Optical Coherence Tomography for Microvascular Lung Vessels Obstructive Thromboinflammatory Syndrome Assessment in Patients With COVID-19: an Exploratory Study

Background:Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection represents a pandemic emergency of dramatic proportions. The clinical course of SARS-CoV-2 infection often meets the criteria for acute respiratory distress syndrome (ARDS), with progressive severity ultimately leading to a rapid death. It appeared that the progressive worsening lung function of patients infected with SARS-CoV-2 was potentially driven by host immune response. SARS-CoV-2 replication in lung epithelial cells causes direct cellular damage and release of pro-inflammatory alarmins from dying cells. The successive complement system activation causes massive local release of pro-inflammatory cytokines and consequent severe collateral tissue injury and massive vascular endothelial and alveolar epithelial cell damage and microvascular thrombosis. Functional implications of this peculiar ARDS pathogenesis include a progressive worsening of ventilation/perfusion imbalances and a loss of hypoxic vasoconstriction reflexes, with a marked component of microvascular pulmonary thrombosis, as suggested by lactate dehydrogenase and D-dimer elevations. In the late stages of ARDS, the progression of endothelial damage with microvascular thrombosis can spread locally in the lung and potentially extends the systemic inflammatory reaction involving the microvascular bed of the kidneys, brain and other vital organs. A new mechanism of lung damage was recently proposed, with dramatic alveolar endothelial damage leading to a progressive endothelial pulmonary syndrome with microvascular thrombosis and suggests MicroCLOTS (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) as an atypical ARDS working hypothesis. In fact, thromboembolic events rate in COVID-19 patients appears not negligible, and a prophylactic utilization of low molecular weight heparin (LMWH) should be considered.Several biomarkers are under investigation to better determine the risk of thromboembolic events and to determine the patients who could benefit more of a prophylactic therapy with LMWH. Among others, D-Dimer is often elevated in COVID-19 patients and should be used as the most important parameter for thromboembolic risk stratification, together with other inflammation index like C-reactive-protein, interleukin 6 (IL-6) and ferritin. Nevertheless, a not negligible part of patient with COVID-19 pneumonia presents high D-dimer level with computed tomography (CT) scan negative for pulmonary embolism. Despite these patients could presents pulmonary microvascular thrombosis (MicroCLOTS), it has never been proven and an aggressive anticoagulant treatment is currently not utilized. A diagnostic technique more sensible than the CT scan on the small pulmonary arteries could theoretically allow the detection of MicroCLOTS thus justifying a more aggressive anticoagulant regimen.

Optical coherence tomography:The optical coherence tomography (OCT) is a near-infrared light source-based imaging technique with a resolution of 10-20 um. It acquires longitudinal sequences of cross-sectional images (100 frames/s) in a blood-free environment, resulting in sharp border definition between lumen and vessel wall. It is routinely used in percutaneous coronary intervention (PCI) to better characterize vessel anatomy, as well as ascertainment of full stent deployment and expansion. Moreover, OCT has been shown to have a good correlation with histology even in the evaluation of pulmonary artery morphology, particularly in the evaluation of pulmonary arterial wall thickness. Furthermore, OCT has been used to better characterized distal Type Chronic Thromboembolic Pulmonary Hypertension, and to guide its treatment with percutaneous transluminal pulmonary angioplasty. Hong et al evaluated with OCT three patients who were highly suspected for peripheral pulmonary arteries thrombi but had negative CT scan for pulmonary embolism. Thrombi were found in most of imaged vessels in these patients. Red and white thrombi can be differentiated, according to features of the thrombus on OCT images. After anticoagulation treatment, these patients' symptoms and hypoxemia improved. Repeated OCT imaging showed that most thrombi disappeared or became smaller. OCT was also used in evaluation of pulmonary arterial vasculopathy in Systemic Sclerosis, showing an unexpected evidence of pulmonary artery thrombus formation in 19% of systemic-sclerosis patients with pulmonary arterial hypertension.

There are sufficient data showing OCT to be a useful tool to identify intravascular thrombi in patients with chronic thromboembolic pulmonary hypertension, together with an increase in vessel wall thickness in most patients with pulmonary hypertension.

Aim of the study:To evaluate by intravascular OCT study the presence of microvascular pulmonary thrombosis in patients with COVID-19, high D-dimer levels and contrast CT scan negative for pulmonary thrombosis. Investigators will also evaluate the extension of microvascular pulmonary thrombosis in patients with contrast CT scan positive for pulmonary embolism in areas where contrast CT scan was negative.

Inclusion Criteria (part A): 1) Severe pulmonary coronarvirus disease 19 (COVID 19) with suspect for MicroCLOTS (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) AND 2) Contrast CT scan negative for pulmonary thrombosis AND 3) D-Dimer > 10 mcg/mL OR 4) 5 < D-dimer < 10 mcg/mL and either C Reactive Protein (CRP) > 100 mg/dL or IL-6 > 6 pg/mL or ferritin > 900 ng/L; (part B): 1) Severe pulmonary coronarvirus disease 19 (COVID 19) with suspect for MicroCLOTS (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) AND 2) Contrast CT scan positive for pulmonary thrombosis