key: cord-0759995-3tz4gthu
authors: Dangis, Anthony; Gieraerts, Christopher; Bruecker, Yves De; Janssen, Lode; Valgaeren, Hanne; Obbels, Dagmar; Gillis, Marc; Ranst, Marc Van; Frans, Johan; Demeyere, Annick; Symons, Rolf
title: Accuracy and reproducibility of low-dose submillisievert chest CT for the diagnosis of COVID-19
date: 2020-04-21
journal: Radiol Cardiothorac Imaging
DOI: 10.1148/ryct.2020200196
sha: 645d90a2a3a2a84eb92a7357c0a7fe53c7cf6704
doc_id: 759995
cord_uid: 3tz4gthu

PURPOSE: To demonstrate the accuracy and reproducibility of low-dose submillisievert chest CT for the diagnosis of COVID-19 infection in emergency room (ER) patients. MATERIALS AND METHODS: This was a HIPAA-compliant, institutional review board-approved retrospective study. From March 14(th) to March 24(th) 2020, 192 ER patients with symptoms suggestive of COVID-19 infection were studied with low-dose chest CT and real time polymerase chain reaction (RT-PCR). Image analysis included likelihood of COVID-19 infection and semi-quantitative extent of lung involvement. CT images were analyzed by 2 radiologists blinded to RT-PCR results. Reproducibility was assessed with McNemar test and intra-class correlation coefficient (ICC). Time between CT acquisition and report was measured. RESULTS: When compared to RT-PCR, low-dose submillisievert chest CT demonstrated excellent sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for diagnosis of COVID-19 (86.7%, 93.6%, 91.1%, 90.3%, and 90.2%, respectively), in particular in patients with clinical symptoms for >48h (95.6%, 93.2%, 91.5%, 96.5%, and 94.4%, respectively). In patients with a positive CT, likelihood of disease increased from 43.2% (pre-test probability) to 91.1% or 91.4% (post-test probability), while in patients with a negative CT, likelihood of disease decreased to 9.6% or 3.7% for all patients or those with clinical symptoms for >48h, respectively. The prevalence of alternative diagnoses based on chest CT in patients without COVID-19 infection was 17.6%. Mean effective radiation dose was 0.56±0.25 mSv (SD). Median time between CT acquisition and report was 25 minutes (IQR: 13-49 minutes). Intra- and interreader reproducibility of CT was excellent (all ICC□0.95) without significant bias in Bland-Altman analysis. CONCLUSION: Low-dose submillisievert chest CT allows for rapid, accurate and reproducible assessment of COVID-19 infection in ER patients, in particular in patients with symptoms lasting longer than 48 hours. Chest CT has the additional advantage of offering alternative diagnoses in a significant subset of patients.

represents the gold standard for the diagnosis of COVID-19 with very high specificity and can be easily obtained by throat swab sampling. The sensitivity of RT-PCR has been reported to be around 70% in initial reports which is rather low for screening (4) . One negative RT-PCR test therefore does not exclude COVID-19 and multiple repeat tests may be required to make the final diagnosis, leading to multiple days of uncertainty for both patients and healthcare professionals.

Chest computed tomography (CT) may represent an additional tool for the initial assessment of patients with possible COVID-19 infection. COVID-19 pneumonia causes bilateral, peripheral and basal predominant areas of ground-glass opacities (GGO), typically evolving to consolidation at later stages of the disease (5, 6) . A previous study has demonstrated excellent sensitivity (97%) but poor specificity (25%) of chest CT for the diagnosis of COVID-19 (7) . These results suggest a complementary approach combining the high sensitivity of chest CT with the I n p r e s s high specificity of RT-PCR may be effective for early COVID-19 diagnosis. Given the very common and rapidly increasing clinical indication of chest CT for COVID-19 diagnosis, accurate and reproducible assessment with a low radiation dose (submillisievert) protocol may result in major radiation dose reductions on a population level (8) . The purpose of this study was to investigate whether submillisievert chest CT could be used to rapidly, accurately and reproducibly stratify patients with possible COVID-19 infection.

This retrospective study was compliant with the Health Insurance Portability and Accountability Act and was approved by our institutional review board (Imelda Hospital, Bonheiden, Belgium).

Informed consent was waived. From March 14 th to March 24 th 2020, 192 consecutive patients with possible COVID-19 infection and both RT-PCR and low-dose chest CT at presentation were included. The RT-PCR results were obtained from the patient electronic medical record.

