Optical Coherence Tomography for Microvascular Lung Vessels Obstructive Thromboinflammatory Syndrome Assessment in Patients With COVID-19: an Exploratory Study
Phase: NA
Conditions: Covid19, Pulmonary Embolism
Sponsor: IRCCS San Raffaele

 
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Optical coherence tomography for microvascular lung vessels obstructive 
thromboinflammatory syndrome assessment in patients with COVID-19: an exploratory 
study.  
Protocol Version 1.0 _ 06/May/2020 
Promoter/P.I.: Dr. M Montorfano 
Signature:     
 
 
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 organs1. 
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 hypothesis1.  
In fact, thromboembolic events rate in COVID-19 patients appears not negligible2, and a prophylactic 
utilization of low molecular weight heparin (LMWH) should be considered3. 
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 patients3,4 and should be used as the most important 

 
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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)1, 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 m5. 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 expansion6. 
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 thickness7. 
Furthermore, OCT has been used to better characterized distal Type Chronic Thromboembolic 
Pulmonary Hypertension8, and to guide its treatment with percutaneous transluminal pulmonary 
angioplasty9.  
Hong et al10 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 hypertension11.  
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 hypertension12,13. 
 

 
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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. 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.  
 
 
Inclusion Criteria (part A) 
- 
Age > 18 
- 
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 
 
Inclusion Criteria (part B) 
- 
Age > 18 
- 
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  
 
OCT procedure 
- 
Femoral vein echo-guided puncture; 6 Fr 11 cm sheath insertion. 

 
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- 
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 
o 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 
o 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: 
o on “healthy” (without ground glass appearance at CT scan) area in the same lung 
o  on contralateral lung, both in “ground glass” and “healthy” areas according to CT 
scan. 
 
PRIMARY ENDPOINT 
- 
Overall safety of OCT procedure in COVID-19 pneumonia patients 
- 
Presence of microvascular pulmonary thrombosis at OCT assessment in COVID-19 patients, 
both in “ground glass” and “healthy” ventilated areas.  
 
SECONDARY ENDPOINT 
- 
Pulmonary artery vessel anatomy characterization in COVID-19 patients 
- 
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).  
- 
Dynamic correlations with standard inflammatory, coagulation and tissue damage  
 

 
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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 a proof of concept 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 imaging related complications (expected/unexpected) and 
serious events (SAEs) (expected/unexpected and/or related/not related) and the percentage of subjects 
experiencing imaging related event  (IRE) 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). 
Patients will be censored at study closure, withdrawn of consent or loss to follow-up.  
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.  
Circumstances that may warrant termination include, but are not limited to: 

 
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 Determination of unexpected, significant, or unacceptable risk to subjects; 
 
Adverse events (AE) 
AE is defined as any untoward medical occurrence in a patient or clinical investigation subject who 
underwent to a clinical procedure regardless of its causal relationship to the clinical procedure itself.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the performing of the clinical procedure. 
The occurrence of an AE may come to the attention of study personnel during the hospitalization 
period, or during follow up visits and interviews of a study subject presenting for medical care, or 
upon review by a study monitor.  
Each AE will be recorded only once on the “Adverse Event” CRF page, with seriousness and 
maximum intensity that occurred over the duration of the event. Each event will also be evaluated 
with respect to causality and actions taken. All AEs will be monitored and recorded throughout the 
study. For all adverse events that require the subject to be discontinued from the study, the event(s) 
will be followed until final resolution or stabilization of the event(s).  
The Investigator will classify and evaluate each AE as follows: 
• 
Description of event (if the event consists of a cluster of signs and/or symptoms, record a 
diagnosis [e.g.: “flu”] rather than each sign and symptom) 
• 
Onset date 
• 
Stop date (if resolved) 
• 
Seriousness (see definition of serious adverse events below) 
• 
Intensity (“Mild” [does not interfere with daily activities]; “Moderate” [interferes with daily 
activities]; “Severe” [prevents daily activities]) 
• 
Relationship to study intervention (Not Related, Possibly Related, Probably Related) 
• 
Action taken (None, Required concomitant treatment, Permanent discontinuation of study 
intervention, Other [explain]) 
• 
Outcome (recovered without sequelae, Resolved with sequelae, Ongoing, Unknown, Death) 
Serious Adverse Events (SAE) 
An SAE is an AE that meets 1 or more of the following criteria: 

 
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 Results in death 
 Is immediately life-threatening (places the subject at immediate risk of death from the event 
as it occurred) 
 Requires or prolongs in-patient hospitalization 
 Results in a persistent or significant disability or incapacity 
 Results in a congenital anomaly or birth defect or malignancy 
 Is medically important 
 Requires medical intervention to prevent permanent impairment or damage 
 
 
Imaging-related events  
Intra-procedural adverse events will be recorded and considered as potential imaging-related events 
(IRE). IRE will be defined as the occurrence of clinical symptoms (worsening of respiratory failure, 
requiring invasive mechanical ventilation, hemoptysis), adverse angiographic outcomes (dissection, 
perforation, vasospasm, thrombus formation, abrupt closure), requiring interruption of the imaging 
procedure during intra-polmonary imaging and will be routinely registered by the operator. Major 
peri-procedural adverse events will be also be recorded: death, acute kidney injury, major bleedings, 
contrast media reaction, access-site related complications. 
 
 
 
Fundings: The procedure will be covered by SSN. The other costs (see attached table of costs) will 
be covered by COVID BIOB funds.  
 

 
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