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      Managing high clinical suspicion COVID-19 inpatients with negative RT-PCR: a pragmatic and limited role for thoracic CT

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          Abstract

          As the COVID-19 pandemic sweeps across the UK there remain issues with reverse-transcription polymerase chain reaction (RT-PCR), the gold standard diagnostic method. Delays in obtaining results have been particularly problematic. Some patients, including those with high clinical suspicion of COVID-19, test falsely negative on initial RT-PCR test, sometimes requiring multiple subsequent tests to return an eventual positive result. Suggested possible reasons for this include: suboptimal clinical sampling techniques; variations in viral load; and manufacturer test kit sensitivity.1 With surging caseloads, managing these RT-PCR ‘negative’ patients is proving hugely challenging. An emerging bottleneck to effective care is dealing with isolation capacity. Inpatients who are truly PCR negative can be moved to a non-isolation ward, thereby freeing up isolation beds for COVID-19 positive patients and also reducing risk of nosocomial virus transmission. Patients with high index clinical suspicion of COVID-19, but who test negative on initial RT-PCR test, continue to be managed with respiratory isolation precautions, often undergoing repeat PCR testing. However, this means further delay while awaiting subsequent test results. Against this backdrop, an effective pathway to deal with negative COVID-19 RT-PCR results in the setting of high clinical probability is urgently needed. A further important concern is developing regarding deisolation on patient discharge to either home or community care: a confirmed COVID-19 diagnosis - or confirmed alternative, non-COVID-19 diagnosis - is key to imparting advice to families and carers. Imaging has been suggested as a potential solution to some of these problems. Most patients undergo chest radiograph (CXR) at presentation to hospital, with CXRs being hot-reported using a template classification system produced by British Society of Thoracic Imaging (BSTI).2 This stratifies patients into one of four groups based on CXR: COVID classic/probable; COVID indeterminate; COVID normal; and Non-COVID. Frontline doctors have found this a useful adjunct to clinical assessment. In mainland China, CT was often a first-line investigation for COVID-19. However, such practice was burdensome on radiology departments and hugely challenging for infection control. CT in COVID-19 shows typical findings of ground glass opacity, peripheral consolidation or a combination of both. Ai et al reported CT sensitivity from their Wuhan cohort of 97% when compared with RT-PCR.3 When combined with the possibility for near instantaneous results, it is perhaps not surprising that CT has seen most widespread use in endemic regions of China, Italy and Iran. Some reports have also described typical CT findings consistent with COVID-19 in patients with initial negative RT-PCR who subsequently tested positive on repeat RT-PCR testing.3 4 Several authors5 and professional societies6 have steadfastly suggested that CT should not be used as a first line or pure diagnostic test – while highly sensitive, CT findings of COVID-19 pneumonia are not specific. In addition, false negative CT rates vary in the literature, ranging from 3%–56% in RT-PCR positive patients.7 CT features tend to peak later (day 6–11) in the disease course.8 Importantly, there are huge resource implications of this approach as the scanner requires decontamination each time a ‘positive’ patient is scanned. Radiographers risk repeated exposures to COVID-19, with high likelihood of illness and absence from work, at a time when healthcare workers are a precious resource. Finally, concerning reports from Italy suggest that over-reliance on CT potentially contributed to ‘dirty’ scanners