Patients who showed negative results on RT-PCR underwent repeat RT-PCR examination the following day. If this second RT-PCR was positive, the patient was considered to be COVID-19 positive. Two PCR methods were used to detect SARS-CoV-2 in nasopharyngeal swabs (eSwab, Copan Diagnostics, Brescia, Italy), both using the E-gene as target. Primers and probe sequences for the E-gene were provided by the Belgian National Reference Center (University Hospital Leuven, Leuven, Belgium). The first platform, the ARIES system (Luminex, Austin, USA), provides an open channel for lab developed tests. It is an all-in-one system with extraction, purification, amplification and detection in one cassette. Luminex SYNCT software is used to analyze and interpret PCR results. It can run up to twelve samples simultaneously with a hands-I n p r e s s on-time of 10 min and a turn-around-time of 1h45. The second platform, the Rotorgene Q (Qiagen, Hilden, Germany), is a real-time PCR instrument. Extraction is performed on NucliSENS EasyMAG (BioMérieux, Marcy l'Étoile, France). Rotor-Gene Q Series software is used to interpret the data. It is a higher volume, batch test, with a capacity of up to 72 samples simultaneously, but time from sample to results is at least 2h45 (due to a longer hands-on time, and separate extraction process). The sensitivity of the SARS-CoV-2 test on Aries was analyzed by testing a dilution series of an inactivated culture of SARS-CoV-2 and was similar to the assay of the Belgian National Reference Center. The sensitivity on Rotorgene Q was validated in relation to Aries analyzing samples on both platforms. No cross reactivity for other human Coronaviruses, Influenza or Respiratory Syncytial Virus (RSV) has been shown.

All patients underwent low-dose chest CT by using a Somatom Definition AS 64-slice 0.6 mm detector scanner (Siemens Healthineers, Forchheim, Germany). We used the vendor-supplied software (Care Dose 4D, Siemens Healthineers) to calculate size-specific radiation dose estimates for a low-dose chest CT protocol adapted from the protocol used for lung cancer screening (9) . Reference values in a so-called average patient were set to 100 kVp and 20 mAs with a pitch of 1.2 and 0.5 second gantry rotation time. A relatively high pitch was used to limit motion artifacts in dyspneic COVID-19 patients. Effective radiation dose was calculated by multiplying the dose-length product (DLP) by 0.014 mSv/mGy · cm as the constant k-value for thoracic imaging (10) . Images were reconstructed at 1 mm slice thickness and 0.7 mm increment with a standard lung-tissue kernel (I50f medium sharp) and at 3 mm slice thickness I n p r e s s and 3 mm increment with a standard soft tissue kernel (I31f medium smooth) using sinogramaffirmed iterative reconstruction (SAFIRE) strength 3. All reconstructions were performed with a FOV of 450 mm and a matrix size of 512 × 512 pixels.

All chest CT images were scored as suggestive for or inconsistent with COVID-19 infection based on the presence of findings as presented by Ng et al. and Shi et al. (11, 12) . In summary, CT findings suggestive of COVID-19 infection were multiple GGOs, bilateral/multifocal involvement, peripheral distribution and, at a later stage, crazy paving, consolidation, and reversed halo sign. CT findings inconsistent with COVID-19 infection were tree-in-bud opacities, centrilobular/peribronchovascular distribution, cavitation, and pleural effusion. A semiquantitative scoring system was used to estimate the extent of pulmonary involvement as reported previously (5, 13) . Each lobe was scored from 0 to 5 with a total score ranging from 0 to 25: score 0, 0% involvement; score 1, <5% involvement; score 2, 5-25% involvement; score 3, 26-50% involvement; score 4, 51-75% involvement, score 5, 76-100% involvement. Two cardiothoracic radiologists (C.G. and R.S. with 8 and 7 years of cardiothoracic imaging experience, respectively) scored the CT scans by consensus and were blinded to the RT-PCR results. One reader (R.S.) reread a random sample of 50 scans after 1 week to assess intrareader reproducibility. These cases were reread by the other reader (C.G.) to assess interreader reproducibility. 

When compared to RT-PCR, low-dose submillisievert chest CT demonstrated excellent sensitivity, specificity, PPV, NPV, and accuracy for the diagnosis of COVID-19 in ER patients (86.7%, 93.6%, 91.1%, 90.3%, and 90.2%, respectively) in particular in patients with clinical symptoms for more than 48 hours (95.6%, 93.2%, 91.5%, 96.5%, and 94.4%, respectively) ( Table   2 ) (Figure 1 ). LR+ and LR-were 13.51 (95% CI 6.57-27.79) and 0.14 (95% CI 0.08-0.25) for all patients and 14.02 (95% CI 6.47-30.40) and 0.05 (95% CI 0.02-0.14) for patients with clinical symptoms for more than 48 hours, respectively. In patients with a positive CT, likelihood of disease increased from 43.2% (pre-test probability) to 91.1% or 91.4% (post-test probability) for all patients or those with clinical symptoms for more than 48 hours. In patients with a negative CT, likelihood of disease decreased from 43.2% (pre-test probability) to 9.6% or 3.7% (post-test probability) for all patients or those with clinical symptoms for more than 48 hours (Figure 2 ).

