Editor: M. Paul

Introduction {#sec1}
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Chest computed tomography (CT) has shown promise as a diagnostic tool for coronavirus disease 2019 (COVID-19) \[[@bib1],[@bib2]\]. Initial studies have described a stereotypical time course with successive radiological stages, ground-glass opacities (GGOs) being the main initial lesion \[[@bib3],[@bib4]\]. Quantitative CT lung analysis shows a good association with patient prognosis in those with non-COVID-19 acute respiratory distress syndrome \[[@bib5]\]. From March 2020, patients admitted to the Strasbourg University Hospital with suspected COVID-19 were managed using a specific protocol, including reverse-transcription polymerase chain reaction (RT-PCR) on respiratory samples and a systematic chest CT to improve the triage of patients. We aimed to determine the early prognostic value of systematic chest CT with quantification of lung lesions in COVID-19 patients performed at the time of admission.

Methods {#sec2}
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We conducted a retrospective study of prospectively collected data. We included patients with positive PCR and CT performed, this study was not interventional so the chest CT was not realized after inclusion in the study. All consecutive patients aged ≥18 years---hospitalized at the Strasbourg University Hospital in March 2020 with COVID-19 confirmed using RT-PCR and a chest CT performed with quantitative evaluation of the lesions---were enrolled in this cohort study. Patients for whom the CT was realized ≥48 h after admission were excluded. Non-contrast-enhanced chest CT images were acquired on an 80-row scanner (Aquilion Prime SP, Canon Medical Systems), with parameters based on the patient\'s morphotype (tension 100--135 kV and maximum mAs 2--50) \[[@bib6]\]. Images were reconstructed with a slice thickness of 1 mm in mediastinal and parenchymal windows using an iterative reconstruction algorithm (AIDR-3D, Canon Medical Systems) and read on dedicated workstations with multiplanar and maximum intensity projection reconstructions. CT angiography was performed secondarily for patients with suspected pulmonary embolism. Visual quantification of the lung lesions was performed at the time of the CT by two different radiologists who were blinded to the patients\' clinical condition. Evaluations were made independently, but discrepancies were resolved by consensus. The CT images were classified as per the percentage of the whole lung parenchyma affected by COVID-19 lesions---GGO and/or consolidations---in the following six groups: normal CT (no lesion), minimal (0--10%), moderate (11--25%), important (26--50%), severe (51--75%), and critical (\>75%) \[[@bib7]\]. To simplify the analysis of the clinical data, the patients were divided into three subgroups: ≤25%, 26--50%, and \>50%.

The primary endpoint was early severe disease, defined as death or intensive care unit (ICU) admission in the 7 days after hospital admission. Statistical analyses were performed using R software (version 3.5.2). This study was approved by the Ethics Committee of Strasbourg University Hospital (N°CE--2020--51). Oral informed consent was obtained from all the patients.

Results {#sec3}
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During the study period, 572 patients were assessed out of 854 patients with positive RT-PCR ([Supplementary Material Fig. S1](#appsec1){ref-type="sec"}). The mean patient age was 66.0 years (standard deviation 16.0; range 20--95 years), and 343/572 patients (60.0%) were men. Among all 572 patients, chest CT was normal in 14 patients (2.4%), and showed minimal, moderate, important, severe, and critical lesions in 68 (11.9%), 224 (39.2%), 171 (29.9%), 82 (14.3%), and 13 patients (2.3%), respectively. Most patients had bilateral involvement (524/572, 91.6%) and GGO (540/572, 94.4%). Consolidations were observed in 372/572 patients (65.0%).

