Imbalances of Regional Pulmonary Ventilation in Patients With Post-acute-COVID-19 Symptoms
Conditions: COVID-19 Pneumonia, Post-acute COVID-19 Syndrome, Electric Impedance
Sponsor: Jan-Christoph Lewejohann

 
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Study protocol 
 
 
 
Prospective observational cohort study 
 
 
 
 
 
 
 
 
 
 
 
Study Acronym: RegioVentPostCOVID-19 
Protocol version: Draft version from 17.11.2021 
Final version from 18.11.2021 
Confidentiality: The contents of this study protocol are to be treated confidentially and may not 
be disclosed to uninvolved parties, either verbally or in writing, without the consent of the study 
directors. 
 
 
 
 
Imbalances of regional pulmonary ventilation 
in patients 
with post-acute-COVID-19 symptoms 
 

 
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Study directors:  
Name: Dr. Jan-Christoph Lewejohann 
Adresse: ZNA, Am Klinikum 1, 07747 Jena 
Tel.:  03641 9 – 32 20 13 
E-Mail: jan-christoph.lewejohann@med.uni-jena.de 
 
PD Dr. med. Philipp A. Reuken 
Klinik für Innere Medizin IV 
Am Klinikum 1 
07747 Jena 
Philipp.reuken@med.uni-jena.de 
 
Data management 
Name: Christian Lippmann 
Studienkoordinator 
Zentrale Notaufnahme 
Tel.:  03641 9 – 32 2001 
E-Mail: christian.lippmann@med.uni-jena.de 
 
Study coordination/ project management 
Klinik für Notfallmedizin 
Zentrale Notaufnahme 
Klinik für Innere Medizin IV – post-COVID Ambulanz 
Am Klinikum 1 
07747 Jena 
 
 

 
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Summary: 
 
In patients with SARS-CoV-2 infection, symptoms may persist for a long time regardless of the 
initial severity of the disease. There is no compelling correlation between the subjectively 
reported symptoms and the diagnostic findings, which in the case of dyspnea include a CT of 
the thorax and a lung function examination.  
With the help of electrical impedance tomography (EIT), the distribution of the respiratory 
volume in the thorax can be recorded non-invasively and radiation-free at the bedside in a 
cross-sectional projection, in addition to the established radiological methods. The EIT shows 
images and associated information depicting the distribution of respiratory volume in a single 
cross-sectional plane. The EIT data maps two-dimensionally the central region of the thorax 
based on a three-dimensional morphological structure that is several centimeters thick. While 
CT provides molecular images of anatomical structures with a high spatial resolution, EIT 
provides functional images with a rather low spatial but very high temporal resolution. EIT 
offers the possibility to obtain a bedside overview of the regional distribution of the ventilation 
situation and to track and verify the effect of therapeutic measures in real time. 
While EIT has so far been intended for use in ICU patients whose regional valvular distribution 
over time is of clinical interest, this technique is not yet established for routine use in the 
assessment of post-COVID symptoms. Our own data on patients with acute COVID disease 
show that regional ventilation deficits can be visualized by EIT (Lewejohann et al., submitted 
for publication).  
The aim of this study is to investigate the correspondence of CT-morphologically detectable 
changes in ventilated lung areas in post-COVID syndrome with changes in regional ventilation 
that can be visualized by EIT. 
 
 

