key: cord-0983216-vvjqw8cb authors: De Smet, Kristof; De Smet, Dieter; Ryckaert, Thomas; Laridon, Emanuel; Heremans, Birgit; Vandenbulcke, Ruben; Demedts, Ingel; Bouckaert, Bernard; Gryspeerdt, Stefaan; Martens, Geert A. title: Diagnostic Performance of Chest CT for SARS-CoV-2 Infection in Individuals with or without COVID-19 Symptoms date: 2020-08-10 journal: Radiology DOI: 10.1148/radiol.2020202708 sha: 5a446f033e3ec8724dbe4439eaaeae4b4a7b73a9 doc_id: 983216 cord_uid: vvjqw8cb BACKGROUND: The use of chest CT for COVID-19 diagnosis or triage in healthcare settings with limited SARS-CoV-2 PCR capacity is controversial. CO-RADS categorization of the level of COVID-19 suspicion might improve diagnostic performance. PURPOSE: To investigate the value of chest CT with CO-RADS classification to screen for asymptomatic SARS-CoV-2 infections and to determine its diagnostic performance in individuals with COVID-19 symptoms during the exponential phase of viral spread. MATERIALS AND METHODS: In this secondary analysis of a prospective trial (Clinical Trial Number: IRB B1172020000008), from March 2020 to April 2020, we performed parallel SARS-CoV-2 PCR and CT with categorization of COVID-19 suspicion by CO-RADS, for individuals with COVID-19 symptoms and controls without COVID-19 symptoms admitted to the hospital for medical urgencies unrelated to COVID-19. CT-CORADS was categorized on a 5-point scale from 1 (very low suspicion) to 5 (very high suspicion). AUC were calculated in symptomatic versus asymptomatic individuals to predict positive SARS-CoV-2 positive PCR and likelihood ratios for each CO-RADS score were used for rational selection of diagnostic thresholds. RESULTS: 859 individuals (median 70 years, IQR 52-81, 443 men) with COVID-19 symptoms and 1138 controls (median 68 years, IQR 52-81, 588 men) were evaluated. CT-CORADS had good diagnostic performance (P<.001) in both symptomatic (AUC=.89) and asymptomatic (AUC=.70) individuals. In symptomatic individuals (41.7% PCR+), CO-RADS ≥ 3 detected positive PCR with high sensitivity (89%, 319/358) and 73% specificity. In asymptomatic individuals (5.3% PCR+), a CO-RADS score ≥ 3 detected SARS-CoV-2 infection with low sensitivity (45%, 27/60) but high specificity (89%). CONCLUSION: CT-CORADS had good diagnostic performance in symptomatic individuals, supporting its application for triage. Sensitivity in asymptomatic individuals was insufficient to justify its use as first-line screening approach. Incidental detection of CO-RADS ≥ 3 in asymptomatic individuals should trigger testing for respiratory pathogens. Chest CT can help determine the temporal disease stage and severity of COVID-19 pneumonia 1-3 . In the early stage of viral replication (day 0-4) ground-glass opacities are the predominant lesion. In the progressive stage (day [5] [6] [7] [8] , crazy paving patterns mark the increased recruitment of inflammatory cells to the lung interstitium. Peak stage (day [10] [11] [12] [13] is marked by consolidation with fibrosis and diffuse alveolar damage. These radiological lesions are also observed in other viral pneumonia and non-infectious inflammatory lung diseases but in a pandemic context might harbor diagnostic potential for SARS-CoV-2 infection especially for patient triage. The reference method for COVID-19 diagnosis, SARS-CoV-2 PCR, is highly specific but has variable sensitivity as low as 70% 4 . In health care settings with limited PCR capacity and long turnaround times, chest CT was proposed as alternative for COVID-19 diagnosis or triage 5 . Studies supporting chest CT as first-line diagnostic tool for COVID-19 showed several methodological concerns [6] [7] [8] . Most studies were underpowered, showed major selection biases including only individuals with COVID-19 symptoms and 40%-50% a priori risk of SARS-CoV-2 infection and used binary scoring of CT without standardized definition of COVID-19-compatible CT. Weighed against the cost and procedural risks of CT, this sparked a controversy 8 9 leading to consensus statements by the Centers for Disease Control and Prevention, the American College of Radiology, the Society of Thoracic Radiology, the American Society of Emergency Radiology, The Fleischner Society, and the Radiological Society of North America (RSNA), opposing CT as first-line COVID-19 diagnostic tool [10] [11] [12] [13] . In this report, we studied the diagnostic power of chest CT versus SARS-CoV-2 PCR using COVID -19 Reporting and Data System classification system (CO-RADS) 14 . CO-RADS was developed by the Dutch Radiological Society to categorize the level of suspicion for COVID-19 pneumonia. It generally aligns with the structured reporting recommended by the RNSA 13 , scoring the level of COVID-19 suspicion on a scale of 1 to 5, with CO-RADS 1 