There were no significant differences in the prevalence of comorbidities based on the extent of the lesions on CT ([Table 1](#tbl1){ref-type="table"} ). Patients with lung involvement \>50% had a significantly higher C-reactive protein (CRP) level and neutrophil count, lower lymphocyte count, and more consolidations on CT compared to those with lung involvement ≤25% (p \< 0.01 for each comparison). Finally, 16/95 patients (16.8%) with lung involvement \>50% were diagnosed with pulmonary embolism.Table 1Baseline characteristics of the 572 COVID-19 patients according to the extent of lesions on CTTable 1Extent of lesions on CTp≤25% (*n* = 306)26--50% (*n* = 171)\>50% (*n* = 95) Age, mean ± SD (years)66.5 ± 16.265.2 ± 16.265.6 ± 14.90.69 Male sex153 (50.0)114 (66.7)76 (80.0)\<0.01 Body mass index, mean ± SD (kg/m^2^)28.7 ± 6.0 (*n* = 265)29.0 ± 5.9 (*n* = 151)29.6 ± 4.3 (*n* = 86)0.13Comorbidity Diabetes76 (24.8)44 (25.7)25 (26.3)0.95 Hypertension161 (52.6)87 (50.9)49 (51.6)0.93 Chronic heart failure30 (9.8)21 (12.3)5 (5.3)0.18 Chronic lung disease58 (19.0)23 (13.5)18 (18.9)0.28 Immunodepression8 (2.6)5 (2.9)3 (3.2)0.94 Active malignancy20 (6.5)9 (5.3)4 (4.2)0.66Clinical findings Fever224 (73.2)146 (85.4)67 (70.5)\<0.01 Dyspnea180 (58.8)140 (81.9)82 (86.3)\<0.01 Cough192 (62.7)126 (73.7)58 (61.1)0.03 Chest pain28 (9.2)17 (9.9)7 (7.4)0.78 SpO~2~ (%)94 ± 4 (*n* = 302)92 ± 6 (*n* = 166)90 ± 8 (*n* = 95)\<0.01 Maximal oxygen level (L/min)2 ± 3 (*n* = 288)4 ± 5 (*n* = 159)9 ± 12 (*n* = 80)\<0.01Time between symptom onset and CT performance (days)6 ± 67 ± 67 ± 4\<0.01Imaging findings Bilateral involvement260 (85.0)169 (98.8)95 (100.0)\<0.01 Ground-glass opacities277 (90.5)169 (98.8)94 (98.9)\<0.01 Consolidations174 (56.9)127 (74.3)71 (74.7)\<0.01 Micronodules20 (6.5)4 (2.3)7 (7.4)0.10 Pulmonary embolism[a](#tbl1fna){ref-type="table-fn"}7 (2.3)6 (3.5)16 (16.8)\<0.01Laboratory findings C-reactive protein (mg/L)59 ± 85 (*n* = 300)104 ± 84 (*n* = 169)154 ± 114 (*n* = 91)\<0.01 Neutrophil count (cells/mm³)4000 ± 2877 (*n* = 302)5100 ± 2900 (*n* = 169)6375 ± 4592 (*n* = 94)\<0.01 Lymphocyte count (cells/mm³)900 ± 527 (*n* = 302)930 ± 590 (*n* = 169)740 ± 475 (*n* = 95)\<0.01 Serum creatinine (μmol/L)74 ± 35 (*n* = 301)77 ± 35 (*n* = 170)84 ± 47 (*n* = 95)0.2 Aspartate aminotransferase (U/L)37 ± 26 (*n* = 242)47 ± 31 (*n* = 143)58 ± 42 (*n* = 84)\<0.01 Lactate (mmol/L)0.9 ± 0.5 (*n* = 186)1.1 ± 0.7 (*n* = 123)1.2 ± 0.9 (*n* = 83)\<0.01Outcome Severe disease on day 7[b](#tbl1fnb){ref-type="table-fn"}70 (22.9)70 (40.9)66 (69.5)\<0.01 Severe disease on day 30[b](#tbl1fnb){ref-type="table-fn"}82 (26.8)74 (43.3)71 (74.7)\<0.01 Death on day 719 (6.2)20 (11.7)16 (16.8)\<0.01 Death on day 3033 (10.8)29 (17.0)27 (28.4)\<0.01[^1][^2][^3][^4]

Overall, 206/572 patients (36.0%) met the criteria for early severe disease, including 55/572 (9.6%) who died. The extent of lesions on the initial CT was associated with severe disease ([Fig. 1](#fig1){ref-type="fig"} A). Among the 14 patients with normal chest CT at admission, none developed severe disease. Most patients with lung involvement \>50% were admitted to the ICU or died (66/95, 69.5%), and this rate was lower in patients with lung involvement of 26--50% (70/171, 40.9%) and ≤25% (70/306, 22.9%) ([Table 1](#tbl1){ref-type="table"}). In multivariate analysis, lung involvement \>50% was significantly associated with early severe disease (odds ratio 2.35, confidence interval 1.24--4.46; p \< 0.01) ([Supplementary Material Table S1](#appsec1){ref-type="sec"}). Survival analysis showed a significantly reduced 30-day event-free survival in patients with lung involvement of 26--50% and \>50% (p \< 0.001) ([Supplementary Material Fig. S2](#appsec1){ref-type="sec"}).Fig. 1Outcome and time from onset of symptoms as per the quantification of lesions on computed tomography (CT). (A) Histogram showing the outcome according to the extent of lesions on CT. (B) Box plot showing the time between symptom onset and CT performance as per the extent of lesions on CT. (C) Scatter plot showing the extent of lesions on CT as per the time between symptom onset and CT performance. In order to ease visualization, noise was randomly added to each point. Curves were fitted through points with the locally weighted scatterplot smoothing (LOESS) method using the 'ggplot 2' R package. Shaded area represents the standard error.Fig. 1

The median time between the onset of the symptoms and CT was 7 days (interquartile range 6.0). This duration was shorter in patients with normal CT or minimal lesions ([Fig. 1](#fig1){ref-type="fig"}B). None of the patients with minimal lesions and symptoms for more than 10 days has developed severe disease, while 10/12 (83.3%) of those with minimal lesions and severe disease presented with symptoms for ≤5 days ([Fig. 1](#fig1){ref-type="fig"}C).

