CT in relation to RT-PCR in diagnosing COVID-19 in The Netherlands: A prospective study.

INTRODUCTION: Early differentiation between emergency department (ED) patients with and without corona virus disease (COVID-19) is very important. Chest CT scan may be helpful in early diagnosing of COVID-19. We investigated the diagnostic accuracy of CT using RT-PCR for SARS-CoV-2 as reference standard and investigated reasons for discordant results between the two tests.
METHODS: In this prospective single centre study in the Netherlands, all adult symptomatic ED patients had both a CT scan and a RT-PCR upon arrival at the ED. CT results were compared with PCR test(s). Diagnostic accuracy was calculated. Discordant results were investigated using discharge diagnoses.
RESULTS: Between March 13th and March 24th 2020, 193 symptomatic ED patients were included. In total, 43.0% of patients had a positive PCR and 56.5% a positive CT, resulting in a sensitivity of 89.2%, specificity 68.2%, likelihood ratio (LR)+ 2.81 and LR- 0.16. Sensitivity was higher in patients with high risk pneumonia (CURB-65 score ≥3; n = 17, 100%) and with sepsis (SOFA score ≥2; n = 137, 95.5%). Of the 35 patients (31.8%) with a suspicious CT and a negative RT-PCR, 9 had another respiratory viral pathogen, and in 7 patients, COVID-19 was considered likely. One of nine patients with a non-suspicious CT and a positive PCR had developed symptoms within 48 hours before scanning. DISCUSSION: The accuracy of chest CT in symptomatic ED patients is high, but used as a single diagnostic test, CT can not safely diagnose or exclude COVID-19. However, CT can be used as a quick tool to categorize patients into "probably positive" and "probably negative" cohorts.

Introduction

Corona virus disease 2019 (COVID-19) [1-3] is a highly contagious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Early differentiation between patients with and without the disease is extremely important [1-3], particularly in patients who visit the emergency department (ED) and patients who are admitted to the hospital. This differentiation is necessary to be able to select patients who need to be isolated to protect other patients and health care personnel [4].

Currently, reverse-transcriptase-polymerase-chain-reaction (RT-PCR) is the reference standard in diagnosing COVID-19. However, RT-PCR may have suboptimal sensitivity, for instance because in early stages of COVID-19, the viral load is below detection limit or because of technical issues, i.e. sampling errors [5]. In addition, in practice, it may take up to 24 hours to get a test result [6], although same day results are achieved most of the times.

As most COVID-19 patients present with pneumonia, computed tomography (CT) scanning of the thorax could be helpful in screening and diagnosing. In addition, CT has the advantage that the results can be available almost directly [7, 8]. Chest CT can show characteristic findings including areas of ground-glass, with or without signs of reticulation (so called “crazy paving pattern”), consolidative pulmonary opacities in advanced stages and the “reverse halo” sign [3, 7–12]. Since peripheral areas of ground glass are a hallmark of early COVID-19, which can easily be missed at chest X-rays, CT scanning has an advantage over chest X-rays in the early stages of COVID-19 [13]. Because COVID-19 related changes can indeed be found on CT scans, some studies suggest that CT scanning could be helpful in discriminating between COVID-19 positive and COVID-19 negative patients at the ED [8, 13–16]. The value of CT is, however, debated because of suspected lack of discriminatory value [17-21]. Complicating this debate, is that the sensitivity of PCR may be suboptimal, which makes it difficult to compare the two tests [5]. Furthermore, the added value of a diagnostic test is effected by the prevalence of disease and data on the performance of CT in a population with a moderate prevalence of COVID-19 are scarce.

In this prospective study, we therefore investigated the diagnostic accuracy of CT scanning in detecting COVID-19 in a population with suspected COVID-19 presenting at the ED using (repeated) RT-PCR testing as reference standard. Since the reference standard has been reported to be suboptimal, we further investigated reasons for discordant test results.

Methods

Setting

This study was performed in Maastricht University Medical Centre (MUMC+), a secondary and tertiary care hospital with around 700 beds and 23,000 ED visits a year. The study was approved by the medical ethics committee of MUMC+ (METC 2020–1564) and informed consent was waived. This study is reported in line with the STARD guidelines for diagnostic accuracy studies [22].

Patients and design

All adult (18 years or older) patients who consecutively visited the ED between March 13 and March 24 2020 with respiratory symptoms including dyspnoea, coughing, sore throat and fever were scanned in a mobile CT scan unit. Of these patients, a nasopharyngeal and/or oropharyngeal swab was taken and tested for presence of SARS-CoV-2. If the first PCR was negative, a second PCR was performed within 48 hours after the first test in patients who were still admitted to the hospital, if deemed indicated by the clinicians, e.g. if no alternative diagnosis was made. We included all symptomatic patients who received a chest CT and at least one PCR test for detection of COVID-19. Five patients who were immediately intubated upon arrival at the ED received no CT scanning and were therefore not included in our study.