corresponding to 'negative' category, CO-RADS 2 to 'Atypical', CO-RADS 3 and 4 corresponding to 'Indeterminate' with 'lower' or 'higher likelihood', and CO-RADS 5 equaling the RNSA 'Typical' category. The purpose of this study was to investigate the value of chest CT with CO-RADS classification to screen for asymptomatic SARS-CoV-2 infections and to determine its diagnostic performance in individuals with COVID-19 symptoms during the exponential phase of viral spread. These data should allow a more evidence-based definition of the possible role of chest CT in COVID-19 triage. Participants This is a secondary analysis of a single-center prospective trial on consecutive individuals admitted to AZ Delta General Hospital in Roeselare, Belgium from March 19, 2020 to April 20, 2020. AZ Delta General Hospital is a central-network regional hospital that provides tertiary healthcare for a community of 500,000 inhabitants. Inclusion criteria: as part of the medical boardapproved triage policy for COVID-19 quarantining, all individuals admitted to the hospital with clinical suspicion of COVID-19 pneumonia (hence 'symptomatic individuals') and individuals without COVID-19 symptoms but admitted for other medical urgencies, scheduled surgery or medical procedures and psychiatric or geriatric care (hence 'asymptomatic individuals'), received a combined screening with chest CT and SARS-CoV-2 PCR within a 24-hour time frame. We used the COVID-19 case definition as specified by the World Health Organization (WHO) interim guidance of February 27, 2020 15 for classifying symptomatic individuals. Exclusion criteria: children < 14 years of age and pregnant individuals without COVID-19 symptoms did not receive standard chest CT. The study was approved by the AZ Delta Institutional Review Board with a waiver of written informed consent from study participants considering the study is based on secondary analysis of existing data (Clinical Trial Number: IRB B1172020000008, study protocol available through the registry of the Belgian Advisory Committee on Bioethics and email request to corresponding author). Authors received no specific funding for this study. CT protocol Within 24h from admission all individuals were imaged by multi-detector CT using either GE LightSpeed VCT scanner (1-mm slice thickness), Siemens Somatom AS (1-mm slice thickness) or I n P r e s s the GE Optmima 660 scanner (1.25-mm slice thickness). All scans were performed without intravenous contrast with the patient in the supine position during end-inspiration. Image evaluation Two cardiothoracic radiologists with 24 and 9 years of experience (Gryspeerdt S., De Smet K.) retrospectively reviewed the CT exams on a PACS workstation (IDS7, Sectra) with multiplanar reconstruction tools. Reviewers were blinded to (a)symptomatic status and PCR result. Final CO-RADS scoring was always reached by consensus. The Dutch CO-RADS (COVID-19 Reporting and Data System) classification system was used to categorize the level of COVID-19 suspicion, exactly as described 14 : CO-RADS score ranges from 1 (very low level of suspicion), 2 (low level), 3 (equivocal), 4 (high level of suspicion) to 5 (very high level of suspicion) (summarized and representative images in Fig. 3 ). See Appendix E1 for detailed CT protocol. Comorbidities were recorded by chest CT (chronic lung disease including emphysema, fibrosis and bronchiectasis and coronary artery disease as derived from coronary artery calcification scoring) or review of medical records (diabetes). SARS-CoV-2 PCR was done with multiplex RT-PCR (hence PCR) for E/N/RdRP genes using Allplex 2019-nCoV assay (Seegene Inc, Seoul, Korea) on nasopharyngeal swabs. The diagnostic performance of categorical CT-assessment by CO-RADS classification (CT-CORADS) was evaluated by calculating area (AUC) under the receiver operating characteristics (ROC) curve compared to SARS-CoV-2 PCR positivity. Likelihood ratios (LR, 95%CI) were calculated for each CO-RADS score in the symptomatic versus the asymptomatic group and visualized in diagrams of pre/post-test probability. According to Bayes' theorem, post-test probability (Ppost) can be derived from pre-test probability (Ppre) and LR according to the formula Ppost = (Ppre x LR) / (1 + Ppre x (LR-1)) I n P r e s s where Ppre represents the prevalence of SARS-CoV-2 PCR-positivity in any population under study. Statistical differences in demographics and comorbidities were evaluated by Mann-Whitney test (age) and Chi-squared test (proportions). Statistical analyses were performed using MedCalc (version 12.2.1, MedCalc Software, Mariakerke, Belgium) and considered significant if P value was less than .05. A total of 1997 consecutive individuals (flowchart Fig. 1 ) admitted to the hospital were allocated by physical