Discussion {#sec4}
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Our study has shown that visual quantification of CT lung lesions is associated with early death or ICU admission in hospitalized patients, especially in patients with lung involvement \>50%.

Several risk factors for severe COVID-19 have been reported, such as older age, male sex, and chronic diseases \[[@bib8],[@bib9]\]. The chest CT has shown benefit in the diagnosis of COVID-19 pneumonia; however, its relevance as a prognostic factor remains unclear \[[@bib1]\]. Based on a study of 134 COVID-19 patients, Liu et al. showed that CT quantification of pneumonia lesions can predict early progression to severe illness \[[@bib10]\].

Although our study has employed one of the largest cohorts on COVID-19 imaging, it has some limitations. We chose to evaluate early prognosis with the outcome on day 7; a longer endpoint may have increased the number of patients with severe disease. However, most deaths and ICU admissions occurred within 7 days after admission in our study, and peak lung involvement was reached before 2 weeks of evolution in previous studies \[[@bib3],[@bib11]\]. Furthermore, we performed visual quantification, while other studies have used dedicated software to quantify lung lesions \[[@bib10],[@bib11]\]. Although this makes our evaluation dependent on the experience of radiologists, this facilitates its generalization to centres that are not equipped with such software.

Four radiological stages have been described, with progressive extent of GGO and the secondary onset of consolidations \[[@bib3],[@bib12]\]. The higher CRP level, neutrophilia and lymphopenia in our severe patients suggested an inflammatory profile that appears to be associated with lung consolidations and subsequent worsening of their respiratory condition \[[@bib13]\]. Consolidations are associated with poor outcome, as previously described \[[@bib14]\]. Patients with lung involvement \>50% were significantly more often diagnosed with pulmonary embolism. This higher risk of thrombosis in patients with severe COVID-19 has been reported, although the pathophysiology remains unclear and may possibly involve several mechanisms \[[@bib15]\].

The timing between the onset of symptoms and the performance of CT was lower for patients with lung involvement ≤25%, indicating that these patients could have presented at an earlier disease stage. However, this difference was only 1 day, raising a question about its clinical relevance. Fourteen patients (2.4%) had no lesions on the initial chest CT, and among these 10/14 had symptoms for ≤3 days, as has previously been reported \[[@bib1],[@bib2]\]. None of these patients died or was admitted to the ICU, suggesting that normal CT at the time of hospital admission could predict a good prognosis.

In conclusion, in addition to its diagnostic value, chest CT could predict severe COVID-19 pneumonia as visual quantification of the lesions appears to be associated with early prognosis. Whether this strategy should be systematically implemented remains to be evaluated in further studies.

Author contributions {#sec5}
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All authors have made substantial contributions to this work and have approved the final manuscript. Concept and design: YR, CK, FD, MO and AL. Acquisition and interpretation of imaging data: MO and AL. Collection of clinical data: YR, CK, FD, YH, NL, VG, PB and SK. Virological analysis: MS. Analysis and interpretation of clinical data: YR, CK and FD. Statistical analysis: YR, TF, FD and VG. Writing of the original draft: YR and FD.

Transparency declaration {#sec6}
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The authors report no conflicts of interest. MO reports personal fees from 10.13039/100015650Canon Medical Systems, outside the submitted work. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Appendix A. Supplementary data {#appsec1}
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The following are the Supplementary data to this article:Multimedia component 1Multimedia component 1 figs1figs1 figs2figs2

Supplementary data to this article can be found online at <https://doi.org/10.1016/j.cmi.2020.07.030>.

[^1]: Data are given in *n* (%) or median ± interquartile range, otherwise specified. The inferential analysis for the categorical data was performed using the χ^2^ test or Fisher\'s exact test (2 × 3 comparison), as per the theoretical size of the samples. Continuous data were compared using a non-parametric test (Kruskal--Wallis test).

[^2]: COVID-19, coronavirus disease 2019; CT, computed tomography; SD, standard deviation; SpO~2~, peripheral oxygen saturation.

[^3]: Only 10/29 pulmonary embolisms were diagnosed at admission.

[^4]: Defined as intensive care unit admission or death.
