Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging, and Hematologic Observations

Abstract

Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology.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.

Keywords: acute respiratory distress syndrome; mechanical ventilation; novel coronavirus disease 2019; pulmonary perfusion; thoracic imaging.

Figure 1.

Physiologic correlations (on admission) between (A) Pa_O2/Fi_O2 and dynamic respiratory system compliance (N = 39; r = 0.485; P = 0.0017); (B) Pa_O2/Fi_O2and positive end-expiratory pressure (PEEP) (N = 38; r = −0.377; P = 0.02); (C) ventilatory ratio (VR) and PEEP (N = 32; r = 0.486; P = 0.0048); (D) Pa_O2/Fi_O2 and VR (N = 38; r = −0.649; P < 0.0001). (E) Associations between computed tomography (CT) features and dynamic compliance (on day of CT scan) showing positive correlations with percentage aeration (N = 39; r = −0.316; P = 0.499) and percentage ground-glass opacification (N = 39; r = −0.466; P = 0.0028) and negative correlations with dense parenchymal opacification (N = 39; r = −0.362; P < 0.0001). (F) Associations between CT features and Murray lung injury score showing negative correlations with percentage aeration (N = 39; r = −0.365; P = 0.022) and percentage ground-glass opacification (N = 39; r = −0.271; P = 0.095) and positive correlations with dense parenchymal opacification (N = 39; r = 0.349; P = 0.03). LIS = lung injury score.

Figure 2.

The computed tomography “vascular tree-in-bud pattern” in two patients with severe coronavirus disease (COVID-19) pneumonia. (A) A 52-year-old male patient scanned on day 1 following intubation. There is bilateral ground-glass opacification and patchy consolidation. Dilated branching and tortuous vessels are present in the left lower lobe representing the vascular tree-in-bud pattern. (B) Targeted, enlarged image of the left lower lobe in the same patient and from the same image slice showing bizarre dilated subsegmental vessels in greater detail (arrows). (C) Targeted image of the right lung in a second patient again showing striking dilatation of vessels in the right upper lobe and a vascular tree-in-bud pattern (arrows). (D) Relationship between the prevalence of the vascular tree-in-bud pattern and duration of hospitalization (*P = 0.013 with Kruskal-Wallis; Dunn’s multicomparison P = 0.0127: group “5–9” vs. “>10”) and ventilation (^#P = 0.0142 with Kruskal-Wallis; Dunn’s multicomparison P = 0.0112: group “5–9” vs. “>10”).

Figure 3.

(A–C) Computed tomography (CT) pulmonary angiography and dual-energy CT (DECT) perfusion in a 47-year-old male patient with coronavirus disease (COVID-19) pneumonia, day 9 after intubation. (A) Soft-tissue reconstruction showing filling defects in lower lobe pulmonary arteries (thick arrows). (B) Maximal-intensity-projection CT images showing vascular tree-in-bud pattern (circled) in the left upper lobe anterolaterally and (C) corresponding DECT perfused blood volume color map showing widespread perfusion defects (thick arrows). (D–F) Representative DECT perfused blood volume color maps in three patients showing wedge-shaped (thick arrows) (D), mottled (thin arrows) (E), and mixed (F) perfusion defects. (G) Axial perfused blood volume images of the lungs in a 32-year-old female patient without COVID-19 or pulmonary embolism demonstrates a homogeneous color map indicating normal iodine distribution.

Figure 4.

Representative thromboelastography (TEG) tracings of a (A) ventilated patient with coronavirus disease (COVID-19) and (B) a control healthy volunteer. The patient TEG shows universal hypercoagulability, with higher α-angle and maximal amplitude (MA), and absent fibrinolysis at 30 minutes (LY30 = 0%). The most frequently used parameters in TEG include reaction time, which reflects the time of latency from start of test to initial fibrin formation, which is prolonged if the patient is on an anticoagulant or has a coagulation factor deficiency. Heparinase TEG eliminates the effect of heparin. The α-angle measures the speed at which fibrin buildup and cross-linking takes place and hence assesses the rate of clot formation but also provides information on fibrin formation and cross-linking. The MA is a measure of the ultimate strength of the fibrin clot, that is, the overall stability of the clot. This is dependent on platelets (80%) and fibrin (20%) interactions. Fibrinolysis activation (the percentage lysis at 30 min after MA) is evident in the control TEG with the red trace beginning to decrease in amplitude. In contrast, the COVID-19 red trace continues to show a slow increase in amplitude. A10 = amplitude 10 minutes after the time blood starts to clot; ACT = activated clotting time; CFF = citrated blood sample activated by the functional fibrinogen test; CK = citrated blood sample activated with kaolin; CKH = citrated blood sample activated with kaolin and heparinase; CRT = citrated blood sample activated with RapidTEG; K = coagulation time (min); LY30 = percentage lysis at 30 minutes after MA; R = reaction time.