Diagnosing Obstructive Lung Disease With Point of Care Ultrasound- A Cross-sectional, Diagnostic Accuracy Test
Conditions: Pulmonary Disease, Chronic Obstructive, Lung Diseases, Obstructive, Asthma, COPD
Sponsor: Soroka University Medical Center

Diagnosing Obstructive Lung Disease with Point of Care Ultrasound-  
A 
sectional
-
Cross
, Diagnostic Accuracy Test     
 
 
 
Clinical Research Center, The Medical Intensive Care Unit, and Pulmonary Institute 
Soroka University Medical Center, 
Be'er-Sheva, Israel 
 
 
 
Protocol SCRC23032 
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September 2023 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1 
Investigator Signature Page 
Study Title: 
Diagnosing Obstructive Lung Disease with Point of Care Ultrasound, A 
Cross-sectional, Diagnostic accuracy test     
Protocol Version: 
Version 1.1 
Protocol Date: 18 June 2023 
Investigator’s Responsibility 
Prior to participation in the study, as the site principal investigator, I understand that I must 
obtain written approval from my local Ethics Committee (EC) and the hospital General Director.   
 As the site Principal Investigator, I must also: 
1. 
Ensure that the study is not commenced until EC and hospital General Director approvals 
have been obtained. 
2. 
Ensure that written informed consent is obtained from each patient prior to any data 
collection using the most recent EC-approved Patient Informed Consent Form. 
3. 
Provide all required data and reports and agree to source document verification of study 
data with the patient’s medical records. 
4. 
Allow EC representatives, to inspect and copy any documents pertaining to this clinical 
investigation. 
Investigator Signature  
I have read and understand the contents of the study protocol and agree to abide by the 
requirements set forth in this document.  
 
 
Dr. Lior Fuchs 
 
 
  
Soroka University Medical Center 
Investigator Name (print) 
 
 
 
Investigative Site (print) 
 
 
 
 
Dr. Lior Fuchs 
 
 
 
 
 
June 18, 2023  
 
Investigator Signature  
 
 
                                Date 

 
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2 
Protocol Summary 
 
OBJECTIVE 
To assess the accuracy of the Point of Care Ultrasound (POCUS) exam in diagnosing obstructive 
lung diseases (OLDs) compared to the gold standard pulmonary function test (PFTs) 
STUDY DESIGN 
A cross-sectional diagnostic accuracy test  
INTERVENTION 
None 
SAMPLE SIZE 
CONSIDERATIONS 
We aim to enroll a total of 200 patients. The calculation stems from the speculation that the Se of 
the test will be 85%, with a confidence interval of 90% and the maximal width of the interval will 
be up to ±7%.  
INCLUSION CRITERIA 
• 
Age 18 or above 
• 
Referral for full pulmonary function tests (PFTs) 
• 
Patients are willing and able to sign a written informed consent form.  
EXCLUSION 
CRITERIA 
• 
Unable to give written informed consent. 
• 
Unable to remain supine. 
• 
Poor effort at PFTs  
• 
Subcutaneous emphysema 
STUDY PROCEDURES 
We plan to conduct random POCUS scans at the respiratory institute of Soroka University Medical 
Center on patients who are sent for pulmonary function tests (PFTs) for any reason and provide each 
patient with a sonographic score, comprised of several criteria (table 1). 
DATA TO CAPTURE 
Aside from the sonographic data, we plan to collect descriptive data from the hospital's medical records 
(i.e., smoking history, comorbidities, past radiographic exams, BMI, etc.) and the PFTs results. 
OUTCOMES AND 
ANALYSES 
The diagnostic accuracy of the POCUS examination, including sensitivity, specificity, positive 
predictive value (PPV), and negative predictive value (NPV) of obstructive lung diseases (OLDs) will 
be calculated using contingency tables with PFTs findings as the gold standard. 
DATA MANAGEMENT 
AND ANALYSIS 
The study will be overseen and managed by the Soroka Clinical Research Center. 

