LAUSR

To the Editor: We thank Dr Quarato and colleagues for their comments regarding our publication. They allow us to clarify some points probably not well understood by the authors of the letter. First of all, our aim was not to show or hypothesize the specific presence of PE in COVID-19. Instead, we aimed to show a US-detected perfusion pattern not typical of atelectasis, pneumonia, or the usual acute respiratory distress syndrome in 3 patients with severe COVID-19 pneumonia. We observed inhomogeneous CEUS enhancement of the consolidations, characterized by extensive hypovascular/avascular gaps, while the small consolidations did not show any enhancement. This does not mean that this pattern is related to PE or pulmonary infarction. In fact, in our discussion, the concept “tissue with large perfusion defects” is clearly defined. Furthermore, it is clearly described that this CEUS behavior can be caused by a range of conditions: ischemia, lung infarct, microangiopathy, changes in coagulation, vasculitis, fibrin thrombus, and hemorrhages. Indeed, we believe that the perfusion pattern in these cases is not due to classic PE; rather, it is attributable to a cytokine release syndrome or complement activation. Therefore, it represents peripheral circulatory changes at the microcirculation level. Moreover, this hypothesis has well-founded bases, and conditions of inhomogeneous perfusion (hypoperfusion and hyperperfusion defects) have subsequently been demonstrated in COVID-19 consolidations with both dual-energy CT and, again, CEUS by other researchers. We also recall that even a condition of hypoxic vasoconstriction, as proposed by Quarato et al, still represents an ischemia from the pathophysiologic point of view. The authors wrote, “US could show an area of PE/infarction only if it is in 70% of the pleural surface accessible to the US, and the adhesion to the pleural surface is total.” We agree that this represents a reasonable principle for pulmonary US. However, what was stated has no relevance for the work under discussion, since the studied consolidations were seen with a basal echo and, therefore, were among those visible with lung US. Computed tomographic and US reports show that PE often appears with a triangular consolidative shape with an echogenic core. Recently, this pattern has been reaffirmed by Copetti et al using US. Although this appearance led us to study the microcirculation of superficial consolidations with CEUS, it is not stated that it is synonymous with pulmonary infarction. Certainly, chronic obstructive pulmonary disease, pulmonary fibrosis, cardiopathy, atherosclerosis, hypertension, pneumoconiosis, and lung cancer may influence the transit time on CEUS imaging, but lung CEUS is used only when a consolidation is clearly explorable. The conditions cited by the authors as reasons for perfusion alterations are, therefore, restricted to cancer. However, lung consolidations due to cancer have morphologic characteristics and a history that are very different from COVID-19 lung manifestations. Finally, we reject the statement, “The actual presence of embolism/necrosis is documentable only by chest CT,” since if the thrombotic/embolic vascular events are very peripheral (ie, subpleural and detectable with US), the CT angiography may not be diagnostic. Interestingly, Lang et al defined points of great interest for the diagnosis and interpretation of lung consolidations in COVID-19 using dual-energy CT in their patients, whereas CT angiography did not show PE. In conclusion, we think that COVID-19 “pneumonia” could be an evolutionary sequence of pathologic phenotypes, and the shift from the viremic to the microangiopathic stages could be crucial for its prevention and therapeutic approach (anticytokine treatment, complement activation control, or lung protective ventilation). This is the sense of our communication, not a “suggested diagnostic iter” but a pathophysiologic hypothesis. In 50 patients with COVID-19 lung consolidations studied with CEUS from our series (under review), treatment was guided by clinical and US findings. Signs of cytokine activation with the presence of consolidations and, above all, the perfusion defects detectable with CEUS were inputs for early treatment with sarilumab, a human monoclonal antibody against the interleukin 6 receptor heparin. Although anecdotally, only 1 patient, with advanced lung cancer, died, the other patients had an uneventful recovery from their respiratory failure.