examination and anamnesis into two groups. First, 859 individuals were admitted with WHO-listed symptoms of COVID-19 pneumonia (hence 'symptomatic individuals'): 443 males (median age 71 years, IQR 54-80 years) and 416 females (median age 68 years, IQR 51-82 years) (Table 1) . Second, 1138 individuals were admitted for medical needs unrelated to WHO-listed COVID-19 symptoms (hence 'asymptomatic individuals'): 588 males (median age 66 years, IQR 53-78 years) and 550 females (median age 70 years, IQR 50-82 years). Demographics and key clinical comorbidities are shown in Table 1 : individuals with or without COVID-19 symptoms showed a similar age-and sex-distribution and a similar prevalence of diabetes and coronary artery disease (Table 1) . PCR-negative symptomatic individuals had higher rates of underlying chronic lung disease (27.9%, 140 of 501) than PCR-positive symptomatic (21.5%, 77 of 358, P<0.05) and PCR-negative asymptomatic individuals (20.6%, 222 of 1078, P<0.05). The overall prevalence of SARS-CoV-2 infection in symptomatic individuals was 41.7% (358 of 859). In (Table 2) . Table 2 indicating that chest CT cannot replace PCR as diagnostic test. In our asymptomatic controls, prevalence of SARS-CoV-2 PCR-positivity was 5.3%, in line with the secondary attack rate at population level of 6.6% during the exponential phase of viral spread 16 . This control group was thus suitable to investigate if chest CT can screen for asymptomatic SARS-CoV-2 infection. Also in I n P r e s s asymptomatic individuals CT-CORADS showed good diagnostic performance. However, various dichotomization scenarios failed to reach the high sensitivity required for a screening test. CO-RADS ≥ 4 attained only 31.7% sensitivity. A negative test (CO-RADS <4) shifted pre-to post-test probability only from 5.3% to 3.9%, insufficient to justify the procedural risk of CT. The specificity of CO-RADS ≥ 4 in asymptomatic individuals, however, was high (94.4%) and resulted in meaningful increase in post-test probability to 24.1%. In a pandemic setting, we propose that such incidental findings should be reported as 'compatible with COVID-19 pneumonia' rather than as 'viral pneumonia' as suggested by the RNSA 13 Like sensitivity and specificity, LR are test properties that, in defined patient populations, are independent of disease prevalence. The actual clinical values of a positive test result to confirm or negative test result to rule-out disease, the positive (PPV) and negative (NPV) predictive value respectively, strongly depend on disease prevalence 19 . Using LR, the post-test probability as indicator of PPV can simply be calculated (formula in Methods) taking the observed prevalence of I n P r e s s PCR-positivity as pre-test probability. Similarly, NPV is 1 minus the post-test probability. PPV is mathematically most influenced by specificity 19 . Meta-analysis showed a low pooled specificity of dichotomic chest CT of 37% for COVID-19 diagnosis 20 with low associated PPV from 1.5%-8.3% in low prevalence (<10%) settings. Our data illustrate that CO-RADS categorization improves specificity and thus discloses higher PPV as LR increase. NPV is mostly influenced by sensitivity 19 . In our data set, sensitivity of chest CT was insufficient to exclude SARS-CoV-2 infection both in symptomatic and asymptomatic patients. This supports the consensus statements that chest CT should not be used as diagnostic test. Our study has limitations. It was conducted in a time frame with high rates of SARS-CoV-2 infections and low prevalence of other viral pneumonia. Higher incidence of seasonal respiratory viral infections will likely decrease specificity of CT-CORADS. Selection bias: study included mostly individuals older than 50 years attending the hospital and excluded pediatric and pregnant individuals. Paucisymptomatic infections in home-quarantined older individuals and asymptomatic infections in younger individuals are underrepresented in our data set. In conclusion, our data show that CT with structured CO-RADS scoring had good diagnostic performance for COVID-19 pneumonia but cannot replace SARS-CoV-2 PCR as diagnostic test. It can be used as alternative triage tool in individuals with COVID-19 symptoms but not for the screening of asymptomatic SARS-CoV-2 infections. The authors declare no conflict of interest. This work was supported by a donation from board members of Fagron (Nazareth, Belgium), a healthcare company, to RADar, the teaching and education initiative of AZ Delta General Hospital, to be used as unconditional research grant for data collection and open access publication. The sponsor had no influence on the study design, data interpretation and drafting of the manuscript. year old woman with medical history of haemochromatosis and psoriatic arthritis