 
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Table of Contents 
 
Page 
Content 
1 
Title Page 
2 
Investigator signature page 
3 
Study protocol 
5 
Abbreviations and Definitions 
6-7 
Background 
8-11 
Design  
12 
Working hypothesis and objectives 
12-13 
Study population 
13 
Enrollment and patient screening 
14 
Study procedure and duration 
15-16 
Data to capture 
17-19 
Statistical Considerations and Analysis Plan 
20-22 
Adverse events  
23-24 
Ethical issues and subject confidentiality 
25 
References 
26 
Supplements 
 
 
 
 

 
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Abbreviations and Definitions 
Abbreviation 
Term 
A4C 
Apical 4-chamber (view) 
COPD 
Chronic obstructive lung disease 
DLCO 
Diffusing capacity for carbon monoxide 
GS 
Gold standard  
LV 
Left ventricle 
mMRC 
Modified Medical Research Council (Dyspnea Scale) 
OLD 
Obstructive lung diseases 
PFTs 
Pulmonary function test(s) 
POCUS 
Point of care ultrasound 
PLAX 
Parasternal long axis (view) 
SX 
Subxiphoid (view) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Definitions 
3 
Background 
Point of care ultrasound (POCUS) is a valuable bedside tool for rapidly assessing multiple 
cardiorespiratory conditions (1). Its portability and ease of use make it particularly useful in 
acute care settings, where quick diagnostic information is crucial for optimal patient care (2). It 
has the advantage of immediate interpretation and clinical integration of the imaging results 
without radiation exposure. The POCUS assessment is considered quick and relatively simple 
even by non-radiologist novice trainees (3). It can closely monitor patients through repeatable 
exams in short periods, providing clinicians with an essential real-time image that can reinforce 
or weaken the initial diagnosis. Some even advocate its routine use as part of the physical exam 
and refer to it as the “new stethoscope” (4) The POCUS exam has been strongly validated as an 
accurate diagnostic tool in multiple lung pathologies such as pneumonia, pulmonary congestion, 
pleural effusions, and pneumothorax (5–8). It was found to be especially valuable in the acutely 
dyspneic patient, adding vital diagnostic information with great accuracy (9–11).  
In contrast, POCUS has yet to be found as an efficient tool for diagnosing patients who suffer 
from obstructive lung disease (OLD) such as chronic obstructive pulmonary disease (COPD). 
This is probably due to air trapping in OLDs, considered the “great nemesis” of ultrasound. 
Nevertheless, based on multiple observations and personal clinical experience, we believe that 
POCUS can, in fact, efficiently recognize those patients with air trapping, mainly those with 
COPD.  
In the last decade, we have used POCUS as part of the physical examination at the bedside 
regularly. We noticed that among COPD patients, we often detect very poor cardiac imaging on 
the parasternal long axis, apical four-chamber views (thoracal views), and relatively clear and 
noticeable cardiac imaging in the sub-costal view. In our experience, this group is characterized 
explicitly by multiple sonographic lung artifacts such as anterior predominant “A-lines” and the 
absence of “B-lines”. We hypothesize that the poor thoracal visibility is due to air trapping 
which interferes with the ultrasound waves. On the other hand, the clear cardiac images seen 
from the sub-costal view might be explained by the hyperinflated lungs shifting the heart 
downward, causing better cardiac imaging than is usually seen. 
We plan to perform a cross-sectional observational study at the pulmonary institute of Soroka 
university medical center. We will conduct random POCUS scans on patients who are sent for 
pulmonary function tests (PFTs) for different suspected lung diseases.  
A presumptive diagnosis will be made on-site based on the sonographic data collected. The 
accuracy of the POCUS in identifying OLD will be compared to the full PFTs, considered the 

 
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gold standard for diagnosing OLD and air trapping. We believe that the POCUS exam, 
identifying poor thoracal and exceptionally good subcostal views will accurately identify those 
with confirmed OLD and air trapping. 
Our goal is to assess whether the POCUS exam accurately diagnoses OLD and air-trapping 
compared to standard PFTs. If so, this finding will have great applicability for identifying OLD 
patients early, even in remote areas where full PFTs are not accessible and referring them for 
further diagnostic workup. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4 
Method 
 