acting as virus transmission vectors, thereby exacerbating COVID-19 spread among staff and COVID-19 naive patients. We agree with Hope et al 5 that “…CT does not add diagnostic value” if used indiscriminately but would disagree that it has no role to play in diagnostic workup. They state “it is clear that the positive results can only be believed if the pre-test probability of disease is high.” This is supported by data from Wong et al where “in the scenario of high clinical suspicion of COVID-19 it is conceivable that a positive CXR can obviate the need for a CT”, thereby reducing burden on CT units during the COVID-19 pandemic.9 While awaiting the RT-PCR result, most suspected COVID-19 patients are clinically diagnosed with the triad of clinical assessment, CXR and blood tests. CT could however play a limited, but important, role in providing diagnostic radiological confirmation in patients with clinically suspected - but RT-PCR negative - disease. This would potentially help resolve whether a patient with suspected high clinical probability of COVID-19 has an alternative diagnosis in addition to influencing infection control strategy (namely the ability to stepdown a patient to a deisolation ward). We have seen patients with negative RT-PCR at presentation with ‘classic/probable’2 changes on CXR and repeat RT-PCR which returns positive. However, there remain a small proportion of patients in whom multiple RT-PCRs are negative and whose CXRs are repeatedly ‘normal’ or ‘indeterminate’, although clinical suspicion remains high. These ‘high clinical probability’ patients are those unwell enough to be admitted to hospital and are not presumed to represent the complete spectrum of COVID-19 patients, most of whom have mild symptoms requiring self-isolation in the community. Our institution has thus devised a pragmatic protocol (figure 1), using CT to help diagnose this group of patients. Capacity for CT use in this limited way has been created as a result of cancelling elective/routine CT requests for other indications, thereby permitting not only rapid access to CT scanning but also allowing ample time for scanner terminal clean in between cases. In our algorithm, CT is performed in patients who return two negative RT-PCR swabs and two CXRs (≥48 hours apart) reported as ‘normal’ or ‘indeterminate’ for COVID-19 (‘double-double negative’). RT-PCR remains the lynchpin of diagnosis and, if negative, is repeated (usually around 48 hours after presentation). The rationale for repeat CXR in patients where the index CXR was not COVID-19 classic/probable is that several patients go on to develop COVID classic appearances, despite a normal/indeterminate index CXR, in the setting of high clinical probability. Figure 1 Proposed infection control management of inpatients with a negative initial COVID-19 nose/throat swab RT-PCR. Patients who are deemed eligible for CT as per our protocol undergo a sequential low dose non-contrast CT thorax and CT pulmonary angiogram (if renal function allows).10 CTPA is performed to ensure occult PE is excluded, particularly in light of reports of increased pro-thrombotic risk in COVID-19. The non-contrast CT prior is performed for two main reasons: i) dependent ground glass is often exaggerated on post-contrast scan and can be mistaken for true ground glass; ii) having a baseline non-contrast scan can be useful if then performing subsequent unenhanced scans. The key to our pathway is thorough clinical assessment as pre-test probability determines how these patients are managed, above all else. As the pandemic progresses it may be that so many cases ‘swamp’ the system that CT is forced to take a more upfront role in patient triage. At present with infection control such a key facet of patient management – as well as staff safety – the RFL NHS Trust negative PCR pathway enables a systematic approach to patient deisolation and stepdown from COVID ward to Non-COVID wards.