was admitted with wheezing, dry cough and increasing dyspnea since 2 weeks. She was subfebrile and hypoxic (89% SpO2). Blood testing showed increased CRP (32.8 mg/L) and leukocytosis with eosinophilia (1.1 x 10e3/µl). CT showed no pleural effusion but presence of multifocal bilateral ground glass opacities, scored as CO-RADS 5. SARS-CoV-2 PCR was repeatedly negative on nasopharyngeal swab. Extended syndromic PCR testing for 33 respiratory pathogens including 14 respiratory viruses was negative. Bronchoalveolar lavage was also repeatedly negative for SARS-CoV-2 PCR but showed high load of eosinophils (52 % of 65 x 10e4 nucleated cells/mL) supporting the diagnosis of acute eosinophilic pneumonia. The woman was successfully treated with corticosteroids. year-old woman was admitted with diarrhea and left iliac fossa pain. She presented no respiratory symptoms, myalgia, loss of taste or smell or abnormal fatigue. Fever (39.4%) was attributed to suspected diverticulitis but a CT abdomen was negative. Standard chest CT scan as part of COVID-19 infection control policy showed multifocal bilateral ground glass opacities and crazy paving pattern, scored as CO-RADS 5. Blood testing showed increased CRP (48.4 mg/L), normal leukocyte count (6.8 x 10e3/μl) and no lymphocytopenia but increased D-dimers (1428 ng/mL) and increased LDH (669 U/L). Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases False-negative results of initial RT-PCR assays for COVID-19: a systematic review Chinese National Health Commission, Chinese Clinical Guidance for COVID-19 Chest Computed Tomography for Detection of Coronavirus Disease 2019 (COVID-19): Don't Rush the Science Chest CT and Coronavirus Disease (COVID-19): A Critical Review of the Literature to Date A role for CT in COVID-19? What data really tell us so far CT screening for early diagnosis of SARS-CoV-2 infection ACR recommendations for the use of chest radiography and computed tomography (CT) for suspected COVID-19 infection. ACR website. www.acr.org/ Advocacy-and Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CTfor-Suspected-COVID19-Infection ASER COVID-19 Task Force: FAQs The Role of Chest Imaging in Patient Management During the COVID-19 Pandemic: A Multinational Consensus Statement From the Fleischner Society Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA CO-RADS -A categorical CT assessment scheme for patients with suspected COVID-19: definition and evaluation World Health Organization Global surveillance for COVID-19 disease caused by human infection with novel coronavirus (COVID-19): interim guidance Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR A systematic review of chest imaging findings in COVID-19 Imaging Publications in the COVID-19 Pandemic: Applying New Research Results to Clinical Practice Diagnostic Performance of CT and Reverse Transcriptase-Polymerase Chain Reaction for Coronavirus Disease 2019: A Meta-Analysis Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection CO-RADS -A categorical CT assessment scheme for patients with suspected COVID-19: definition and evaluation The authors thank Hendrik Verelst, Fien Trenson, Ludovic Cruyt and Jonas De Melio for expert interpretation of chest CT and data contribution to consensus CO-RADS scoring and Boris Keppens for helpful discussions. I n P r e s s 60 1078Pre-test probability = 5.3% CO-RADS ≥ 3 CO- RADS For each study participant, the chest CT scan was evaluated for the following characteristics: (1) presence of ground-glass opacities (early stage, "stage 1"), (2) presence of crazy paving pattern of underlying lung disease such as emphysema or fibrosis. Each of the five lung lobes was assessed for degree of involvement and classified as none (0%), discrete (<5%), minimal (5 -25%), mild (26 -50%), moderate (51 -75%), or severe (> 75%). No involvement corresponded to a lobe score of 0, discrete to a lobe score of 1, minimal to a lobe score of 2, mild to a lobe score of 3, moderate to a lobe score of 4, and severe to a lobe score of 5. An overall lung "CT-severity score" was reached by summing the five lobe scores (range of possible scores, 0 -25). CT-severity score was not used in the current study.The stage was estimated by consensus evaluation of the predominant radiological presentation:ground-glass opacities (early stage, 0-4 days, "stage 1"), (2) presence of crazy paving pattern (progressive stage, 5-8 days, "stage 2"), (3) presence of consolidation (peak stage, 10-13 days, "stage 3") 2 The Dutch CO-RADS (COVID-19 Reporting and Data System) classification system was used to categorize the level of COVID-19 suspicion, exactly as described 2 . CO-RADS score ranges from 1 (very low level of suspicion), 2 (low level), 3 (equivocal), 4 (high level of suspicion) to 5 (very high level of suspicion).