Design  
In this cross-sectional study, we plan to conduct random POCUS scans at the respiratory 
institute of Soroka University Medical Center on patients who are sent for pulmonary function 
tests (PFTs) for any reason. The POCUS examiners will be blinded to the reason for referral or 
the patient's medical history in general. We plan to include all patients at the age of 18 or above 
who performed full PFTs and have signed the informed consent form. We intend to enroll 
200patients who meet the inclusion criteria and none of the exclusion criteria.  
The examiners performing the scans will be skilled POCUS instructors with at least two years of 
experience in the field of cardiac and lung POCUS. The ultrasound examination will be 
conducted at a supine position and will include 2 parts: 
1. An anterior chest scan to detect A-lines versus B-lines in lung zone 1 (Figure 1)  
2. A 3-part cardiac scan consisting of a parasternal long-axis view, an apical 4-chambers 
view, and a sub-xiphoid view. (Figure 2). 
Each patient will be met by the POCUS team once and scanned once, as described, in 
one lung zone and the three formal cardiac views.  
Data from the medical records (i.e., smoking history, comorbidities, past radiographic exams, 
BMI, etc.) and the PFTs results will be collected by a third party, blinded to the POCUS exam. 
Eventually, the accuracy of the POCUS exam in identifying OLD will be compared to the gold 
standard of diagnosis, the full PFTs.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 – The ultrasound probe is placed at zone 1 on the anterior chest. 

 
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Figure 2 – The formal 3-part cardiac exam (Parasternal long axis view (PLAX), Apical four-
chambers view (A4C), and the subcostal view (sub-xiphoid, SX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis Considerations and Calculation  
Chest scan grading  
The anterior chest (Zone 1) will be examined bilaterally (see Figure 1) searching for A-lines 
(meaning aerated “open” alveoli) versus B-lines (which suggest alveolar flooding). A 
sonographic scan consistent with multiple A-Lines on both sides of the chest strengthens the 
diagnosis of OLD. Patients with three A-Lines or more will claim the maximal grade of 2 points 
on the corresponding side, meaning that a “perfect” score regarding the anterior chest is 4 (see 
Table 1).   
Cardiac views grading 

 
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We will use three formal echocardiographic views for scoping the heart: The PLAX, A4C, and 
SX views (see Figure 2). Each view will provide the patient with an image quality score ranging 
from 0-2 depending on the quality of the view (see Table 1). The score for the different cardiac 
views, from “No discernable anatomy” to “Great view”, is relied on the level of detection of the 
left ventricular endocardial border. This criterion applies to all three cardiac views. We expect 
that a scan consisting of OLD will be characterized by poor PLAX and A4C views and great SX 
views. Therefore, maximal cardiac score (=6) will be granted to a scan consisting of a great (i.e. 
when the left ventricle (LV)endocardial border is clear) SX view and no discernable anatomy 
noticed in the PLAX and A4C views.  
 
Grading synthesis 
A sum of the cardiac and chest scans will give a final sonographic score between 0 to 10. 
a scan most consistent with OLD will be given a score of 10.    
  
In the case of any abnormal finding in the chest or the cardiac POCUS, direct notification to the 
pulmonologist and the primary caregiver will be given by the research team, as well as written 
notification in the patient's electronic medical record. The patient and the primary caregiver will 
be notified that this exam is not a diagnostic cardiac exam focused only on detecting the level of 
the endocardial imaging quality. If b lines or abnormal left ventricular function are detected, the 
information will be transferred to involved teams. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 1 
The Sonographic Score Components for the Diagnosis of OLD 
 
Obstructive lung disease (OLD definition)-  
An umbrella term for diseases characterized by airway obstruction, airflow limitation, and in 
severe cases air trapping. Within this group and specifically among the adult population, the 
most common is chronic obstructive pulmonary disease (COPD)(12). Since most adult patients 
with air trapping encountered have COPD, we will use the terms COPD and OLD 
interchangeably.  
 