RT-PCR

Laboratory confirmation of SARS-CoV-2 was performed with RT-PCR assay. First, RNA was extracted from clinical samples with the MagNA Pure 96 system (Roche, Germany). RT-PCR assay was performed using as targets RdrP-gene and E-gene according to the previous published protocol. Thermal cycling was performed on an Quantstudio 5 (Applied Biosystems, US). Validation of the method was performed in accordance with the protocol established by the RIVM and ErasmusMC [23]. Oligonucleotides were synthesised and provided by Tib-Molbiol (Berlin, Germany) or by Biolegio (Netherlands). All swabs were also tested for Influenza A, B, respiratory syncytial virus (RSV) and human metapneumovirus.

Chest CT

The chest CT was obtained in a mobile CT scan unit (Alliance Medical equipped with GE lightspeed 16 slice scanner) upon arrival at the ED. CT scans were performed in caudo-cranial scanning direction without intravenous contrast injection, at 120kVp and 50–210 mAs, depending on their weight, using 16 x 1.25 collimation, 0.5s rotation time reconstructed at 1.25 mm slices with 1.25 mm increment. Patients were instructed to hold their breath if clinically possible. The procedure was performed taking all measures into account to prevent contamination of patients and personnel, which included cleaning procedures and use of protective equipment by patients (if possible) and personnel. Images were reconstructed using a moderately soft reconstruction filter (“DETAIL”) at mediastinal window and a sharp reconstruction filter (“LUNG”) at lung window settings. either suspicious or not suspicious for COVID-19 related pneumonia. The chest CT scans were read using a standardizing reporting scheme using the items reported as typical or atypical for COVID-19 [14, 24]. Scans were reported suspicious if findings reported as typical for COVID-19 were noted or non-suspicious if they were normal or showed findings typical for a bacterial pneumonia or respiratory bronchiolitis. Cases showing features of any viral infection, i.e. without the typical subpleural distribution of COVID-19, which is not usually seen in other viral pneumonia, were reported equivocal, but considered positive. Initial judgement of the CT scan was performed by a senior resident. The final reading and reporting were performed by an experienced chest radiologist within 12 hours of scanning. Both judgements were made with the specific request to check for signs of COVID-19 and, in many cases, included the nature and duration of the symptoms. Since the PCR results were available after 12–24 hours, both readers were unaware of the PCR test results.

Data collection

From electronic medical records, we retrieved the following data: demographic data (age, sex); comorbidity; duration and severity of current disease; PCR results and other microbiological data; CT scan reports; discharge diagnosis. Severity of disease was classified in two ways: 1) using the severity score for community acquired pneumonia, quantified by the CURB-65 score (Confusion, Urea, Respiration, Blood pressure, Age; low/medium risk: 0–2 vs. high risk: 3–5 [25]), and 2) by establishing the absence or presence of sepsis using the SOFA score (Sepsis-related Organ Failure Assessment; 0–1 vs. ≥2 [26]).

Data analysis and statistics

All statistical analyses were performed using IBM SPSS version 26 (Chicago, Illinois, USA) and MedCalc (https://www.medcalc.org/). We performed a descriptive analysis of baseline characteristics of included patients. Continuous variables were reported as medians with interquartile ranges (IQRs) and categorical variables as proportions. In case of missing values, valid percentages were used.

We compared the CT scan results with the RT-PCR testing results. Diagnostic accuracy of the CT scan in terms of sensitivity, specificity, positive and negative predictive value (PPV and NPV, resp.) and likelihood ratios (LRs; all with 95% confidence intervals (CI)) was assessed. Next, we calculated the diagnostic accuracy (sensitivity, specificity, PPV, NPV and LR) with respect to the severity of disease (CURB-65 score: low/medium vs. high risk) and the absence/presence of sepsis (SOFA score: 0–1 vs. ≥2). The Chi Square test was used to compare the sensitivity and specificity between patients with low and high severity of disease.

A sample size calculation with regard to the diagnostic accuracy analysis was made based on the assumption of a prevalence of disease of 40%, and in order to detect a change in sensitivity from 70 to 90% with a power of 80% and a significance level of <0.05. The required sample size would be at least 78 [27].

Discordances between CT results and PCR testing results were further investigated by retrieving data on alternative diagnoses and, if possible, duration of symptoms (using ancillary viral/bacterial test results and discharge diagnoses in medical charts (e.g. pneumonia caused by influenza)). These data were analysed in a descriptive way.

Results

Patient characteristics

During the study period, 193 symptomatic ED patients had both a chest CT and RT-PCR test for diagnosing COVID-19. The median age of these patients was 66 years and 58.5% were male (Table 1). Most patients (72.5%) had one or more comorbidities. Cardiovascular comorbidity was highly prevalent, as was chronic pulmonary disease (19.7%). In total, 118 (61.1%) patients were admitted to the hospital.

