# Thymic Hyperplasia and COVID-19 Pulmonary Sequelae: A Bicentric CT-Based Follow-Up Study
## 2 Materials and Methods  
This multicenter retrospective study was performed at Centro Diagnostico Italiano (Center 1) and at Fatebenefratelli Hospital--ASST Fatebenefratelli Sacco (Center 2), both in Milan, Italy, after approval from the local Ethics Committee (Comitato Etico Sacco Area 1, Milan, Italy; study ID 2417, approved on 29 September 2021). We included consecutive adult patients who were previously hospitalized for RT-PCR-proven SARS-CoV-2 infection, did not need invasive ventilatory support during hospitalization, and were referred by a pulmonologist for a 3-month follow-up unenhanced chest CT--performed between January 2021 and September 2021--due to post-COVID symptoms. In both centers, chest CT scans were executed on the same scanner (Somatom Definition Flash, Siemens Healthineers), with the following acquisition parameters: reference kV, 120; reference mAs, 150 (with automated tube current modulation); rotation time, 0.5 s; collimation, 128 \(\times\) 0.6 mm; pitch value, 1; scan direction, craniocandal, and reconstructed as follows: for lung, slice thickness of 0.75 mm with reconstruction spacing of 0.5 mm; for mediastinum, slice thickness of 3 mm and reconstruction spacing of 1 mm. Image datasets were transferred to the picture archiving and communication system for assessment with lung parenchyma and mediastinal windows and were independently reviewed by two radiologists with 10 and 16 years of experience in chest imaging. Their inter-reader reliability for the assessment of pulmonary sequelae and thymic appearance was evaluated with [PERSON]'s \(\kappa\), interpreted according to the Landis and Koch scale [16]. After inter-reader reliability analysis, the remaining discrepancies were solved by consensus. Pulmonary sequelae were graded (pulmonary sequelae score) on a 0-6 scale [14] as follows: grade 0 corresponded to absent or minor pulmonary parenchymal abnormalities; 1 to limited ground-glass opacities; 2 to bilateral ground-glass opacities, involving less than 50% of pulmonary parenchyma; 3 to grade 2 but with the coexistence of inter/intralobular septal thickening, resulting in a crazy paving appearance; 4 to bilateral ground-glass opacities involving more than 50% of pulmonary parenchyma; 5 to grade 4 with the coexistence of crazy paving aspects; and 6 to grade 5 with associated pulmonary fibrosis. The categories of pulmonary sequelae were then dichotomized as category 0 (corresponding to absent or minor pulmonary parenchymal alterations) versus categories 1-6 (from limited ground-glass opacities to bilateral diffusion with associated pulmonary fibrosis). Thymic fat involution was graded (T score) on a four-point scale [17] as follows: 1, well-recognizable thymus characterized by predominantly soft-tissue attenuation, similar to the muscle density; 2, approximately 50% thymus with fatty involution and 50% characterized by soft-tissue-attenuated thymus; 3: predominantly fatty thymus; 4, complete thymus fatty replacement, without any identifiable soft tissue component in the anterior mediastum. The thymus classification was dichotomized as categories 1-3 (from no fat infiltration--i.e., thymic hyperplasia--to fat infiltration >50%) versus category 4 (complete thymic fat involution) (Figures 1-3). Using SPSS (version 26.0; IBM), direct comparisons of thymic status and pulmonary sequelae were performed with [PERSON]'s exact test, while age-stratified comparisons (considering age 45 as a cut-off for commonly observed thymic involution) were performed with the Cochran-Mantel-Haenszel test. After univariate binary logistic regression, multivariable binary logistic regression was used to calculate adjusted odds ratios (ORs) for the development of pulmonary sequelae, with 95% CI. Figure 1: (**a**) Mediastinal window showing a grade 2 T score, with approximately 50% of the thymus with fatty involution and 50% characterized by soft-tissue-attenuated tissue. No pulmonary alterations are visible on the lung parenchyma CT reconstruction (**b**).