 
 
 
 
 
 
 
 
 
 
Right-sided 
Anterior chest  
(A-lines) 
Left-sided 
Anterior 
chest  
(A-lines) 
Parasternal 
long-axis view 
Apical four-
chamber view 
Sub-xiphoid 
view 
0 
Multiple B-lines 
or No 
discernable A-
lines 
Multiple B-
lines or No 
discernable A-
lines 
Great view 
(sub-
endocardium 
noticed) 
Great view 
(sub-
endocardium 
noticed) 
No discernable 
anatomy 
1 
1-2 A-lines 
1-2 A-lines 
Acceptable 
view 
Acceptable 
view 
Acceptable view 
2 
3 or more A-
lines 
3 or more A-
lines 
No discernable 
anatomy 
No discernable 
anatomy 
Great view (sub-
endocardium 
noticed) 

 
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4.1 
Working Hypothesis 
We hypothesize that a high sonographic score (8-10 points) will have at least an equal 
diagnostic accuracy compared to the reference diagnosis with PFTs.  
 
4.2 
Objectives 
4.2.1 Primary Objective 
o To evaluate the validity (sensitivity and specificity) of the diagnostic accuracy of 
combined lung and cardiac ultrasound in obstructive lung disease (OLD), 
referring to PFTs as the diagnostic gold standard.  
 
4.2.2 Secondary Objective 
o To estimate the association between the sonographic score and the most recent 
(<5 years) computed tomography (CT) scan score (i.e., emphysema score).  
o To estimate the association between the sonographic score and the patient's 
subjective severity of dyspnea (estimated by the mMRC scale).  
o To estimate the association between the sonographic score and the patient's 
diffusion lung capacity (DLCO).  
o To determine the sonographic components that are the most sensitive for the 
diagnosis of COPD.  
o To assess the additive value of the patient's smoking status to the diagnostic 
accuracy of the sonographic score.  
4.3 
Study Population 
The study population will be screened at the respiratory institute of Soroka University Medical 
Center and will include patients who are referred for pulmonary function tests (PFTs) for any 
reason. The study population will be enrolled according to the following inclusion and exclusion 
criteria. 
4.3.1 Inclusion Criteria- 
• Age 18 or above 
• Referral for full pulmonary function tests (PFTs) 
• Patients are willing and able to sign the informed consent form.  
4.3.2 Exclusion Criteria 
• Unable to give written informed consent. 
• Unable to remain supine. 

 
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• 
Poor effort at PFTs  
• 
Subcutaneous emphysema 
 
4.3.3 Withdrawal Criteria 
Participants who are unable or unwilling to complete the study procedures during their pulmonary 
institute visit or withdraw their consent for the researcher to access their electrical medical record and 
case report form within the following year after participation will be withdrawn from the study. 
Nevertheless, the results collected until the point of withdrawal will still be included in the study 
results as appropriate. 
 
4.4 
Enrollment 
Before participating in this study, the Investigator must obtain written approvals from the ethics 
committee and other local regulatory bodies as appropriate approval for the protocol and the 
informed consent form. Failure to obtain a signed and hand-dated informed consent before the 
procedure constitutes a protocol violation, which is reportable to the EC. 
 
4.5 
Patient Screening 
The screening will be performed at the respiratory institute of Soroka University Medical Center 
and will include patients who are sent for pulmonary function tests (PFTs) for any reason.  
Soroka university medical center is a 1,000-bed university-affiliated referral center in Southern 
Israel, directly serving a population of over 700,000 and serving as a tertiary hospital for nearly 
1 million people.  
Patients who are sent for pulmonary function tests (PFTs) for any reason and fulfill all the 
inclusions and none of the exclusion criteria will be approached and offered participation by a 
study research member. A study research member will explain the study’s purpose, procedures, 
and intent to each potential participant. Interested patients will be asked to provide written 
consent before performing any study procedure. 
 
4.6 
Study Procedures 
The study will be performed in a fully paired fashion, i.e., a direct comparison in which all study 
participants receive the index test (sonographic assessment)and the reference standard (PFTs). 

 
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This should enhance the resulting precision relative to the number of study participants. The 
three following steps are planned to take place at the same visit: 
 
1. Enrollment, including obtaining written informed consent.   
2. PFTs, performed as planned.  
3. A sonographic evaluation comprised of both lung and cardiac POCUS scans, 
performed by an experienced sonographer, blinded to the patient's medical history 
or PFTs results.  
Steps two and three can be replaced in order as long as the POCUS operator is blinded 
to the PFTs results. The PFT technician is not part of the study team and will be 
blinded to the POCUS findings as well.  
 