Table 1

Patient characteristics.

n (%), median (IQR)	All patients N = 193
Demographics
Age (years)	66 (55–76)
Male	113 (58.5)
Comorbidity
No comorbidity	53 (27.5)
Hypertension	79 (40.9)
Diabetes mellitus	31 (16.1)
Myocardial infarction	31 (16.1)
Cerebrovascular disease	23 (11.9)
Heart failure	15 (7.8)
Peripheral vascular disease	15 (7.8)
Chronic pulmonary disease	38 (19.7)
Malignancy	27 (14.0)
Chronic kidney disease	17 (8.8)
Liver disease	10 (5.2)
Disease severity
CURB-65 score	1 (0–2)
SOFA	3 (1–4)
Chest CT
CT suspicious for COVID-19	109 (56.5)
RT-PCR
PCR SARS-CoV2 positive	83 (43.0)
Admission	118 (61.1)

CURB-65: Confusion, Urea, Respiration, Blood pressure, Age; SOFA: Sepsis-related Organ Failure Assessment

Of the chest CT scans, 109 (56.5%) were judged as suspicious for COVID-19. In 83 (43.0%) patients, the PCR was positive for SARS-CoV-2 (Table 1). In 7 of these patients, a PCR was necessary on a second sample to confirm the suspected diagnosis, because the first PCR was negative or inconclusive.

Diagnostic accuracy of chest CT for COVID-19 in all patients and subgroups

In 83 patients with a positive PCR, 74 CT scans were judged as suspicious for COVID-19 (Table 2). In all 110 patients with a negative PCR, 75 CT scans were judged as not suspicious for COVID-19. This results in a sensitivity of 89.2% (95%CI: 80.4–94.9%) and specificity of 68.2% (95%CI: 58.6–76.7%) of the CT for diagnosing COVID-19 (Table 3). The PPV was 67.9% (95%CI: 61.4–73.7%) and NPV 89.3% (95%CI: 81.6–94.0%).

Table 2

Overview of chest CT and RT-PCR results.

	PCR SARS-CoV-2 positive	PCR SARS-CoV-2 negative	Total
CT suspicious for COVID-19	74	35	109
CT not suspicious for COVID-19	9	75	84
Total	83	110	193

Table 3

Diagnostic accuracy of Chest CT for diagnosing COVID-19 in all patients and in relation to disease severity.

	N (%)	Sensitivity %(95%CI)	Specificity %(95%CI)	PPV %(95%CI)	NPV %(95%CI)	LR+ (95%CI)	LR-(95%CI)
Total group	193 (100)	89.2 (80.4–94.9)	68.2 (58.6–76.7)	67.9 (61.4–73.7)	89.3 (81.6–94.0)	2.81 (2.11–3.72)	0.16 (0.08–0.30)
Disease severity
CURB-65 0–2	176 (91.2)	88.3 (79.0–94.5)	69.7 (59.7–78.5)	69.4 (62.5–75.6)	88.5 (80.4–93.5)	2.91 (2.1–4.0)	0.17 (0.09–0.31)
CURB-65 ≥3	17 (8.8)	100.0 (54.1–100.0)	54.5 (23.4–83.3)	54.5 (38.6–69.6)	100.0	2.20 (1.15–4.20)	0.0
SOFA score 0–1	56 (29.0)	62.5* (35.4–84.8)	70.0 (53.5–83.4)	45.5 (31.2–60.5)	82.4 (70.6–90.1)	2.08 (1.14–3.82)	0.54 (0.28–1.04)
SOFA score ≥2	137 (71.0)	95.5* (87.4–99.1)	67.1 (54.9–77.9)	73.6 (66.5–79.6)	94.0 (83.7–98.0)	2.91 (2.07–4.08)	0.07 (0.02–0.20)

95%CI: 95% Confidence Interval; CURB-65: Confusion, Urea, Respiration, Blood pressure, Age; LR+, positive likelihood ratio; LR-, negative likelihood ratio; PPV, positive predictive value, NPV, negative predictive value; SOFA, Sepsis-related Organ Failure Assessment.

*significantly different with a p-value <0.001 (Chi-Square test)

Diagnostic accuracy of the chest CT in relation to disease severity

Of all patients, 91.2% were classified as mild/medium risk pneumonia according to the CURB-65 score, with 71.0% having sepsis (SOFA score ≥2, Table 3). The sensitivity of the CT tended to be higher (100.0%) in those with severe risk pneumonia than in patients with low/medium risk pneumonia (88.3%, p = 0.38). In patients with sepsis, sensitivity was significantly higher than in those without sepsis (95.5 vs. 62.5%, p<0.001).

Analysis of discordant CT and RT-PCR results

In 44 (22.8%) patients discordant findings between CT and PCR were observed. In most cases, the CT scan was considered suspicious for COVID-19, while the PCR was negative (35/110, 31.8%). In the majority of these, the diagnosis at discharge was pulmonary infection (n = 26; 74.3%). In 9 of these 26 patients, other viral pathogens (Influenza A virus: n = 2; Human metapneumovirus: n = 5; Rhinovirus: n = 1, non-COVID corona virus: n = 1) and in 2, bacterial pathogens were found. In an additional 8 patients with pulmonary infection, COVID-19 disease was found unlikely based on the discharge diagnosis (all had at least 2 negative PCRs). However, in 7 patients with pulmonary infection, COVID-19 disease was found likely or could not be excluded. Median duration of symptoms at the moment of CT scanning and PCR was 5 days (in 1 less than 48 hours) in these 7 patients.

