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      Diagnosis of SARS-CoV-2 Infection based on CT scan vs. RT-PCR: Reflecting on Experience from MERS-CoV

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          Abstract

          As of 29th February 2010 the World Health Organization had reported a total of 83 652 COVID-19 cases in 51 countries in addition of China [1]. The diagnosis of respiratory viruses such as Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and SARS-CoV relies on detection of the virus by real-time RT PCR (rRT-PCR) for in vitro qualitative detection. The current recommendations are likewise to use rRT-PCR for the detection of SARS-CoV-2 in respiratory samples. There are many knowledge gaps facing the global health community in dealing with the new emerging SARS-CoV-2. Among the most pertinent is early identification of cases to facilitate application of isolation policies. The currently available RT-PCR kits are variable, offering sensitivities ranging between 45 and 60%; thus, especially early in the course of an infection, repeat testing may be required to make a diagnosis. This is not easy to apply with the global shortage of testing kits. This mirrors experience with MERS-CoV. In a study of 336 MERS patients, 89% had a positive result after 1 swab, 96.5% had a positive result after 2 consecutive swabs, and 97.6% had a positive result after 3 swabs (Figure 1 ) [2]. China has changed the case definition over the last 2 months to improve the ability to detect new cases. Data have emerged on the value of CTscan of chest in early diagnosis of cases. Multiple reports published to date have revealed higher sensitivity of CT chest in early detection of SARS-CoV-2 cases [3]. In a study of 51 patients, the positivity rate for a single respiratory swab was 70%, an additional 24% (94% cumulative) after a second test, and an additional 3.9% (98% cumulative) after a third test (Figure 1) [4]. However, an abnormal CT scan findings compatible with viral pneumonia was seen in 98% of patients [4]. This difference had resulted in the recommendations of authors to state that CT scan is more sensitive than PCR. Reasons for low sensitivity of PCR may include insensitive nucleic acid detection methods and variations in the accuracies of different tests, low initial viral load or improper clinical sampling [4]. An additional reason may be that lower respiratory samples may be better than upper respiratory samples, as is the cases with MERS-CoV [5] [6]. Figure 1 Cumulative Positive Rate of Swabs for the diagnosis of SARS-CoV-2 and MERS-CoV based on RT-PCR. Figure 1 In another study of 167 patients, concordant CT scan and PCR test results were observed in 93% of patients, and a discordant results were observed in 4% (positive PCR but negative CT scan) and in 3% (negative initial PCR and positive CT scan) [7]. In a larger study of 1014 SARS-CoV-2 patients, 59% had positive RT-PCR and 88% had positive CT scan; using RT-PCR as a reference, the sensitivity of chest CT imaging was 97% [8]. Growing evidence of the limitations of rRT-PCR prompts further consideration of the limitations of this diagnostic test. First, there are already over 7 different SARS-CoV-2 nucleic acid PCR tests [9]. When considering the viral load in samples, it has shown that upper respiratory tract samples have their peak viral loads 3 days after onset of symptoms, and that nasal, rather than throat samples have the highest viral loads [10]. As the current SARS-CoV-2 epidemic evolves globally we need better diagnostic tests that are rapid, reliable, validated and widely available. For hospitalized patients diagnostic algorithms based on a combination of RT-PCR and CT scan of the chest may prove to be necessary in order to ensure accurate detection of cases and to facilitate infection prevention measures. It is also very important to learn from the previous MERS-CoV epidemic and reflect on that experience, especially that a single negative upper respiratory sample is not enough to rule out infection. It may be prudent to keep those patients in isolation while we obtain additional swabs or be able to safely get lower respiratory samples for definite diagnosis. Declaration of Competing Interest All authors have no conflicts of interest.

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          Most cited references 8

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          SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients

          To the Editor: The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, and has been declared a public health emergency of international concern by the World Health Organization, may progress to a pandemic associated with substantial morbidity and mortality. SARS-CoV-2 is genetically related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries in 2002–2003. 1 The epidemic of SARS-CoV was successfully contained through public health interventions, including case detection and isolation. Transmission of SARS-CoV occurred mainly after days of illness 2 and was associated with modest viral loads in the respiratory tract early in the illness, with viral loads peaking approximately 10 days after symptom onset. 3 We monitored SARS-CoV-2 viral loads in upper respiratory specimens obtained from 18 patients (9 men and 9 women; median age, 59 years; range, 26 to 76) in Zhuhai, Guangdong, China, including 4 patients with secondary infections (1 of whom never had symptoms) within two family clusters (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The patient who never had symptoms was a close contact of a patient with a known case and was therefore monitored. A total of 72 nasal swabs (sampled from the mid-turbinate and nasopharynx) (Figure 1A) and 72 throat swabs (Figure 1B) were analyzed, with 1 to 9 sequential samples obtained from each patient. Polyester flock swabs were used for all the patients. From January 7 through January 26, 2020, a total of 14 patients who had recently returned from Wuhan and had fever (≥37.3°C) received a diagnosis of Covid-19 (the illness caused by SARS-CoV-2) by means of reverse-transcriptase–polymerase-chain-reaction assay with primers and probes targeting the N and Orf1b genes of SARS-CoV-2; the assay was developed by the Chinese Center for Disease Control and Prevention. Samples were tested at the Guangdong Provincial Center for Disease Control and Prevention. Thirteen of 14 patients with imported cases had evidence of pneumonia on computed tomography (CT). None of them had visited the Huanan Seafood Wholesale Market in Wuhan within 14 days before symptom onset. Patients E, I, and P required admission to intensive care units, whereas the others had mild-to-moderate illness. Secondary infections were detected in close contacts of Patients E, I, and P. Patient E worked in Wuhan and visited his wife (Patient L), mother (Patient D), and a friend (Patient Z) in Zhuhai on January 17. Symptoms developed in Patients L and D on January 20 and January 22, respectively, with viral RNA detected in their nasal and throat swabs soon after symptom onset. Patient Z reported no clinical symptoms, but his nasal swabs (cycle threshold [Ct] values, 22 to 28) and throat swabs (Ct values, 30 to 32) tested positive on days 7, 10, and 11 after contact. A CT scan of Patient Z that was obtained on February 6 was unremarkable. Patients I and P lived in Wuhan and visited their daughter (Patient H) in Zhuhai on January 11 when their symptoms first developed. Fever developed in Patient H on January 17, with viral RNA detected in nasal and throat swabs on day 1 after symptom onset. We analyzed the viral load in nasal and throat swabs obtained from the 17 symptomatic patients in relation to day of onset of any symptoms (Figure 1C). Higher viral loads (inversely related to Ct value) were detected soon after symptom onset, with higher viral loads detected in the nose than in the throat. Our analysis suggests that the viral nucleic acid shedding pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 4 and appears different from that seen in patients infected with SARS-CoV. 3 The viral load that was detected in the asymptomatic patient was similar to that in the symptomatic patients, which suggests the transmission potential of asymptomatic or minimally symptomatic patients. These findings are in concordance with reports that transmission may occur early in the course of infection 5 and suggest that case detection and isolation may require strategies different from those required for the control of SARS-CoV. How SARS-CoV-2 viral load correlates with culturable virus needs to be determined. Identification of patients with few or no symptoms and with modest levels of detectable viral RNA in the oropharynx for at least 5 days suggests that we need better data to determine transmission dynamics and inform our screening practices.
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            Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases