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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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            Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR

            Summary In a series of 51 patients with chest CT and RT-PCR assay performed within 3 days, the sensitivity of CT for COVID-19 infection was 98% compared to RT-PCR sensitivity of 71% (p<.001). Introduction In December 2019, an outbreak of unexplained pneumonia in Wuhan [1] was caused by a new coronavirus infection named COVID-19 (Corona Virus Disease 2019). Noncontrast chest CT may be considered for early diagnosis of viral disease, although viral nucleic acid detection using real-time polymerase chain reaction (RT-PCR) remains the standard of reference. Chung et al. reported that chest CT may be negative for viral pneumonia of COVID-19 [2] at initial presentation (3/21 patients). Recently, Xie reported 5/167 (3%) patients who had negative RT-PCR for COVID-19 at initial presentation despite chest CT findings typical of viral pneumonia [3]. The purpose of this study was to compare the sensitivity of chest CT and viral nucleic acid assay at initial patient presentation. Materials and Methods The retrospective analysis was approved by institutional review board and patient consent was waived. Patients at Taizhou Enze Medical Center (Group) Enze Hospital were evaluated from January 19, 2020 to February 4, 2020. During this period, chest CT and RT-PCR (Shanghai ZJ Bio-Tech Co, Ltd, Shanghai, China) was performed for consecutive patients who presented with a history of 1) travel or residential history in Wuhan or local endemic areas or contact with individuals with individuals with fever or respiratory symptoms from these areas within 14 days and 2) had fever or acute respiratory symptoms of unknown cause. In the case of an initial negative RT-PCR test, repeat testing was performed at intervals of 1 day or more. Of these patients, we included all patients who had both noncontrast chest CT scan (slice thickness, 5mm) and RT-PCR testing within an interval of 3 days or less and who had an eventual confirmed diagnosis of COVID-19 infection by RT-PCR testing (Figure 1). Typical and atypical chest CT findings were recorded according to CT features previously described for COVD-19 (4,5). The detection rate of COVID-19 infection based on the initial chest CT and RT-PCR was compared. Statistical analysis was performed using McNemar Chi-squared test with significance at the p <.05 level. Figure 1: Flowchart for patient inclusion. Results 51 patients (29 men and 22 women) were included with median age of 45 (interquartile range, 39- 55) years. All patients had throat swab (45 patients) or sputum samples (6 patients) followed by one or more RT-PCR assays. The average time from initial disease onset to CT was 3 +/- 3 days; the average time from initial disease onset to RT-PCR testing was 3 +/- 3 days. 36/51 patients had initial positive RT-PCR for COVID-19. 12/51 patients had COVID-19 confirmed by two RT-PCR nucleic acid tests (1 to 2 days), 2 patients by three tests (2-5 days) and 1 patient by four tests (7 days) after initial onset. 50/51 (98%) patients had evidence of abnormal CT compatible with viral pneumonia at baseline while one patient had a normal CT. Of 50 patients with abnormal CT, 36 (72%) had typical CT manifestations (e.g. peripheral, subpleural ground glass opacities, often in the lower lobes (Figure 2) and 14 (28%) had atypical CT manifestations (Figure 3) [2]. In this patient sample, difference in detection rate for initial CT (50/51 [98%, 95% CI 90-100%]) patients was greater than first RT-PCR (36/51 [71%, 95%CI 56-83%]) patients (p<.001). Figure 2a: Examples of typical chest CT findings compatible with COVID-19 pneumonia in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 74 years old with fever and cough for 5 days. Axial chest CT shows bilateral subpleural ground glass opacities (GGO). B, female, 55 years old, with fever and cough for 7 days. Axial chest CT shows extensive bilateral ground glass opacities and consolidation; C, male, 43 years old, presenting with fever and cough for 1 week. Axial chest CT shows small bilateral areas of peripheral GGO with minimal consolidation; D, female, 43 years old presenting with fever with cough for 5 days. Axial chest CT shows a right lung region of peripheral consolidation. Figure 2b: Examples of typical chest CT findings compatible with COVID-19 pneumonia in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 74 years old with fever and cough for 5 days. Axial chest CT shows bilateral subpleural ground glass opacities (GGO). B, female, 55 years old, with fever and cough for 7 days. Axial chest CT shows extensive bilateral ground glass opacities and consolidation; C, male, 43 years old, presenting with fever and cough for 1 week. Axial chest CT shows small bilateral areas of peripheral GGO with minimal consolidation; D, female, 43 years old presenting with fever with cough for 5 days. Axial chest CT shows a right lung region of peripheral consolidation. Figure 2c: Examples of typical chest CT findings compatible with COVID-19 pneumonia in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 74 years old with fever and cough for 5 days. Axial chest CT shows bilateral subpleural ground glass opacities (GGO). B, female, 55 years old, with fever and cough for 7 days. Axial chest CT shows extensive bilateral ground glass opacities and consolidation; C, male, 43 years old, presenting with fever and cough for 1 week. Axial chest CT shows small bilateral areas of peripheral GGO with minimal consolidation; D, female, 43 years old presenting with fever with cough for 5 days. Axial chest CT shows a right lung region of peripheral