In 9 patients with a suspicious CT scan and a negative PCR, another diagnosis than pulmonary infection was made. Four patients had another pulmonary diagnosis (bronchiectasis (n = 1), asthma (n = 2), pleural effusion due to ascites (n = 1)), while in 4 patients, a cardiac diagnosis (heart failure (n = 3), acute coronary syndrome (n = 1)) was made.

In 9 patients (10.8%), CT scans were not suspicious for COVID-19, while the PCR was positive. In 2 of these patients, a second PCR was positive after a first negative test. In these cases, the CT scan was not repeated to check for new abnormalities. In one patient, respiratory symptoms were present for less than 48 hours, in 6 patients, symptoms were present for more than 48 hours, and in 2 patients, symptom duration was not clear.

Discussion

In this prospective study in patients presenting at the ED with a clinical suspicion of COVID-19, we found that chest CT scan when compared to RT-PCR had a high sensitivity of 89% and an LR- of 0.16. Specificity was moderate (68%), with an LR+ of 2.81. Sensitivity of the CT was higher in patients with more severe disease—high CURB-65 score (≥3) or sepsis (SOFA ≥2)—than in those who were less severely ill. In 77% of all patients, the results of the chest CT and the PCR test were concordant, however in 11% of patients with a positive PCR, CT scans were not considered suspicious for COVID-19. In addition, in about a third of patients tested negative by PCR, the CT was positive. Most of these patients had a discharge diagnosis of pneumonia (74%), which was caused by another viral pathogen in one fourth of patients, while in 20%, COVID-19 could not be excluded.

The diagnostic ability of chest CT was found to be rather high, and in 77%, concordant findings of CT and PCR were found. Nevertheless, it should be noted that 11% of COVID-19 were missed and 32% were incorrectly assigned a suspected COVID-19. In a situation where isolating each patient separately is not possible, these patients are placed at a COVID-19 cohort, where they can be exposed to COVID-19 positive patients with possible devastating consequences.

The results of diagnostic accuracy should be interpreted with care for several reasons. One of these reasons is because it is known that both CT and PCR can be false negative in early stages of COVID-19 [5, 7, 16]. This is why we included repeated PCRs and explored discordant test results, which showed that in about 26% of patients with false positive CT scans, other viral pathogens were detected. Another reason is that this study was performed at the end of the respiratory virus season, and the added value of the CT scan might be lower during typical respiratory virus season. It can be argued, in addition, that with changing incidence of COVID-19, and thus, a changing pre-test probability, the added value of the CT scan will change. In other studies, the sensitivity of chest CT for COVID-19 was found to be higher, up to 97% in a study with 1014 Chinese patients, but at the cost of low specificity (25%) [14]. In another study in 81 Chinese patients with PCR proven COVID-19, sensitivity was 93% [10]. A lower sensitivity of 80% was reported in 30 symptomatic cruise ship passengers [17]. In contrast, PCR was found to be negative in 71% of 51 Chinese patients, of whom 98% had CT abnormalities [15]. We have chosen to consider all chest CTs with abnormalities that could be related to COVID-19 as suspicious, even though the changes were judged to compatible with non-COVID-19 related pneumonia or other respiratory conditions. However, in case no signs of a viral interstitial pneumonia were present, the CT scan was considered negative for COVID-19. Considering these cases negative would have improved the specificity, but at the cost of lower sensitivity. It must further be noted that the CT scans were judged with the specific request to search for COVID-19. This may have biased the radiologists into considering (equivocal) changes as COVID-19 related, thereby increasing sensitivity and decreasing specificity. Last, as COVID-19 is a new disease, and the first patient with COVID-19 presented in our hospital the 10th of March, it is possible that with increasing experience the accuracy of the judgment of the chest CT will improve over time.

Evaluation of discharge diagnosis revealed that in 7 (20%) of discordant, “false positive” CT scans, COVID-19 was found likely by the clinicians. Correction for these discordances would increase both sensitivity and specificity of the CT scan but this should be considered with care because of the small sample. Of the patients with false negative chest CTs (11%), only one patient had a documented short duration of symptoms (<48 hours). In total, 7 second PCRs were needed to diagnose COVID-19, which underlines the importance of good sampling and repeated testing to definitely exclude COVID-19 in symptomatic patients.

Not surprisingly, the sensitivity of the CT scan was higher in the more severely ill patients. In 17 patients with high-risk CURB-65 scores (≥3) and in 137 patients (71%) with sepsis (SOFA ≥2), sensitivity was 100% and 96%, resp. This finding was reported in other studies as well [2, 28] and is not surprising, because in more severe disease, more abnormalities can be expected to be found on the chest CT [7]. The high sensitivity for patients with a high-risk CURB-65 score was, however, at the cost of low specificity, but this was not the case for patients with sepsis. In addition, the numbers of patients in this subanalysis was small and confidence intervals were wide, so no hard conclusions on this topic can be drawn.

