Pulmonary Optical Coherence Tomography in COVID-19 Patients
Pulmonary Optical Coherence Tomography in COVID-19 Patients
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. We'll 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.
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

 Exclusion Criteria: 1) Age < 18 2) Pregnancy or breastfeeding 3) Known allergy to iodinated
 contrast dye 4) Hemodynamic instability 5) Glomerular Filtration rate < 30 ml/min 6) Active
 bleeding or absolute contraindication to anticoagulant therapy

 OCT procedure: Femoral vein echo-guided puncture; 6 Fr 11 cm sheath insertion; Unfractionated
 heparin administration (70 - 100 U/kg) to achieve an activated clotting time (ACT) between
 250 and 300 seconds; Pulmonary artery cannulation with 5 Fr Multipurpose (MP) catheter
 (Cordis, Dublin, Ohio) and Storq wire (Cordis); Pulmonary artery pressure measurement;
 Selective pulmonary artery cannulation and angiography (The choice of the pulmonary arteries
 to be cannulated will be driven by "ground glass" area at CT scan); 5Fr MP catheter will be
 changed for 6Fr MP guiding catheter over the Storq wire; Storq wire removal and 0.014"
 Balance wire distally advanced; OCT images acquisition (In order to remove all the blood, as
 well as to obtain clear images, iodinated contrast is infused at a flow rate of 5 mL/s over 4
 s, at 400 psi of pressure (Acist, Eden Prairie, Minnesota). Automatic pullback at 20 mm/s);
 If needed, blood samples can be taken through Recover catheter (Hexacath, Rueil-Malmaison,
 France).

 The same procedure will be performed: on "healthy" (without ground glass appearance at CT
 scan) area in the same lung and on contralateral lung, both in "ground glass" and "healthy"
 areas according to CT scan.

 PRIMARY ENDPOINT: 1) Overall safety of OCT procedure in COVID-19 pneumonia patients 2)
 Presence of microvascular pulmonary thrombosis at OCT assessment in COVID-19 patients, both
 in "ground glass" and "healthy" ventilated areas.

 SECONDARY ENDPOINT: 1) Pulmonary artery vessel anatomy characterization in COVID-19 patients
 2) Correlations with single trans-thoracic echocardiography (TTE) pulmonary hypertension (PH,
 estimated systolic pulmonary artery pressure > 35 mmHg) and right ventricular disfunction
 (RVD: tricuspid annular plane systolic excursion < 17 mm or Doppler tissue imaging S wave <
 9.5 cm/sec) 3) Dynamic correlations with standard inflammatory, coagulation and tissue damage
 biomarkers: CRP, ferritin, D-dimer, NT-proBNPO, troponins, LDH)

 Study design, sample size, statistical analysis: The study is an open label, prospective,
 interventional clinical study of the safety, tolerability and potential diagnostic value of
 optical coherence tomography for microvascular lung vessels obstructive thromboinflammatory
 syndrome assessment in patients with COVID-19 pneumonia.

 This is an exploratory study and will be conducted in 10 patients with mild-to-severe ARDS.
 The sample size calculation was designed for safety assessment based on a reference
 population of last 100 patients who underwent OCT at our Institution for coronary Artery
 Disease (CAD) in which a rate of SAEs lower than 1% have been recorded (personal
 communication)

 Primary endpoint: As for safety analysis, the number of ADR (expected/unexpected) and SAEs
 (expected/unexpected and/or related/not related) and the percentage of subjects experiencing
 ADR and SAEs in the study will be summarized by severity and within body system involved.
 Narratives will also be presented.

 Secondary endpoints: Continuous variables will be summarized with indices of location (i.e.
 mean or median) and dispersion (i.e. standard deviation or interquartile range), as
 appropriate. All relevant estimates will be reported with the corresponding 95% Confidence
 Intervals (CI).

 The time to event endpoints will be described using the Kaplan-Meier approach and estimates
 at pre-defined time points will be obtained along with 95%Cis. Patients will be censored at
 study closure, withdrawn of consent or loss to follow-up.

 Subgroup analyses and regression models (i.e. logistic model on proportions and Cox model on
 time to event outcomes) will be performed considering age, sex, biological features.

 Withdrawal and Premature Termination or Suspension of Study Investigators may terminate a
 study subject's participation in the study if: any clinical AE, or other medical condition or
 situation occurs such that continued participation in the study would not be in the best
 interest of the subject, the subject meets an exclusion criterion, either newly developed or
 not previously recognized (except those caused by ARDS and SARS-CoV-2 infection), that
 precludes further study participation; this study may be suspended or prematurely terminated
 if there is sufficient reasonable cause. Written notification, documenting the reason for
 study suspension or termination, will be provided.

 Fundings: not appropriate. The procedure will be charged to SSN as a diagnostic procedure
 applied to patients clinically suspected of microCLOTS in COVID-19 pneumonia.
Inclusion Criteria:

 (part A)

 -  Severe pulmonary coronarvirus disease 19 (COVID 19) with suspect for MicroCLOTS
 (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) AND

 -  Contrast CT scan negative for pulmonary thrombosis AND

 -  D-Dimer > 10 mcg/mL OR

 -  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)

 -  Severe pulmonary coronarvirus disease 19 (COVID 19) with suspect for MicroCLOTS
 (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) AND

 -  Contrast CT scan positive for pulmonary thrombosis

 Exclusion Criteria:

 -  Age < 18

 -  Pregnancy or breastfeeding

 -  Known allergy to iodinated contrast dye

 -  Hemodynamic instability

 -  Glomerular Filtration rate < 30 ml/min

 -  Active bleeding or absolute contraindication to anticoagulant therapy