consolidation. Figure 2d: Examples of typical chest CT findings compatible with COVID-19 pneumonia in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 74 years old with fever and cough for 5 days. Axial chest CT shows bilateral subpleural ground glass opacities (GGO). B, female, 55 years old, with fever and cough for 7 days. Axial chest CT shows extensive bilateral ground glass opacities and consolidation; C, male, 43 years old, presenting with fever and cough for 1 week. Axial chest CT shows small bilateral areas of peripheral GGO with minimal consolidation; D, female, 43 years old presenting with fever with cough for 5 days. Axial chest CT shows a right lung region of peripheral consolidation. Figure 3a: Examples of chest CT findings less commonly reported in COVID-19 infection (atypical) in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 36 years old with cough for 3 days. Axial chest CT shows a small focal and central ground glass opacity (GGO) in the right upper lobe; B, female, 40 years old. Axial chest CT shows small peripheral linear opacities bilaterally. C, male, 38 years old. Axial chest CT shows a GGO in the central left lower lobe; D, male, 31 years old with fever for 1 day. Axial chest CT shows a linear opacity in the left lower lateral mid lung. Figure 3b: Examples of chest CT findings less commonly reported in COVID-19 infection (atypical) in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 36 years old with cough for 3 days. Axial chest CT shows a small focal and central ground glass opacity (GGO) in the right upper lobe; B, female, 40 years old. Axial chest CT shows small peripheral linear opacities bilaterally. C, male, 38 years old. Axial chest CT shows a GGO in the central left lower lobe; D, male, 31 years old with fever for 1 day. Axial chest CT shows a linear opacity in the left lower lateral mid lung. Figure 3c: Examples of chest CT findings less commonly reported in COVID-19 infection (atypical) in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 36 years old with cough for 3 days. Axial chest CT shows a small focal and central ground glass opacity (GGO) in the right upper lobe; B, female, 40 years old. Axial chest CT shows small peripheral linear opacities bilaterally. C, male, 38 years old. Axial chest CT shows a GGO in the central left lower lobe; D, male, 31 years old with fever for 1 day. Axial chest CT shows a linear opacity in the left lower lateral mid lung. Figure 3d: Examples of chest CT findings less commonly reported in COVID-19 infection (atypical) in patients with epidemiological and clinical presentation suspicious for COVID-19 infection. A, male, 36 years old with cough for 3 days. Axial chest CT shows a small focal and central ground glass opacity (GGO) in the right upper lobe; B, female, 40 years old. Axial chest CT shows small peripheral linear opacities bilaterally. C, male, 38 years old. Axial chest CT shows a GGO in the central left lower lobe; D, male, 31 years old with fever for 1 day. Axial chest CT shows a linear opacity in the left lower lateral mid lung. Discussion In our series, the sensitivity of chest CT was greater than that of RT-PCR (98% vs 71%, respectively, p<.001). The reasons for the low efficiency of viral nucleic acid detection may include: 1) immature development of nucleic acid detection technology; 2) variation in detection rate from different manufacturers; 3) low patient viral load; or 4) improper clinical sampling. The reasons for the relatively lower RT-PCR detection rate in our sample compared to a prior report are unknown (3). Our results support the use of chest CT for screening for COVD-19 for patients with clinical and epidemiologic features compatible with COVID-19 infection particularly when RT-PCR testing is negative.
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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

                Journal
                Thorax
                Thorax
                thoraxjnl
                thorax
                Thorax
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0040-6376
                1468-3296
                July 2020
                21 April 2020
                21 April 2020
                : 75
                : 7
                : 537-538
                Affiliations
                [1 ] departmentDepartment of Radiology , Royal Free London NHS Foundation Trust , London, UK
                [2 ] departmentDepartment of Respiratory Medicine , Royal Free London NHS FoundationTrust , London, UK
                [3 ] departmentDepartment of Microbiology , Royal Free London NHS Foundation Trust , London, UK
                Author notes
                [Correspondence to ] Dr Samanjit S Hare, Department of Radiology, Royal Free London NHS Foundation Trust, London, United Kingdom; samhare@ 123456nhs.net

                ANT and AB are joint first authors.

                DDC and SSH are joint senior authors.

                Article
                thoraxjnl-2020-214916
                10.1136/thoraxjnl-2020-214916
                7361024
                32317269
                ea3d2d03-b2ad-4fd3-8a08-233a997a9f2f
                © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

                This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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                Controversies and Challenges in Respiratory Medicine
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                2313
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                Surgery
                imaging/ct mri etc,infection control,viral infection
                Surgery
                imaging/ct mri etc, infection control, viral infection

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