Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia.
Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography.
Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29–79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic “shutdown”. The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6).
Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis
Mechanically ventilated patients with severe COVID-19 pneumonia present with hypercapnic respiratory failure and a relatively preserved respiratory system compliance initially (9), reflecting increased pulmonary dead space and a predominant defect in pulmonary perfusion. To the best of our knowledge, the current study is the first to systematically evaluate the combined physiologic, hematologic, and morphologic abnormalities in patients with COVID-19 pneumonia. Our observations point to an increased physiologic dead space, hypercoagulability (with absent fibrinolysis), and imaging signs of major vascular involvement. Accordingly, and in light of emerging pathologic evidence of major vascular involvement, we suggest that our results support the presence of a widespread pulmonary angiopathy in severe COVID-19 pneumonia.
Interest in the physiology of COVID-19–induced ARDS stemmed from the proposal by Gattinoni and colleagues of two broad (but almost certainly overlapping) phenotypes: “type L,” with high lung compliance and limited ground-glass opacification on CT and responsive to lower PEEP, and “type H,” in which compliance is low and disease more extensive on CT, potentially benefitting from higher PEEP (1). This apparently simple dichotomy has attractions but has been questioned: Bos and colleagues found no relationship between compliance and qualitative CT measurements, suggesting that these phenotypes may not be mutually exclusive. However, our data also confirm considerable overlap in phenotypes, with all patients showing a significant (>50% of lung volume) combination of ground-glass and diffuse parenchymal opacification, presumably related to the progression of disease. The latter was confirmed with patients showing a higher Murray lung injury score showing lower percentage aeration/ground-glass opacification but greater dense parenchymal opacification.
The ventilatory ratio—a simple bedside index of physiological dead space fraction in patients with ARDS —was associated with worsening hypoxemia, in line with other studies of COVID-19–related ARDS. Moreover, the association between higher PEEP (i.e., lower PaO2/FiO2) and worsening hypoxemia and greater physiological dead space fraction (i.e., higher ventilatory ratio) all point to disproportionate vascular dysregulation compounded by redirection of perfusion away from overdistended oxygenated alveoli, without the benefits of additional lung recruitment, in line with recent studies of the variable efficacy of lung recruitment in COVID-19–induced ARDS.
Two crucial observations from our study shed light on the possible pathophysiological explanation for this increased physiological dead space: first, the frequent presence of dilated, branching, and/or tortuous vessels in the peripheral lung, and second, perfusion defects on DECT. We believe that the dilatation of peripheral vessels is an extension of the enlarged vessels reported by others. Albarello and colleagues commented on enlarged tubular vessels in two patients. In a larger study, Caruso and coworkers found enlarged subsegmental vessels in 89% of 158 patients. The peripheral location and branching nature of the dilated vessels in our study bears a striking resemblance to the CT findings in rare patients with pulmonary tumor thrombotic microangiopathy: in the first report of its kind, the authors described the pathologic and CT features of a 48-year-old patient with progressive breathlessness. On thin-section CT, there were bilateral longitudinal branching opacities, the so-called “vascular tree-in-bud” pattern. Cardiac catheterization confirmed severe pulmonary hypertension, and at postmortem, most small arteries and arterioles were occluded by fibrocellular intimal hyperplasia and clumps of tumor cells were seen in some arterioles. The logical explanation, presumably, is that the small arterioles—normally not resolved on CT—were enlarged and thus rendered visible. It has been previously suggested that vessel enlargement in COVID-19 pneumonia might be a marker of increased blood flow. However, we do not subscribe to this explanation but instead suspect that the vascular tree-in-bud pattern in COVID-19 likely is a manifestation of pulmonary thrombotic angiopathy. Support for this comes from postmortem data. In one of these studies, features of diffuse alveolar damage were present in all cases, but COVID-19 lungs were distinguished by the presence of widespread microthromboses and striking new vessel growth; the latter was termed “intussusceptive angiogenesis” and linked with increasing hospitalization. Intriguingly, albeit in a small number, we also found a linkage between the vascular tree-in-bud pattern and duration of both hospitalization and ventilation before CT. Thus, it is tempting to speculate that the vascular tree-in-bud pattern in COVID-19 pneumonia may be an important CT marker of immunothrombosis and angiogenesis.
