Setting
In the Reggio Emilia province (Northern Italy, 532,000 inhabitants, six hospitals), the first case of SARS-CoV-2 infection was diagnosed on February 27, 2020. Up to March 24, there were 1200 RT-PCR-confirmed cases and the epidemic was still spreading. The study was approved by the Area Vasta Emilia Nord Ethics Committee on 04/07/2020 (protocol number 2020/0045199). Patients’ written consent to publish their images was obtained, and patients’ informed consent to participate in the study was obtained whenever possible, given the retrospective nature of the study.
Study design
This was a cross-sectional study assessing sensitivity and specificity of CT for COVID-19 pneumonia at two different thresholds of suspicion, using RT-PCR as the reference standard.
Study population
All consecutive patients who presented to the Reggio Emilia province ERs between March 13th and March 23rd for suspected COVID-19 and underwent both CT and RT-PCR were eligible. Subjects with a time gap between CT and RT-PCR > 3 days were excluded.
During the COVID-19 outbreak, the diagnostic protocol for these patients included nasopharyngeal and oropharyngeal swabs for RT-PCR, blood tests, chest X-rays, and CT scan in cases of suggestive X-ray findings or negative X-rays but highly suggestive clinical features. A structured CT report was introduced on March 13th.
Reference standard
Two issues hamper the measure of CT accuracy for COVID-19. Firstly, the clinical sensitivity of RT-PCR, our reference standard, although not yet quantified, is not 100% [5]. Secondly, the target condition of our index test, i.e., CT, is viral pneumonia, while RT-PCR target condition is SARS-CoV-2 infection.
While the second issue cannot be easily solved, to overcome the first problem we used different definitions of reference standard: 1) the first RT-PCR within 3 days after CT; 2) the first RT-PCR and, if negative, repeated RT-PCR tests in the following 15 days; if not repeated, the patient was considered non-COVID19; 3) as in definition 2, but RT-PCR-negative patients who were not retested were classified as COVID19 or non-COVID19 in the same proportion as patients who were actually retested in that group of CT results.
A commercial One-Step Reverse Transcription RT-PCR (GeneFinder ™ COVID -19 PLUS Real Real Amp Kit) was used and RT-PCR assay was performed on an Applied Biosystems 7500 Sequence Detection System.
CT acquisition technique
CT scans were performed using one of three scanners (128-slice Somatom Definition Edge, Siemens Healthcare; 64-slice Ingenuity, Philips Healthcare; 16-slice GE Brightspeed, GE Medical System) without contrast media injection, with the patient in supine position, during end-inspiration. Scanning parameters were: tube voltage 120 KV, automatic tube current modulation, collimation width 0.625 or 1.25 mm, acquisition slice thickness 2.5 mm, and interval 1.25 mm. Images were reconstructed with a high-resolution algorithm at slice thickness 1.0/1.25 mm. Patients wore face masks, and thorough decontamination of the room was performed after each patient.
CT analysis and structured reporting
During routine reporting, each radiologist completed both the usual radiology report as well as a structured report about the probability of COVID-19 pneumonia based on CT findings (highly suggestive, suggestive, non-suggestive) (Fig. 1), the presence/absence of ground-glass opacities and consolidations, and the extension of pulmonary lesions using a visual scoring system (< 20%, 20-40%, 40-60%, and > 60% of parenchymal involvement) (Fig. 2). Swab results were unknown when reporting, so radiologists were blinded to RT-PCR. However, they were frequently informed of blood test results and of patients’ clinical features.
Blood tests
When available, C-reactive protein (CRP) level, LDH, total leukocyte, lymphocyte, neutrophil, and platelet counts measured on ER admission were collected. The tests were carried out in the Hospital Clinical Laboratories with routine automated methods. Oxygen saturation level (SpO2) was also collected for patients who had it measured before being provided with oxygen support.
These tests were included since previously associated with COVID-19 diagnosis, severity and prognosis: increased CRP reflects host inflammatory response, along with increased total leukocyte and neutrophil counts; elevated LDH concentrations may be a sign of end-organ damage; decreased platelet count may be associated with an underlying coagulopathy; lymphopenia may represent a concomitant immune dysfunction and has been associated with increased disease severity and worse prognosis; SpO2 provides information on lung damage and functionality [19,20].
Statistical analyses
CT scan sensitivity, specificity, and positive predictive value (PPV) for COVID-19 pneumonia were computed for two different thresholds: highly suggestive only, and highly suggestive plus suggestive findings.
Accuracy measures according to the three reference standard definitions reported above were calculated with relative 95% confidence intervals (CI) computed on the exact binomial distribution.
Distribution of clinical characteristics across groups of CT and RT-PCR results is reported. Associations between clinical characteristics and CT and RT-PCR classes were measured through Pearson’s chi2 and Fischer’s exact distribution. For blood tests, we report mean (±SD) and median (IQR) stratified by groups of CT and RT-PCR results. Comparisons between groups were conducted with one-way ANOVA and linear regression models adjusted for sex and age.
P values are reported as continuous measures and no prefixed significance threshold was used.
We used Stata 13.0 SE (Stata Corporation, Texas, TX) software package.