In this study we evaluated lung perfusion disturbances in areas of apparently healthy lung parenchyma in conventional chest CT images in patients with COVID-19 pneumonia as a severity predictor, through iodine distribution maps obtained with sCTA. The main findings of this prospective cohort were highly correlated and reliable with our prior small prospective cohort  study: (1) perfusion abnormalities were very common amongst included participants; and (2) with increasing severity of hypoperfusion abnormalities, patients had a statistically significant increase in their chance to require admission to ICU (p = 0.001), and to require IMV (p < 0.001). The higher rate of mortality was in the severe perfusion anomalies group (17.7%) in relation to the other groups but did not reach statistical significance (p = 0.44). This could be explained by the large number of patients with moderate and severe perfusion alterations, and fewer with mild alterations.
ACE2 is an important regulator of the renin-angiotensin system, and SARS-CoV-2 binds to host ACE2 receptors as the functional receptor for invasion into human cells.
Initially, when the virus reaches the air space it produces local inflammation with important local endothelial dysfunction, thrombosis, angiogenesis and vasodilation [10, 11, 12].
When the virus spreads to the pulmonary blood circulation, SARS-COV-2 binds to ACE2, and due to viral blockade and down-regulation, both Angiotensin I (Ang I) and Angiotensin II (Ang II) accumulate. Also, as angiotensin-converting enzyme (ACE) is not engaged by the virus, the conversion of Ang I to Ang II continues unabated, leading to unopposed accumulation of Ang II . Probably in the early phases, Ang II produces vasoconstriction and endothelial dysfunction with less production of nitric oxide, also resulting in vessel constriction and finally causing hypoperfusion and establishing a progressive V/Q mismatch, with extensive areas of apparently healthy but hypoperfused lung that functions as alveolar dead space [9, 13]. This phenomenon could explain in part the L phenotype proposed by Gattinoni et al. at the beginning of the pandemic [14, 15], which found severe hypoxemia in patients without significant air space compromise. Late and in more advanced stages, excessive Ang II it would end up producing inflammation, vasodilatation, capillary leakage, edema, and a pro-coagulant state, eventually accompanied by microvascular thrombosis [9, 15].
A third important finding was that the presence of vascular tortuosity was significantly associated with the admission to ICU (p = 0.001) and the requirement of IMV (p = 0.001). Once SARS-COV-2 reaches the alveolus, active replication and release of the virus cause the host cell to undergo pyroptosis, liberating damage-associated molecules, with disruption of the alveolar-capillary barrier, resulting in vascular leakage and alveolar edema. Also, it can locally cause pulmonary endothelitis, thrombosis, angiogenesis and vasodilation resulting in high perfusion to areas of hypoventilated lung and an abnormally low V/Q ratio that can promote hypoxemia [6, 10, 12].
We found pulmonary embolism in twenty patients (10.5%), and all of them had an abnormal perfusion CT. Most cases of pulmonary embolism were found amongst individuals with severe perfusion defects localized at segmental or subsegmental level. It has been suggested that SARS-Cov-2 in severe forms of the disease induces an excessive inflammatory state via a cytokine storm combined with endothelial injury and pulmonary vascular microthrombosis, which could considerably increase the risk for venous thromboembolism and mainly pulmonary embolism, for which some meta-analyses have shown a pooled prevalence ranging from about 13–30% [16–19]. In non-severe COVID-19, these microthrombi are broken down by the highly active fibrinolytic function in the lungs to allow gas exchange which is noted as an elevation in D-dimers, but in severely ill patients, the pulmonary coagulation system becomes markedly activated, which can manifest clinically as increased oxygen requirements [20, 21]. The role of empirical anticoagulation in some COVID-19 subgroups has been considered but is not recommended in general population because it is associated with higher bleeding risk and does not improve the survival rates [22, 23].
Another salient finding to highlight from our study is that a significant correlation was found between the extent of lung parenchymal disease and perfusion abnormalities (p < 0.001) with lung perfusion scores of 7 or more points (severe perfusion abnormalities) being a significant predictor of ICU admission after adjustments for parenchymal disease extension, vascular tortuosity, sex and age were made (p = 0.010). The limited sample size of our preliminary cohort study was hampered due to its inability to control for relevant clinical confounders. In this second study, we were able to isolate lung perfusion as an important prognostic marker in COVID-19.
Finally, it should be noted that the observed agreement between two radiologists was very high, with a median Kappa statistic of 0.95. Vascular tortuosity was the domain with least consensus between observers (𝜅=0.9), and on the other hand, evidence of pulmonary embolism showed the highest level of agreement between radiologists (𝜅=1.0).
This study has limitations. First, some of the iodine maps were uninterpretable
and 63.8% had artifacts that did not preclude their interpretation. Second, sCTA is a new postprocessing technique and thus, has not been as extensively validated as Dual Energy Computed Tomography (DECT). However, it is a promising approach that digitally subtracts a precontrast CT scan from a contrast–enhanced CT scan after motion correction and has higher contrast-to-noise ratio at same dose than DECT. Since it is software-based, it is significantly less expensive and potentially more available than costly DECT equipment. Nevertheless, being a novel approach, concerns regarding potential bias resulting from subtraction of non-contrast images from contrast-enhanced images need to be addressed, and greater experience and better knowledge of typical pitfalls is needed to improve the diagnostic accuracy [24, 25, 26].
Third, perfusion imaging involves more radiation than conventional CT techniques. Finally, it is unclear whether these perfusion abnormalities are unique to COVID-19 or if they can also be found in other multifocal pneumonias and other causes of ARDS.