COVID-19: What Iodine Maps From Perfusion CT can reveal—A Prospective Cohort Study

This study was approved by our Institutional Review Board at the Hospital Naval Almirante Nef and written informed consent was waived. A prospective cohort study was undertaken to assess the prognostic ability of lung perfusion using subtraction CT angiography (sCTA). Patients (> 18 years old) with confirmed SARS-CoV-2 infection by real-time reverse transcription polymerase chain reaction (RT-PCR) that required hospitalization were consecutively enrolled at three hospitals between April and May 2020. These centers included the Hospital Naval Almirante Nef (Viña del Mar, Chile), Hospital San Martín de Quillota (Quillota, Chile), and Hospital IESS Los Ceibos (Guayaquil, Ecuador). These facilities are tertiary-care hospitals able to provide on-site CTA scans and intensive care management of severe COVID-19 cases when needed.

Forty-five patients were included in this study. However, due to uninterpretable iodine map results, four of these participants had to be excluded from analyses. This left 41 patients (22 males and 19 females) in the study. In all cases, a basic clinical and demographic profile was obtained that included information regarding sex, age, duration of clinical symptoms, and laboratory studies including D-dimer, alveolar oxygenation to inspired oxygen (Pa/Fi) ratio at baseline and sequential organ failure assessment (SOFA) score. Baseline lung CT characteristics were recorded as well such as the predominant imaging pattern (ground-glass opacities, consolidation or mixed pattern), the extension of involved lung, presence of pleural effusion, evidence of right-ventricular overload and pulmonary embolism. These data were recorded along with sCTA features (see below) in an anonymized registry.

All participants were followed-up until hospital discharge searching for the development of any of the study endpoints. These endpoints included intensive-care unit (ICU) admission, initiation of invasive mechanical ventilation (IMV) and death. The decision to intubate or admit to an ICU facility was left to the attending physician's discretion.

All CT scans were performed within 24 h of admission to the hospital, in supine position. Imaging data were acquired with multidetector-CT (Canon Aquilion Prime 160 and 80, and Canon Aquilion RXL 16).

After positioning, an unenhanced scan was obtained, followed by IV injection of 100 mL iodinated contrast medium at a rate of 5 mL/seg (Visipaque 320, GE Healthcare, Milwaukee, Wis and Optiray 320, Mallinckrodt Medical, St Louis, Mo). After bolus triggering at the level of the pulmonary artery with a relative threshold of 150 HU, an early pulmonary arterial angiographic phase was obtained, followed eight seconds later by a delayed pulmonary arterial phase. All the exams were performed with the same acquisition parameters: kV (100 kV), automatic exposure control (Standard), similar range and field-of-view (FOV: L or LL), collimation (1.0 × 16 for Canon Aquilion RXL 16; 0.5 × 80 for Canon Aquilion Prime 80 and 160), pitch factor (1.4), and same rotation speed (0.5 s for Canon Aquilion RXL 16 and 0.35 s for Canon Aquilion Prime 80 and 160). The acquired images had the same reconstruction parameters: slice thickness (1.0 mm), reconstruction interval (0.8 mm) and convolution filter (mediastinum). Average dose DLP (mGy/cm) was 1093 (range: 847–1932). Breathing instructions were the same for all examinations.

sCTA is a technique that uses software-based motion correction between an unenhanced and an enhanced CT scan to obtain an iodine distribution map of the lung parenchyma. Iodine distribution maps of the early and delayed arterial phases were obtained using SureSubtraction software (version 7.0; Canon Medical Systems, Japan). Iodine maps were generated with gray-scale and identical color window tables, ranging from blue (low iodine enhancement) to yellow (high iodine enhancement).

Areas of injured parenchyma in both lungs were assessed for a predominant pattern. These were characterized as ground glass opacities, consolidation and mixed pattern. Airspace compromise was assessed for each of the 5 lobes considering the extent of anatomic involvement, as follows: 0 points for no involvement; 1 point for < 30% involvement; 2 points for 31–60% involvement; and 3 points for > 61% involvement. The resulting CT severity score was the sum of each individual lobar score (0–15). Areas of airspace disease were also assessed for the presence of increased perfusion or hypoperfusion. Peripheral vascular dilatation and vascular tortuosity were also assessed in each lobe.

Areas of apparently healthy lung parenchyma were assessed for preservation of anteroposterior and apicobasal perfusion gradient or hypoperfusion. Hypoperfusion in apparently normal lung parenchyma was characterized according to its distribution (focal or diffuse), and extension. The latter was graded using a scoring system: first, both lungs were divided into five lobes (upper right and left lobes, middle lobe, and lower right and left lobes). Then, the extension of hypoperfusion in apparently healthy lung parenchyma in each lobe was categorized as normal perfusion (0 points), less than 50% of the lobe affected (1 point), and 50% of the lobe or more affected (2 points). This resulted in an overall score that ranged from 0 to 10 points, with higher scores indicating more severe hypoperfusion. Using this score, patients were divided in three groups. Patients with 3 points or less were considered to have mild perfusion abnormalities, those with 4–6 points had moderate abnormalities and those with 7 or more points had severe abnormalities.

A single radiologist with over 15-years experience (MS) in reading CT analyzed the images of included patients in all hospitals. The attending physicians did not have information regarding sCTA perfusion results. However, data regarding overall CT characteristics of included participants was made available to clinicians as per current protocols at study centers.