Intra-and interreader reproducibility for CT scores of lung involvement were excellent (ICC: 0.968 and 0.954; 95% CI: 0.942-0.983 and 0.918-0.974, respectively) without significant bias in Bland-Altman analysis (0.2 and -0.5, 95% LOAs: -2.0, 2,5 and -3.0, 1.9, respectively). When evaluating any diagnostic test, it is important to understand how the test result affects the probability of the disease in question being present (17) . In this regard, likelihood ratios and post-test probabilities are more informative than sensitivity and specificity analysis. 

When compared to the largest study to date comparing chest CT and RT-PCR by Tao et al. (7), our results indicate a significantly higher specificity of CT for the diagnosis of COVID-19.

A possible explanation for this discrepancy, already mentioned by the authors in their study limitations, is their use of RT-PCR assays with a low positive rate, likely resulting in an overestimation of CT sensitivity but an underestimation of CT specificity. The use of highly sensitive RT-PCR assays in our study probably explains the higher specificity and overall accuracy in our population. However, it remains important to stress that a negative CT scan does not completely rule out COVID-19 infection and a negative CT should not trick caregivers into a false sense of security in a patient with possible COVID-19 infection. Additionally, although no exact radiation dose levels are available, reference scan settings in this study were 120 kVp and 30-70 mAs versus 100 kVp and 20 mAs in our study. When comparing these reference values, this leads to an estimated radiation dose reduction by a factor of 5. Given the widespread use of chest CT for COVID-19 detection, our results demonstrate the feasibility of using low-dose chest CT to achieve an important reduction in radiation dose on a population level during this pandemic. However, during a public health crisis it is important to note that radiation dose considerations should not be the determining factor in deciding imaging strategies.

Previous studies have suggested CT could be used to track COVID-19 lung involvement over time (5, 6) . However, a key remaining issue has been to formally assess the reproducibility of CT measures of lung involvement, essential for the validity of interpreting changes in lung This study has several limitations. First, we acknowledge the inherent selection bias of this retrospective cohort study. Second, our study cohort only included patients who presented at the ER, so our cohort represents the more severe disease spectrum of COVID-19. Mild or asymptomatic cases with only upper respiratory tract involvement likely have more false negative findings on chest CT. Third, with the development of more sensitive and rapid test kits for COVID-19 with a turnaround of less than one hour, the need for COVID-19 screening with CT I n p r e s s will reduce. Rapidly expanding knowledge on this disease and its risk factors may lead to the implementation of diagnostic algorithms allowing for a more selective implementation of chest CT in COVID-19 subjects and a lower number of true negative cases. This will ensure optimal delivery of diagnostic imaging and treatment guidance while minimizing radiation exposure and unnecessary movement of patients within the hospital. Fourth, despite the use of new highly sensitive RT-PCR assays, this technique is not perfect. Some 'false positives' with typical CT and clinical findings but negative RT-PCR may still be COVID-19 infected (Figure 4 ). Further studies are warranted to examine whether these patients may have viral infection limited to the lower respiratory tract. Finally, the use of advanced deep-learning based iterative reconstruction algorithms and state-of-the-art hardware may result in better image quality at similar radiation doses.

In conclusion, low-dose submillisievert chest CT allows for rapid, accurate and reproducible assessment of COVID-19 infection in ER patients, in particular in patients with symptoms lasting longer than 48 hours. Chest CT may have the additional advantage of offering alternative diagnoses in a significant subset of patients.

I n p r e s s I n p r e s s 

Hosts and sources of endemic human coronaviruses

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

World Health Organization. Coronavirus disease (COVID-19) outbreak

Sensitivity of chest CT for COVID-19: comparison to RT-PCR

Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia

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

Benefits and harms of CT screening for lung cancer: a systematic review

Reduced lung-cancer mortality with volume CT screening in a randomized trial

The 2007 recommendations of the International Commission on Radiological Protection

Imaging profile of the COVID-19 infection: radiologic findings and literature review

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

Chest CT Findings in Cases from the Cruise Ship "Diamond Princess

Evidence-based medicine: How to practice and teach it, 4-th edition

Statistical methods for assessing agreement between two methods of clinical measurement

Acute pericarditis

Diagnostic tests 4: likelihood ratios

ACR Recommendations for the use of chest radiography and computed tomography (CT) for suspected COVID-19 infection

The human metapneumovirus: a case series and review of the literature

I n p r e s s I n p r e s s