Interestingly, most patients (91%) presented with low/medium risk pneumonia (CURB-65 0–1). It is important to realize that 5 patients who were immediately intubated upon arrival at the ED received no CT scanning and were therefore not included in our study. However, although most included patients had no high risk pneumonia, many (71.0%) were septic.

The main advantage of the CT scan is that its’ results are available almost immediately after scanning, in contrast to the PCR test, which may take up to 24 hours, although this usually takes less time. This advantage is dependent on the availability of a CT scan, personnel and a logistically well designed way to perform these scans. We rented an extra (mobile) CT scanner and placed it in a tent in front of the ED. During this time-frame, highly suspicious patients are kept in isolation, awaiting the PCR results. A chest CT scan can help to differentiate those with high risk (suspicious CT) and those with low risk of COVID-19 (non-suspicious CT). It would be interesting to investigate whether combining the results of chest CT with clinical characteristics would increase the discriminatory value, which is extremely important especially if patients have to be placed in cohorts.

Our study has some limitations. External validity may be limited in this study due to its single centre set-up. In addition, especially in patients with mild symptoms who were not admitted to the hospital, no second PCR-testing was done after an initial negative result. A third limitation is that in the 5 patients who were intubated directly upon arrival at the ED, no CT scan was made. However, many patients who were seriously ill were included in the study, as demonstrated by the high proportion of patients being septic.

In conclusion, the diagnostic accuracy of chest CT in symptomatic ED patients is good, but not good enough to safely diagnose or exclude COVID-19, especially when patients are placed in cohorts. However, CT can be used as a quick tool to categorize patients into “probably positive” and “probably negative” cohorts.

(SAV)

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26 May 2020

PONE-D-20-13081

CT in relation to RT-PCR in diagnosing COVID-19 in the Netherlands: a prospective study

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Reviewer #1: PONE-D-20-13081

The goal of this publication is to evaluate the accuracy of CT for the diagnosis of COVID-19, using RT-PCR as the gold standard.

Strengths:

The topic of diagnosing COVID-19 with CT has been much debated. The study has some strengths compared to earlier literature. It is a prospective study of consecutive adult patients through the ED of a large volume center.

193 patients in a high prevalence area (43% had COVID) were included. Sensitivity of 89.2% and specificity of 68.2% is reported.

Weaknesses:

While “typical” imaging findings of COVID-19 are discussed, limited information is provided about how CT was actually used in the study to assess for COVID in a binary fashion. The suggestion is that many findings were considered positive: “In case of pneumonia, in which COVID-19 was unlikely but could not be excluded, the scan was judged positive.” More details are needed about the threshold for a “positive” CT.

The issue of blinding needs to be addressed. It is stated that CT readers were not aware of PCR status. But what were they aware of? Did they not presentation history, likelihood of COVID versus alternative diagnoses, etc. Along these lines, details should be provided about patients with and without COVID to address the question of whether COVID status might correlate with other characteristics in this cohort.

The attempt to discuss disease severity is welcome, as a criticism of earlier publications on the same topic (some included in the discussion) is that CT is good at detecting pneumonia in patients with pneumonia and COVID. Unsurprisingly, all COVID patients with severe risk for pneumonia had CT findings (what patient with pneumonia does not have CT findings?), but the specificity is poor.

The potential role of CT as a screening test needs to be developed. The conclusion makes the following statement about the diagnostic accuracy of CT: “not good enough to safely diagnose or exclude COVID-19.” If CT can neither rule in nor rule out disease, what practical role can it play for screening or diagnosis?

The conclusion need to couch the results in the context of a high prevalence environment. Discussion of how CT might perform in the lower prevalence environments we are likely to see in coming months should be included.

Specific points:

1. The details about discordant cases are interesting, but it is hard to draw conclusions from them. For this reason, the sensitivity and specificity numbers should not be revised to account for these cases.

2. CT is fast, but cumbersome to perform in the time of COVID-19. This should be added to the discussion.

Reviewer #2: Appraised by a revised tool for the quality assessment of diagnostic accuracy studies (QUADAS2), your research is qualified. Due to some limitation of PCR assay, the accuracy of chest CT as a diagnostic tool for COVID-19 is an important issue during the progress of pandemic. Although there were some published reports in this topic, we still need more studies to clarify the certainty of evidences especially from the countries other than China. Therefore, it is worth to publish your research before accomplishing the answers of the below issues.

1.Did you calculate the power for your diagnostic study by statistical software based upon the prospective design of this research? If no or insufficient power, please mention it as one of the limitations of your study.

2.You did not introduce the software for statistical analysis. You should demonstrate the 95% confidence interval of sensitivity, specificity, likelihood ratio, and other results.

3.You performed some sensitivity analyses including CURB-65 score and SOFA score to distinguish the different diagnostic value in different severity of patients. Is it possible to perform more sensitivity analyses toward CT findings? You mentioned that “Chest CT can show characteristic findings including areas of ground-glass, with or without signs of reticulation (so called “crazy paving pattern”), consolidative pulmonary opacities in advanced stages and the “reverse halo” sign. Since peripheral areas of ground glass are a hallmark of early COVID-19, which can easily be missed at chest X-rays, CT scanning has an advantage over chest X-rays in the early stages of COVID-19.” Can you calculate the diagnostic values of above characteristic findings in CT?