4.7 
Study Duration 
The evaluation is estimated to be around 10 minutes from the initial consent and will not 
interfere with the purpose of the patient's visit. We will collect the sonographic data 
prospectively based on the POCUS examination performed, while additional medical data will 
be collected retrospectively from the medical records (as specified below). We expect 
enrollment in the study to last for approximately twelve months.  
 
 
 
 
 
 
 
 
4.8 
Data to Capture 
4.8.1 Required Data 
We aim to collect the sonographic data as well as the PFT results for each participant. 
Furthermore, we plan to gather descriptive data from the medical records including –  

 
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1. Age -continuous variable. Values: above 18. 
2. Gender - dichotomic variable (Female=1, Male=0). 
3. BMI - continuous variable. 
4. Smoking history (pack years)- continuous variable. 
5. Comorbidities - nominal variable. Values: dichotomic variable (Yes=1, No=0) 
6. Hypertension – ordinal variable. (0=Normal, 1=Elevated, 2= Stage 1, 3 = Stage 2, 4= 
Hypersensitive crisis). Values: 0=systolic<120 & diastolic<80, 1=systolic=120-129 & 
diastolic<80, 2=systolic=130-139 & diastolic 80-89, 3=systolic>140 & diastolic>90, 4= 
systolic>180 & diastolic>110. 
7. Diabetes - dichotomic variable (Yes=1, No=0) 
8. Other Lung diseases (such as cystic fibrosis, bronchiectasis, Interstitial lung disease, etc) - 
dichotomic variable (Yes=1, NO=0) 
9. Ischemic Heart Disease - dichotomic variable (Yes=1, No=0) 
10. Degree of dyspnea (based on the mMRC Dyspnea Scale) - ordinal variable (1=Grade 1 ,2= 
Grade 2, 3=Grade 3, 4 =Grade 4). See supplements for mMRC dyspnea scaling system. 
11. Hemoglobin level (g%) - continuous variable. 
12. Latest Venous/Arterial pH- continuous variable.  
13. Latest Venous/Arterial HCO3- - continuous variable. 
14. Latest Venous/Arterial pCO2- continuous variable. 
15. Latest Arterial pO2 - continuous variable. 
a. The blood attributes under investigation will be derived retrospectively from the 
electronic medical record of the current hospitalization, and blood tests will not be 
performed as part of this trial.  
16. Past computed tomographic scans (most recent and up to 5 years prior) - ordinal variable 
(0= no emphysema (score 0),1=≤25% emphysema (score 1),2=≤50% emphysema (score 
2), 3=≤75% emphysema (score 3),4=>75% emphysema (score 4)). 
All required data for this study will be collected via electronic case report forms (eCRF). 
 
 
4.8.2 Data Collection  
The final set of CRFs is designed to accommodate the specific features of the trial design. 
Modification of CRFs will only be made if deemed necessary by Soroka CRC. The CRFs will be 
filled out manually by the study personnel and or will be collected through the computer services 
database. 

 
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The following data will be collected: 
• 
Demographic data: Age, Gender, BMI 
• 
Detailed medical history, including smoking history, comorbidities, degree of dyspnea 
reported (based on mMRC score), and recent computed tomographic scan (up to 5 years 
prior). 
• 
PFT results  
• 
POCUS exam results 
5 
Statistical Considerations and Analysis Plan 
5.1 
Sample Size Considerations  
In this study, the sample size calculation was aimed to ensure an accurate estimate of sensitivity 
(Se) and specificity (Sp) of the POCUS examination vs the gold standard PFTs. We aim to 
enroll a total of 200 patients. The calculation stems from the speculation that the Se of the test 
will be 85%, with a confidence interval of 90% and the maximal width of the interval will be up 
to ±7%.  
 
 
 
 
 
 
 
 
 
 
5.2 
Statistical Analyses 
Data collected in this study will be 
documented using summary tables. Descriptive statistics will be provided. The statistics for 
continuous variables will include mean, standard deviation, minimum, maximum, and sample.  
Categorical variables will be described with numbers and percentages. Comparisons between 
the groups will be presented with Differences (with 95% Confidence Intervals) and/or P-values. 
Percentages will be rounded to one decimal place. 

