*4.3. Radiology*

In CARDS, the pre-existing typical radiological COVID-19 pneumonia features with bilateral, lower lung predominant, and multifocal lesions, become progressively consolidative. The typical rounded opacities, termed "COVID balls", increase in extent and density, and evolve into fibrotic bands [18]. Typical chest CT findings in COVID-19 pneumonia are classified as typical, atypical, and indeterminate, as defined by the Radiological Society of North America (RSNA) expert consensus statement [19]. In CARDS, the chest CT features are similar to ARDS from other etiologies [20]. Importantly, in survivors of CARDS, the amount of irreversible fibrosis should not be overrated. The presence of the initial consolidation seems to protect against the subsequent development of fibrosis. The fibrotic lung changes that are seen in survivors are predominantly present in the anterior or non-dependent lobes of the lungs [20]. The posterior or dependent portions of the lungs are thus, relatively preserved. This is clinically relevant because areas that initially show consolidations have potentially reversible alterations and should not be over-interpreted as fibrosis [20]. In addition, areas that initially resemble fibrosis and traction bronchiectasis can potentially be reversible as well after the resolution of the air space opacities [20]. Excellent examples of chest CT features have been described by Gosangi et al. [20]. Complications of CARDS are ventilatory-associated lung injury, leading to lung tension cysts, pneumomediastinum, pneumopericardium, pulmonary interstitial emphysema (PIE), and pneumothorax [20].

## *4.4. Pathophysiology*

In CARDS, the pathological feature of ARDS is diffuse alveolar damage (DAD). A cytokine storm has been suggested to initiate and promote lung fibrosis progression and severity. A profibrotic macrophage response of the SARS-CoV-2 infection also triggers lung fibrosis. It has been shown that macrophages in COVID-19 express genes associated with profibrotic functions [21]. In ARDS and multiple organ failure, the cytokine storm is thought to be the predominant mechanism leading to tissue damage [22]. In the pulmonary interstitium, there is not only excessive deposition of extracellular matrix (ECM) but there are also changes in the structure and composition of the ECM [23]. Moreover, in reaction to injury of the alveolar epithelial cells, type II alveolar epithelial (AT II) cells proliferate and differentiate into type I alveolar (AT I) cells [24,25]. Aging and loss of AT II cells are involved in the pathogenesis of lung fibrosis, and AT II is highly associated with fibrosis in virus-infected patients [24].
