar to a region of the RdRP gene found in bat (2) the induction of changes in the expression of proteins/ coronavirus RaTG13 and 96% similar to the RaTG13 overall genes in the host during and after infection. As of March 24, genome sequence.1 Of 104 strains sequenced between 2020, the genomic and proteomic compositions of SARS-CoV- December 2019 and mid-February 2020, 99.9% sequence 2 have been identified, but the host response to the virus is still homology was observed, but, more recently, changes in the under investigation. The first genome sequence of SARS-CoV- viral genome have been catalogued, showing a higher sequence 2 was conducted with metagenomic RNA sequencing, an 2,17 unbiased and high-throughput method of sequencing multiple diversity.
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