4.You described the detailed methods very well. You mentioned that “ The chest CT was obtained in a mobile CT scan unit (Alliance Medical equipped with GE148 lightspeed 16 slice scanner) upon arrival at the ED.” Please introduce more details about how to avoid nosocomial contamination in your policies.

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Reviewer #1: No

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Submitted filename: Reviewer Attachments for Manuscript Number PONE-D-20-13081.docx

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3 Jun 2020

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: PONE-D-20-13081

The goal of this publication is to evaluate the accuracy of CT for the diagnosis of COVID-19, using RT-PCR as the gold standard.

Strengths:

The topic of diagnosing COVID-19 with CT has been much debated. The study has some strengths compared to earlier literature. It is a prospective study of consecutive adult patients through the ED of a large volume center.

193 patients in a high prevalence area (43% had COVID) were included. Sensitivity of 89.2% and specificity of 68.2% is reported.

Weaknesses:

While “typical” imaging findings of COVID-19 are discussed, limited information is provided about how CT was actually used in the study to assess for COVID in a binary fashion. The suggestion is that many findings were considered positive: “In case of pneumonia, in which COVID-19 was unlikely but could not be excluded, the scan was judged positive.” More details are needed about the threshold for a “positive” CT.

First, we would like to thank you for your thorough review in these extraordinary circumstances. Please note that the scans were judged in first stage of the pandemic and limited experience and guidelines existed. The judgement is therefore reflective of real clinical practice. The comment you made concerns the equivocal scans. A small part of the scans showed signs that might have been compatible with COVID-19, but also of other pulmonary diseases, such as bacterial pneumonia or pre- existent conditions. We decided to categorize these scans as positive for COVID-19.

We realize that this could have been made more clearly in our manuscript and replaced the following line:

“In case of pneumonia, in which COVID-19 was unlikely but could not be excluded, the scan was judged positive.”

by

“In case the chest CT was equivocal, i.e. it showed features compatible with COVID-19 but also with alternative pulmonary diseases, the scan was judged as a positive CT scan if at least some ground glass areas, that may be due to a viral infection, were present. However, if CT features were considered typical of a lobar pneumonia or respiratory bronchiolitis, the CT scan was judged as negative.” (lines 160-165, Methods).

In addition, we made the following changes to the Discussion:

We have chosen to consider all chest CTs with abnormalities that could be related to COVID-19 as suspicious, even though the changes were judged to be more likely compatible with non-COVID-19 related pneumonia....(and added) ... or other respiratory conditions. However, in case no signs of a viral interstitial pneumonia were present, the CT scan was considered negative for COVID-19 (lines 303-305)

The issue of blinding needs to be addressed. It is stated that CT readers were not aware of PCR status. But what were they aware of? Did they not presentation history, likelihood of COVID versus alternative diagnoses, etc.

The radiologists were not blinded for the clinical condition of the patient. They were aware of the pandemic and were working in the mobile CT scan unit, which was used for making chest CTs to screen for COVID19 only. In addition, the chest CTs were ordered using preprinted CT application forms, which mentioned the phrase: “COVID-19 screening” and, in many cases, the nature and duration of the complaints. This comment is therefore very true, and we decided to add the following sentence to the Methods section.

..... The final reading and reporting were performed by an experienced chest radiologist within 12 hours of scanning. ....

“Both judgements of the CT scan were made with the specific request to check for signs of COVID-19 and, in many cases, included the nature and duration of the symptoms.” (lines 166-168)

... Since the PCR results were available after 12-24 hours, both readers were unaware of the PCR test results.

And added the following to the Discussion:

Considering these cases negative would have improved the specificity, but at the cost of lower sensitivity.

.... “It must be noted that the CT scans were judged with the specific request to search for COVID-19. This may have biased the radiologists into considering (equivocal) changes as COVID-19 related, thereby increasing sensitivity and decreasing specificity.” ...... (lines 306-309)

Along these lines, details should be provided about patients with and without COVID to address the question of whether COVID status might correlate with other characteristics in this cohort.

We are not sure what the reviewer means with this comment. The focus of the manuscript was on the diagnostic accuracy of chest CT and not on the characteristics of COVID and non COVID patients.

The attempt to discuss disease severity is welcome, as a criticism of earlier publications on the same topic (some included in the discussion) is that CT is good at detecting pneumonia in patients with pneumonia and COVID. Unsurprisingly, all COVID patients with severe risk for pneumonia had CT findings (what patient with pneumonia does not have CT findings?), but the specificity is poor.