Descriptive statistics including medians, means, standard deviations, interquartile ranges (IQR) and absolute and relative frequencies were used first to describe the study sample. Bivariate comparisons between groups were performed using Fisher's Exact test for categorical variables and Student's t test or Mann–Whitney's test for continuous variables after reviewing data distribution and variances. Association between quantitative variables were sought using Pearson's or Kendall's correlation coefficients. Discrete quantitative variables (such as computed tomography scores) were evaluated using Kendall's tau coefficient. The development of any of the aforementioned study endpoints was evaluated using Kaplan–Meier survival curves which were then compared using the logrank statistic. Ninety-five percent confidence intervals were calculated whenever appropriate. Analyses were undertaken by an independent statistician who had no participation in the decision to admit or intubate any of the included patients, using STATA 15.0 SE® (College Station, TX: StataCorp LLC). A two-sided p value of < 5% was considered to be statistically significant.

All patients had SARS-CoV-2 infection confirmed by a positive RT-PCR. The mean age was 55.2 ± 16.5 years and the median duration of symptoms was 7 (IQR 5–8) days. Laboratory investigations were often abnormal. Twenty-three patients (59%) had abnormal D-dimer levels, which averaged 1057 ± 984.1 ng/mL. The average Pa/Fi ratio on admission was 307 ± 110.2 and the median SOFA score was 2 (IQR 1–2) points, which was similar between study groups (p = 0.09). Patients with hypoperfusion abnormalities on apparently healthy lung parenchyma on sCTA showed lower Pa/Fi values (294 ± 111.3 vs. 397 ± 37.7, p = 0.035), and higher D-dimer levels (1156 ± 1018 vs. 378 ± 60.2, p < 0.01). A summary of baseline clinical characteristics is shown in Table 1.

The most common patterns seen in lung CT scans were ground-glass opacities (23 patients, 56.1%), followed by mixed pattern with predominant ground-glass opacities (10 patients, 24.4%) and mixed pattern with predominant consolidation (8 patients, 19.5%).

There were no major differences in the predominant radiological pattern between normal and abnormal perfusion groups. Multilobar lung involvement was common among included patients but tended to be less among patients without perfusion abnormalities (p = 0.02). In the same way, the median CT severity score was higher and statistically significant in the group with perfusion abnormalities (7 (IQR 5–10) vs. 3 (IQR 2–5), p = 0.01).

Pulmonary embolism was found in two patients (4.8%), and both had an abnormal perfusion CT. Pleural effusion was infrequent among included participants (7 patients, 17.1%). No patient showed signs of right ventricular overload at baseline. Vascular dilatation, defined as a 1.5-fold increase in arterial diameter compared to the accompanying bronchus, was observed in 40 (97.5%) patients. Vascular tortuosity was found in 14 patients, all belonging to the group with perfusion abnormalities. The median number of lobes with vascular dilatation was also higher in the group that showed perfusion anomalies. The presence of vascular tortuosity was significantly associated with the requirement of invasive mechanical ventilation (HR 5.9, 95% CI 1.83–18.91, p = 0.003) (Fig. 1).

Perfusion abnormalities were common among included participants with 36 (87.8%) patients having hypoperfusion in areas of non-injured parenchyma. These anomalies had most commonly a diffuse distribution (23 patients, 63.9%). The median perfusion-CT score for areas of decreased perfusion was 5 points (IQR 3–9). Patients were then categorized in three groups using the aforementioned scoring system according to the extension of perfusion abnormalities in non-injured lung. Eleven patients (26.8%) were identified as having mild perfusion anomalies, 13 patients (31.7%) had moderate perfusion abnormalities and 17 (41.5%) had severe abnormalities (Figs. 2, 3).

Nineteen patients (46.3%) were admitted to the ICU during follow up, and 14 (34.2%) required IMV. Two patients (4.9%) died during hospitalization. None of the patients with normal perfusion CT scans required admission to the ICU or IMV, and all survived. Survival analyses showed significant differences in the probability of ICU admission and initiation of IMV between perfusion score groups, which are shown in Fig. 4a, b. Patients with severe hypoperfusion in apparently healthy lung parenchyma had a greatly increased probability of being admitted to the ICU, with a HR of 11.9 (95% CI 1.55–91.9, p = 0.017) when contrasted with patients with mild perfusion abnormalities. Similar findings were seen regarding the initiation of IMV (HR 7.8 95% CI 1.05–61.1, p = 0.025). Patients with moderate hypoperfusion anomalies also had an increased risk of ICU admission and of requiring IMV, albeit without statistical significance (HR 4.5 95% CI 0.53–38.4, p = 0.17 and HR 2.60, 95% CI 0.27–25, p = 0.41, respectively). A summary of study outcomes is shown in Table 2. Thirty-four of these patients (94.4%) showed increased perfusion to areas with visible parenchymal abnormalities, with the remaining two patients showing perfusion defects in these zones (5.6%) as their predominant finding (Fig. 5). 14 (34%) patients had mild artifacts on iodine maps that did not interfere with the analysis of the images. A moderate correlation was found between perfusion CT score and CT severity score (TauB = 0.47), which was statistically significant (p < 0.001). This association is shown in Fig. 6.