 
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Primary Objective Analyses  
To evaluate the diagnostic accuracy of the "sonographic COPD score" for COPD diagnosis, we 
will calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive 
value (NPV). We will then construct a Receiver Operating Characteristic (ROC) curve based on 
the sensitivity and specificity values to evaluate the performance of the POCUS score compared 
to the gold standard test, the pulmonary function test. The area under the ROC curve (AUC) will 
be calculated to assess the accuracy of the POCUS score in diagnosing COPD. Performances are 
evaluated at two different operation points: the first one is at 80% of sensitivity, and the other is 
at knee-point, which represents the best point reached by the ROC curve, close to the upper left 
bond. The presence of obstructive lung disease (OLD) detected by both ultrasound and PFTs 
will be labeled as true positive, the presence of OLD detected only by ultrasound and not by 
PFTs will be labeled as a false positive, no OLD detected by both ultrasound and PFTs will be 
labeled as true negative, and the presence of OLD detected by PFTs and not by ultrasound will 
be labeled as a false negative. 
Secondary Objective Analyses  
• To estimate the association between the sonographic score and the most recent (<5 years) 
computed tomography (CT) scan score (i.e., emphysema score) - we will use a Spearman's 
rank correlation coefficient.  
• To estimate the association between the sonographic score and the patient's subjective 
severity of dyspnea (estimated by the mMRC scale)- we will use the Mann-Whitney U test 
to determine the association between the sonographic score and the mMRC scale. 
• To estimate the association between the sonographic score and the patient's diffusion lung 
capacity (DLCO) - We will use the Mann-Whitney U test to determine the association 
between the sonographic score and DLCO. 
• To determine the sonographic components that are the most sensitive for the diagnosis of 
OLD - we can use a logistic regression analysis. The regression will provide estimates of the 
effect of each sonographic component on the probability of being diagnosed with OLD. In 
this analysis, we can use the sonographic components as predictor variables and OLD 
diagnosis as the outcome variable. 
• To assess the additive value of the patient's smoking status to the sonographic score's 
diagnostic accuracy- will be based on a logistic regression analysis. In this analysis, we can 
use the sonographic score and smoking status as predictor variables and OLD diagnosis as 

 
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the outcome variable. The regression will provide estimates of the effect of each predictor on 
the probability of being diagnosed with OLD, as well as an estimate of the additional effect 
of smoking status beyond the sonographic score. 
All statistical tests and/or confidence intervals, as appropriate, will be performed at =0.05 (2-
sided) or =0.025 (1-sided), except for those specified otherwise.  All p-values reported will be 
rounded to three decimal places. All statistical analyses will be conducted using SPSS 29.0 
statistical software (IBM Corp Armonk, NY, USA). 
 
5.3 
Primary Endpoints 
Our primary endpoint is to diagnose OLD with POCUS examination (compared to the PFT 
which is considered the gold standard).  
6 
Adverse Events 
There are no known adverse events to the point-of-care ultrasound exam. 
 
6.1 
Adverse Event Definition 
6.1.1 Adverse Event 
Any undesirable experience (sign, symptom, illness, abnormal laboratory value, or other 
medical events) occurring to a subject, that is considered related to the investigational treatment 
regimen prescribed as part of the clinical protocol, predefined in the clinical protocol, and/or 
Instructions For Use, that is identified or worsens during a clinical study. 
6.1.2 Treatment-related Adverse Event  
A 
related
-
treatment
 adverse event is defined as any adverse event, for which a causal 
relationship between the treatment and the event is at least a reasonable possibility, i.e., the 
relationship cannot be excluded.  
6.1.3 Serious Adverse Event 
A serious adverse event is considered one of the following: Death, Life-threatening, 
Hospitalization (initial or prolonged), Disability - significant, persistent, or permanent change, 
impairment, damage or disruption in the patient's body function/ structure, physical activities, or 
quality of life, Congenital anomaly or requires intervention to prevent permanent impairment or 
damage. 

 
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In the event of a serious adverse event, the investigational site must inform the EC up to 48 
hours after becoming aware of the event. An initial written report will be provided to the EC 
within 2 working days after the investigator learns of an unanticipated adverse treatment effect. 
All unanticipated adverse effects are to be reported throughout the entire time that the patient 
remains active in the study.   
 