The DECT scanning technique, although lacking a routine role in the imaging of lung disease, has certainly attracted attention as an alternative means of assessing pulmonary perfusion in acute and chronic thromboembolic disease. In the specific context of chronic thromboembolic disease, there is high concordance between findings on DECT and traditional ventilation-perfusion imaging. Indeed, patterns of perfusion abnormality appear to differ significantly between chronic thromboembolic disease and patients with pulmonary arterial hypertension . The striking finding of abnormal pulmonary perfusion on DECT has not, to the best of our knowledge, been fully explored in COVID-19 pneumonia. Abnormalities of perfusion were seen in all patients with assessable lobes, irrespective of whether this was in dependent or nondependent areas of the lung. This finding in patients with the most severe COVID-19–related respiratory failure suggests that vascular dysregulation is not, as has been proposed, restricted to those with the early or so-called “type L” phenotype. The finding of abnormal perfusion, although supporting the hypothesis of major vascular involvement, was certainly unexpected in the context of ARDS where, given the inflammatory pathology, one might have expected regions of overperfused lung on DECT.
Given the preferential respiratory route of entry and significant expression of ACEII in vascular endothelium, it might be speculated that SARS-CoV-2 might, through direct endothelial infection (facilitated by the ACEII receptor uptake), lead to significant pulmonary microvascular endothelial injury with associated viremia. Interestingly, SARS-CoV-1 has been shown to induce pulmonary cellular necrosis, and the pathobiological processes leading to immunothrombosis (endothelial injury, vascular inflammation, and thrombotic microangiopathy) might then serve to explain our observation of dilated peripheral vessels and perfusion defects on imaging. Furthermore, the vascular injury and so-called “cytokine storm” of COVID-19, with its release of eicosanoids (e.g., arachidonic acid), could stimulate platelet aggregation, simultaneous with a release of adenine nucleotides from activated platelets promoting thrombus formation, further amplifying the platelet response. Indeed, pulmonary vascular inflammation, in particular, leukocyte–platelet interactions, is associated with the development of ARDS from non-COVID etiologies.
The issue of deep venous thrombosis (DVT) and acute PE in COVID-19 pneumonia merits brief consideration. Approximately 90% of symptomatic PEs are known to originate from thrombi located in lower limbs . Moreover, in line with other viral pneumonias, PE is reported in patients with COVID-19 and, admittedly, was present on CT in 15 of 39 patients in our study. Thus, it might conceivably be argued that the dilated peripheral vessels in our patients were simply being rendered visible on CT by embolic material from upper- or lower-limb DVT. However, against this, DVT was recorded in only 4 of 22 patients undergoing lower-limb compression ultrasound or CT venography, and only 1 patient with PE had DVT. Furthermore, it is noteworthy that dilatation of peripheral vessels with embolic material has, as far as we are aware, never been documented in patients with acute or chronic PE. Although accepting fully that DVT occurs commonly in critically ill patients (and that these may result in PE), we suggest that in COVID-19 there may be dual pathologies at play, namely, acute PE from DVT and a widespread pulmonary angiopathy.
We regard the hematological tests in our patients as important and complementary, serving to confirm hypercoagulability (as evidenced by raised MA, functional fibrinogen levels), and absent fibrinolysis given the LY30 of 0% in all patients. The term fibrinolysis “shutdown” refers to the acute impairment of fibrinolysis. Impaired fibrinolysis is regarded as a predictor of first and recurrent PE. Although use of TEG outside cardiac surgery and liver disease is limited, there is emerging evidence from several studies for a role for viscoelastic tests in assessing the bleeding and thrombotic risk in critically ill patients with infection/inflammation. Furthermore, hypercoagulability as evidence by TEG has been shown to be predictive of thrombosis in patients with trauma and in the general population.
There are clear limitations to our study, not least the small sample size, the retrospective observational nature, the absence of matched (non–COVID-19) controls, the lack of a validation cohort, and, given the tertiary nature of our practice, the focus on patients with severe COVID-19–induced respiratory failure. The physiology does not directly prove pulmonary angiopathy, but we believe such relatively simple bedside physiological assessments may enable further diagnostic evaluation of vascular abnormalities and pulmonary angiopathy in severe COVID-19. Future studies comparing a matched control group of patients with non–COVID-19–related ARDS are clearly necessary to ascertain whether the imaging findings we report herein are truly related to SARS-CoV-2. However, in light of current evidence of a significant vascular component to COVID-19, we propose that our observations not only provide important noninvasive evidence of pulmonary vascular involvement through imaging but also add to the understanding of clinicophysiological phenotypes and pathobiology of COVID-19 pneumonia/ARDS.
In summary, our observations on CTPA and DECT, coupled with the physiologic and hematologic features, point to major pulmonary vascular involvement in severe COVID-19 pneumonia. Further validation of these imaging markers is clearly warranted, but in light of the emerging pathologic evidence of angiopathy, we believe our findings have implications for further pathobiologic and therapeutic studies.
Reference & source information: https://www.atsjournals.org/
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