It is true that sensitivity in severely ill patients was higher, and (a bit, for sepsis) at cost of specificity. The radiologists, however, did not judge all pneumonia cases automatically as COVID-19. We now realize that this is not made perfectly clear to the readers, and kindly refer to the changes made according to your earlier remarks (first comment). In addition, we added the following to the Discussion:

“The high sensitivity for patients with a high-risk CURB-65 score was, however, at the cost of low specificity, but this was not the case for patients with sepsis.“ (lines 327-329)

The potential role of CT as a screening test needs to be developed. The conclusion makes the following statement about the diagnostic accuracy of CT: “not good enough to safely diagnose or exclude COVID-19.” If CT can neither rule in nor rule out disease, what practical role can it play for screening or diagnosis?

Agreed, this could have been made more clear.

We added the following to the Conclusion/Abstract:

..”However, CT can be used as a quick tool to categorize patients into “probably positive” and “probably negative” cohorts. “ (lines 73-74; 358-359)

The conclusion need to couch the results in the context of a high prevalence environment. Discussion of how CT might perform in the lower prevalence environments we are likely to see in coming months should be included.

In the Discussion we already mentioned the influence of increasing incidence on the added value of CT (higher PPV, lower NPV), but the same is true for decreasing incidence (lower PPV, higher NPV).

We changed that sentence into the following...

It can be argued, in addition, that with increasing changing incidence of COVID-19, and thus, a higher changing pre-test probability, the added value of the CT scan will decrease.”... (lines 294-296)

Specific points:

1. The details about discordant cases are interesting, but it is hard to draw conclusions from them. For this reason, the sensitivity and specificity numbers should not be revised to account for these cases.

We agree that this extra calculation accounts for a small proportion of our patients, and therefore, these results were only shortly mentioned in the Discussion. We rephrased the sentence to de-emphasize the statement.

“Correction for these discordances would increase both sensitivity and specificity of the CT scan but this should be considered with care because of the small sample.” (lines 315-318)

2. CT is fast, but cumbersome to perform in the time of COVID-19. This should be added to the discussion.

Agreed, the advantage of the CT scan depends on its availability.

We added the following to the Discussion:

“This advantage is dependent on the availability of a CT scan, personnel and a logistically well designed way to perform these scans. We rented an extra (mobile) CT scanner and placed it in a tent in front of the ED.”...

(lines 340-342)

Reviewer #2: Appraised by a revised tool for the quality assessment of diagnostic accuracy studies (QUADAS2), your research is qualified. Due to some limitation of PCR assay, the accuracy of chest CT as a diagnostic tool for COVID-19 is an important issue during the progress of pandemic. Although there were some published reports in this topic, we still need more studies to clarify the certainty of evidences especially from the countries other than China. Therefore, it is worth to publish your research before accomplishing the answers of the below issues.

1. Did you calculate the power for your diagnostic study by statistical software based upon the prospective design of this research? If no or insufficient power, please mention it as one of the limitations of your study.

First, we would like to thank you for your thorough review in these strange and probably very busy times.

We made a sample size calculation on the assumption of a prevalence of disease of 40%, and in order to detect a change in sensitivity from 70 to 90% with a power of 80% and a significance level of <0.05. The required sample size would be at least 78. Our study was therefore sufficiently powered.

We added the following to the statistics section:

“A sample size calculation with regard to the diagnostic accuracy analysis was made based on the assumption of a prevalence of disease of 40%, and in order to detect a change in sensitivity from 70 to 90% with a power of 80% and a significance level of <0.05. The required sample size would be at least 78.” (lines 194-197)

2. You did not introduce the software for statistical analysis. You should demonstrate the 95% confidence interval of sensitivity, specificity, likelihood ratio, and other results.

In response to your first comment: you are correct, a sentence on the statistical software program used is added to the statistics section.

“All statistical analyses were performed using IBM SPSS version 26 (Chicago, Illinois, USA) and MedCalc (https://www.medcalc.org/).”(lines 181-182)

In response to the second comment: these were added, see the changes made throughout the manuscript.

3. You performed some sensitivity analyses including CURB-65 score and SOFA score to distinguish the different diagnostic value in different severity of patients. Is it possible to perform more sensitivity analyses toward CT findings? You mentioned that “Chest CT can show characteristic findings including areas of ground-glass, with or without signs of reticulation (so called “crazy paving pattern”), consolidative pulmonary opacities in advanced stages and the “reverse halo” sign. Since peripheral areas of ground glass are a hallmark of early COVID-19, which can easily be missed at chest X-rays, CT scanning has an advantage over chest X-rays in the early stages of COVID-19.” Can you calculate the diagnostic values of above characteristic findings in CT?

This analysis is unfortunately not possible to make. There are several signs suggestive of COVID-19 on chest CT. This study was not designed to investigate the diagnostic value of the individual signs and lacks power to do this in retrospect.

4.You described the detailed methods very well. You mentioned that “ The chest CT was obtained in a mobile CT scan unit (Alliance Medical equipped with GE148 lightspeed 16 slice scanner) upon arrival at the ED.” Please introduce more details about how to avoid nosocomial contamination in your policies.

The mobile CT scan unit was placed in a tent in front of the ED. The tent was divided into compartments with beds each being surrounded by walls. Personnel was fully protected by wearing personal protection material.

The CT scan was cleaned after each scan.