            Background Chest CT is used for diagnosis of 2019 novel coronavirus disease (COVID-19), as an important complement to the reverse-transcription polymerase chain reaction (RT-PCR) tests. Purpose To investigate the diagnostic value and consistency of chest CT as compared with comparison to RT-PCR assay in COVID-19. Methods From January 6 to February 6, 2020, 1014 patients in Wuhan, China who underwent both chest CT and RT-PCR tests were included. With RT-PCR as reference standard, the performance of chest CT in diagnosing COVID-19 was assessed. Besides, for patients with multiple RT-PCR assays, the dynamic conversion of RT-PCR results (negative to positive, positive to negative, respectively) was analyzed as compared with serial chest CT scans for those with time-interval of 4 days or more. Results Of 1014 patients, 59% (601/1014) had positive RT-PCR results, and 88% (888/1014) had positive chest CT scans. The sensitivity of chest CT in suggesting COVID-19 was 97% (95%CI, 95-98%, 580/601 patients) based on positive RT-PCR results. In patients with negative RT-PCR results, 75% (308/413) had positive chest CT findings; of 308, 48% were considered as highly likely cases, with 33% as probable cases. By analysis of serial RT-PCR assays and CT scans, the mean interval time between the initial negative to positive RT-PCR results was 5.1 ± 1.5 days; the initial positive to subsequent negative RT-PCR result was 6.9 ± 2.3 days). 60% to 93% of cases had initial positive CT consistent with COVID-19 prior (or parallel) to the initial positive RT-PCR results. 42% (24/57) cases showed improvement in follow-up chest CT scans before the RT-PCR results turning negative. Conclusion Chest CT has a high sensitivity for diagnosis of COVID-19. Chest CT may be considered as a primary tool for the current COVID-19 detection in epidemic areas. A translation of this abstract in Farsi is available in the supplement. - ترجمه چکیده این مقاله به فارسی، در ضمیمه موجود است.
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              Chest CT for Typical 2019-nCoV Pneumonia: Relationship to Negative RT-PCR Testing

              Some patients with positive chest CT findings may present with negative results of real time reverse-transcription–polymerase chain- reaction (RT-PCR) for 2019 novel coronavirus (2019-nCoV). In this report, we present chest CT findings from five patients with 2019-nCoV infection who had initial negative RT-PCR results. All five patients had typical imaging findings, including ground-glass opacity (GGO) (5 patients) and/or mixed GGO and mixed consolidation (2 patients). After isolation for presumed 2019-nCoV pneumonia, all patients were eventually confirmed with 2019-nCoV infection by repeated swab tests. A combination of repeated swab tests and CT scanning may be helpful when for individuals with high clinical suspicion of nCoV infection but negative RT-PCR screening
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                Author and article information

                Contributors
                Journal
                J Hosp Infect
                J. Hosp. Infect
                The Journal of Hospital Infection
                The Healthcare Infection Society. Published by Elsevier Ltd.
                0195-6701
                1532-2939
                6 March 2020
                6 March 2020
                Affiliations
                [1 ]Infectious Disease Unit, Specialty Internal Medicine, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
                [2 ]Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA;
                [3 ]Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;
                [4 ]Director Research Center, King Saud Medical City, Ministry of Health
                [5 ]Al-Faisal University, Riyadh, Saudi Arabia
                [6 ]Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA5
                Author notes
                []Corresponding author. P.O. Box 76; Room A-428-2, Building 61, Dhahran Health Center, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia. ; Tel.: +966 13-870-3524; fax: +966 13-870-3790. jaffar.tawfiq@ 123456jhah.com jaltawfi@ 123456yahoo.com
                Article
                S0195-6701(20)30100-6
                10.1016/j.jhin.2020.03.001
                7124270
                32147407
                © 2020 The Healthcare Infection Society. Published by 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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