6.2 
Intensity of Adverse Event 
The following categories of the intensity of an adverse event are to be used:  
• 
Mild: Awareness of a sign or symptom that does not interfere with the subject’s usual 
activity or is transient, resolved without treatment, and with no sequelae; 
• 
Moderate: Interferes with the subject’s usual activity, but the subject is still able to 
function. 
• 
Severe: Events that interrupt a subject’s usual daily activity and generally require a 
systemic device therapy or other treatment. 
 
6.3 
Anticipated Adverse Event 
In this study, we do not anticipate adverse events.  
  
6.4 
Outcome 
The clinical outcome of the event at the time of the last observation will be characterized as 
follows: 
1. 
Not Recovered/Not Resolved 
2. 
Recovered/Resolved 
3. 
Recovered/Resolved with Sequelae  
4. 
Recovering/Resolving 
5. 
Fatal 
6. 
Unknown 
 

 
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6.5 
Treatment or Action Taken 
The Principal Investigator will decide whether the subject needs any additional treatment or 
withdraw the subject from the study. In any case of detection of any cardiac or lung 
abnormality, a formal notification- verbal as well as written will be placed. The notification of 
any abnormal finding will be transferred to the pulmonologist as well as to the medical team 
from the referral unit.  
 
6.6 
Documentation  
All adverse events, from signing the informed consent until EOS, whether observed directly or 
reported by the patient, will be collected and recorded. Non-serious adverse reactions or events 
are not required to be reported in an expedited manner but will be recorded on the data 
collection forms. 
Serious Adverse events must be listed on the appropriate CRF. All SAEs will be characterized 
by the following criteria:  
1. 
Relatedness 
2. 
Outcome 
3. 
Treatment or action taken. 
All SAEs must be recorded on the SAE Form within 48 hours of the research staff becoming 
aware of the event. 
For each SAE, the following information will be collected: full details in medical terms with a 
diagnosis, if possible, its duration (start and end dates; times, if applicable), action taken, outcome 
and causality in the opinion of the investigator (must be made by a doctor). 
 
6.7 
Expedited Reporting of Serious Adverse Events 
The procedure for reporting any Serious Adverse Event is as follows: 
1. 
Report any serious adverse event to the EC according to the investigational site’s EC 
procedures. 
2. 
Complete appropriate Event Form(s) for any complication and/or serious adverse events. 
3. 
Submit physician/nurse notes or discharge summaries related to the reported event, as 
requested. 

 
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4. 
Report of a subject death must be along with a brief statement of the pertinent details, and 
the death records/certificate or autopsy report, if available/performed. 
Clear pathways have been developed for the reporting and analysis of serious adverse events. 
Study site personnel are responsible for SAE identification. SAEs are reported by the site to the 
local EC, the sponsor within 48 hours of becoming aware of the event.  
 
 
 
7 
Ethical and Regulatory Considerations 
8 
 Subject Confidentiality 
Subject confidentiality will be maintained throughout the study in a way that assures that data 
can always be tracked back to the source data. For this purpose, a unique subject identification 
code will be used that allows the identification of all data reported for each subject.  
Data relating to the study might be made available to third parties (for example in case of an 
audit performed by regulatory authorities) provided the data are treated confidentially and that 
the subject’s privacy is guaranteed. 
 
8.1 
 Sources of Materials 
No tissue or any other physical specimen will be taken from the patients.   
All of the data obtained for this study will be obtained prospectively. 
Copies of data obtained as part of the study will be retained by the clinical research center, with 
appropriate source documentation, on all subjects that sign informed consent. The data utilized 
in this study are described above and consist of information from medical records or study-
specified measures and interventions.  
 