We added this to the Methods section:

“The procedure was performed taking all measures into account to prevent contamination of patients and personnel, which included cleaning procedures and use of protective equipment by patients (if possible) and personnel.”

(lines 154-156)

Submitted filename: Response to reviewers-PONE-D-20-13081R1.docx

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10 Jun 2020

PONE-D-20-13081R1

CT in relation to RT-PCR in diagnosing COVID-19 in the Netherlands: a prospective study

PLOS ONE

Dear Dr. Stassen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

One reviewer still raised some important issues that need to be adequately addressed.

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We look forward to receiving your revised manuscript.

Kind regards,

Yu Ru Kou, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors have adequately addressed the reviewers’ comments. The revised manuscript is qualified and acceptable for publication in the PLOS ONE.

**********

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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Submitted filename: Plos one CT COVID-19_revision decision.docx

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17 Jun 2020

Dear prof Kou and dear reviewer,

Thank you for your review. Below, we respond to the comments made.

Reviewer's Comments:

1.Modestly better with more disclaimers. Still this is a study in a high prevalence area where unspecified imaging criteria are used by non-blinded radiologists to call COVID-19 on CT. More disclaimers are needed, and overall the results are not of clear value moving forward.

We understand from your comments that the way the CT scans were judged can be made more clear. The judgement was made in the same way as in other studies.

We tried to clarify this by changing the text in the Methods section (lines 158-164).

...”The chest CT scans were read using a standardizing reporting scheme using the items reported as typical or atypical for COVID-19 (14, 24). Scans were reported suspicious if findings reported as typical for COVID-19 were noted or non-suspicious if they were normal or showed findings typical for a bacterial pneumonia or respiratory bronchiolitis. Cases showing features of any viral infection, i.e. without the typical subpleural distribution of COVID-19, which is not usually seen in other viral pneumonia, were reported equivocal, but considered positive.”...

We are not sure which additional disclaimers are needed. We think we addressed these disclaimers already. All studies on this topic to date, as far as we know, have been performed under similar circumstances. This study focused on the accuracy of the CT scan in real practice, in which clinical information is always available to radiologists, and in a time frame during which the prevalence of COVID-19 was high.

We kindly refer to the lines 166-168 in the Methods section:

Both judgements of the CT scan were made with the specific request to check for signs of COVID-19 and, in many cases, included the nature and duration of the symptoms. Since the PCR results were available after 12-24 hours, both readers were unaware of the PCR test results.

and to the lines 309-312 in the Discussion:

It must further be noted that the CT scans were judged with the specific request to search for COVID-19. This may have biased the radiologists into considering (equivocal) changes as COVID-19 related, thereby increasing sensitivity and decreasing specificity.

And to the paragraph on the disclaimers (lines 291-314) in the Discussion in which we emphasize the circumstances that have to be taken into account when interpreting the results of chest CT.

Nevertheless, to make these disclaimers more clear, we changed the text of the Discussion: (lines 291-296)

...”The results of diagnostic accuracy should be interpreted with care for several reasons. One of these reasons is because it is known that both CT and PCR can be false negative in early stages of COVID-19 (5, 7, 16)....Another reason...”

With regard to your remark on moving forward:

We feel that investigating the accuracy of chest CT was correctly done in this study in contrast to earlier (in general much smaller; 81, 30, 51 patients resp. (ref 10,17, 15)) studies that sometimes included PCR positive patients only (Shi, ref 10) or mainly asymptomatic patients (shohei, ref 17). We included a casemix of positive and negative patients, who were assessed at the ED because they had respiratory symptoms and/or other symptoms suggestive of COVID-19. We further included an analysis of discordant results, which others did not.

2. Also, information about other patients characteristics would be helpful to determine if non-imaging criteria correlated with COVID status, and influenced the decision of radiologists. For example, did the COVID patients have fevers, and this prompted radiologists to call them positive on imaging.

Before scanning, the patients were triaged by a nurse, whose main task was to evaluate whether a CT scan was needed or not, following a protocol (eg. contact with COVID positive patient, respiratory symptoms). He or she filled out the CT request form, which was labelled as “COVID-19 screening”, and included questions on duration and nature of symptoms. Due to crowding, these data were not filled in systematically, and therefore these could not be retrieved in a reliable way. Not until the CT scan was made, the doctor assessed the patient.

We kindly refer to the Methods section, lines 165-167, in which we address this topic.

Both judgements of the CT scan were made with the specific request to check for signs of COVID-19 and, in many cases, included the nature and duration of the symptoms.

With kind regards, on behalf of the authors,

Patricia Stassen

24 Jun 2020

CT in relation to RT-PCR in diagnosing COVID-19 in the Netherlands: a prospective study

PONE-D-20-13081R2

Dear Dr. Stassen,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Yu Ru Kou, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: defer to editors at this point.

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Reviewer #1: No

29 Jun 2020

PONE-D-20-13081R2

CT in relation to RT-PCR in diagnosing COVID-19 in the Netherlands: a prospective study

Dear Dr. Stassen:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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PLOS ONE