8.2 
Maintaining Records  
The principal investigator will maintain copies of all study-related correspondence, regulatory 
documents, data, shipment of supplement accountability logs, adverse supplement effects and 

 
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other records related to the clinical study. The principal investigator will maintain records related 
to the signed Investigator Agreements. 
8.3 
 Site Record Retention Policy  
All core laboratories and clinical sites will maintain study records until the principal investigator 
notifies them and the reviewing regulatory authorities that research is completed or terminated 
under the clinical investigation in compliance with national law. Record retention dates will be 
provided to study sites by the principal investigator at the onsite closeout visit. 
8.4 
Informed Consent and Ethics Committee 
All subjects must provide written informed consent in accordance with the local clinical site’s EC. 
A signed Informed Consent must be obtained from each subject prior to commencing 
screening/baseline evaluations. One copy of the Informed Consent document will be given to the 
subject and another retained by the Investigator. 
8.5 
Protocol Deviation  
Any incident in which the investigator or site personnel did not conduct the study according to 
the clinical protocol or the investigator’ agreement.  
Protocol deviations are classified to three categories:  
• 
Major deviation: Any deviation from subject inclusion and exclusion criteria or subject 
informed consent procedures. 
• 
Critical finding: any deviation that can affect the wellbeing of the participant, or the 
reliability of the data collected is compromised. 
• 
Minor deviation: Deviation from a clinical protocol requirement such as 
incomplete/inadequate testing procedures, follow-ups performed outside specified time 
windows, etc.  
9 
References 
 
1. 
Moore CL, Copel JA. Point-of-Care Ultrasonography. Vol. 364, n engl j med. 2011.  
2. 
Mayo PH, Copetti R, Feller-Kopman D, Mathis G, Maury E, Mongodi S, et al. Thoracic 
ultrasonography: a narrative review. Vol. 45, Intensive Care Medicine. 2019.  

 
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3. 
Johri AM, Durbin J, Newbigging J, Tanzola R, Chow R, De S, et al. Cardiac Point-of-Care 
Ultrasound: State-of-the-Art in Medical School Education. Vol. 31, Journal of the American 
Society of Echocardiography. 2018.  
4. 
Sekiguchi H. Tools of the Trade: Point-of-Care Ultrasonography as a Stethoscope. Semin Respir 
Crit Care Med. 2016;37(1).  
5. 
Alrajab S, Youssef AM, Akkus NI, Caldito G. Pleural ultrasonography versus chest radiography 
for the diagnosis of pneumothorax: Review of the literature and meta-analysis. Crit Care. 
2013;17(5).  
6. 
Shah VP, Tunik MG, Tsung JW. Prospective evaluation of point-of-care ultrasonography for the 
diagnosis of pneumonia in children and young adults. Vol. 167, JAMA Pediatrics. 2013.  
7. 
Nazerian P, Vanni S, Volpicelli G, Gigli C, Zanobetti M, Bartolucci M, et al. Accuracy of point-
of-care multiorgan ultrasonography for the diagnosis of pulmonary embolism. Chest. 
2014;145(5).  
8. 
Díaz-Gómez JL, Mayo PH, Koenig SJ. Point-of-Care Ultrasonography. Ingelfinger JR, editor. 
New England Journal of Medicine [Internet]. 2021 Oct 21;385(17):1593–602. Available from: 
http://www.nejm.org/doi/10.1056/NEJMra1916062 
9. 
Qaseem A, Etxeandia-Ikobaltzeta I, Mustafa RA, Kansagara D, Fitterman N, Wilt TJ. 
Appropriate use of point-of-care ultrasonography in patients with acute dyspnea in emergency 
department or inpatient settings: A clinical guideline from the american college of physicians. 
Vol. 174, Annals of Internal Medicine. 2021.  
10. 
Zanobetti M, Scorpiniti M, Gigli C, Nazerian P, Vanni S, Innocenti F, et al. Point-of-Care 
Ultrasonography for Evaluation of Acute Dyspnea in the ED. Chest. 2017;151(6).  
11. 
Lichtenstein DA, Mezière GA. Relevance of lung ultrasound in the diagnosis of acute 
respiratory failure the BLUE protocol. Chest. 2008;134(1).  
12. 
Szalontai K, Gémes N, Furák J, Varga T, Neuperger P, Balog J, et al. Chronic obstructive 
pulmonary disease: Epidemiology, biomarkers, and paving the way to lung cancer. Vol. 10, 
Journal of Clinical Medicine. 2021.  
 
 
  
10 Supplements 
 

 
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• 
Modified Medical Research Council (Dyspnea Scale)