 
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Initial situation 
 
Even after several months, a relevant proportion of patients with SARS-CoV-2 infection show 
persistent symptoms [1,2]. On the one hand, there is a significant fatigue and on the other 
hand, dyspnea is relevant. [3] Current guidelines recommend the evaluation of respiratory 
symptoms by pulmonary function testing, pulmonary imaging, and cardiologic evaluation [4], 
although in a relevant proportion of patients no organic correlate of the symptoms can be 
verified. 
Electrical impedance tomography (EIT), which can be used during spontaneous breathing, 
mask ventilation, and mechanical ventilation, can be used to supplement established 
radiological methods by recording the distribution of respiratory volume in the thorax in a cross-
sectional projection non-invasively and without radiation at the bedside. The EIT status 
displays images and related information showing the distribution of respiratory volume in only 
a single cross-sectional plane. The EIT data thereby maps the central region of the thorax in 
two dimensions based on a three-dimensional morphological structure that is several 
centimeters thick. The thickness decreases toward the surface near the electrodes, resulting 
in a lenticular measurement volume. While CT provides snapshots of morphological structures 
with a high spatial resolution, EIT provides functional images with a rather low spatial but very 
high temporal resolution. The spatial distribution of pulmonary ventilation determined by EIT 
showed a good correlation with the results obtained by CT examinations in animal experiments 
and a good correlation between EIT and CT images in patients in critical condition could also 
be demonstrated. 
In the EIT image, ventilated and non-ventilated areas of the lung and their changes as a 
function of time can be seen. Real-time impedance curves show respiration over time. 
Changes in the entire cross-section are reflected by a global impedance curve that correlates 
with the total volume inhaled. A contour plot allows delineation of ventilated regions per breath 
and identification of lung regions with restricted ventilation or delayed inspiratory events in a 
dynamic image as well as in an end-inspiratory trend. In the end-inspiratory trend, this contour 
marks the maximally ventilated lung regions in a selected observation period from 1 min to 120 
min. Negative impedance changes represent inverted curve appearances that can occur 
physiologically as a result of cardiac activity, diaphragmatic movements, or as artifacts (e.g., 
during body movements or belt repositioning), but also in the presence of fluid accumulation 
such as a pleural effusion or deeper expiration than inspiration, as well as pendulum air.  
EIT thus offers the possibility of obtaining a bedside overview of the regional distribution of the 
ventilation situation and of tracking and verifying the effect of therapeutic measures in real 
time. 
While EIT has so far been intended for use in ICU patients whose regional ventilation 
distribution over time is of clinical interest, this method has not yet been validated for other 
patients. However, our own initial data indicate that even in acute COVID patients there are 
recognizable regional reduced ventilations (Lewejohann et al., submitted for publication) and 
EIT may thus represent a useful alternative or supplement for patients with post-COVID 
syndrome.  
 
 

 
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The present study aims to answer the following question  
Is there a correspondence between CT morphologically detectable changes in ventilated lung 
areas in post-COVID patients and changes that can be visualized by elec¬t-roimpedance 
tomography? 
Justification of the treatment and examination procedures 
CT thorax is currently performed as a standard part of the diagnostic work-up when the 
presence of post-COVID syndrome is suspected. In intensive care medicine, the EIT 
examination is already an established non-invasive examination method that provides regional 
information on ventilation-related changes in the air content of the lungs.  In cases of post-
COVID syndrome, changes in regional ventilation distribution are of clinical interest. Potentially 
valuable clinical information can be derived non-invasively from the EIT data 
 
Study objectives  
 
Primary study objective and primary endpoint 
The primary study objective is to match CT morphological changes in regional ventilation in 
post-COVID patients and/or changes in lung function examination with changes that can be 
visualized by electroimpedance tomography. 
EIT is used to measure regional variation in the form of changes in thoracic impedance within 
a single breath. 
Secondary study objectives and secondary endpoints 
Correlation of EIT findings with pulmonary function testing. 
Patient recruitment 
Accessibility of the intended number of patients: given due to COVID-19 pandemic 
- Number of study participants that can be recruited: > 50 
- Patient recruitment procedure: patients are screened and informed/included during 
presentation at the post-COVID outpatient clinic. Currently, approximately 150 patients 
are screened here per month.  
- In this study, 50 patients are to be included and examined. It is planned to recruit this 
number of patients in one center. 
Schedule 
The expected total study duration is 6 months.  
- Recruitment phase: 2 months 
- Duration of the study in the individual patient: approx. 10 min EIT examination. 
- End of study: after examination of n = 50 patients 
 
 

 
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participating study center 
Central Emergency Department of the University Hospital Jena and 
Department of Internal Medicine IV - post-COVID outpatient clinic 
University Hospital Jena 
At the hospital 1 
07749 Jena 
Inclusion criteria 
1) All patients presenting to the post-COVID outpatient clinic with an indication for CT 
thorax as part of the diagnostic workup. 
2) Age over 18 years 
3) Presence of written informed consent. 
Exclusion criteria 
1) Patients in whom the application of the electrode belt could pose a risk for, e.g. 
patients with unstable spinal injuries or fractures. 
2) Patients with a BMI over 50, in these patients the PulmoVista® 500 system should 
not be used according to the manufacturer. 
3) Patients with uncontrolled body movements. 
4) Patients with a pacemaker. 
 
Study procedure 
 
Patients undergoing a chest CT as part of the diagnostic work-up for the presence of post-
COVID syndrome will undergo an EIT examination lasting 10 min after the CT.  
 
Information and consent 
Patient education about the study will be provided prior to each scheduled CT thoracic 
examination. 
Each patient will be informed about the nature, significance, objectives, potential risks, 
anticipated benefits, implications, and other aspects of the clinical trial through a discussion 
between the investigator and the patient. The patient receives the written patient information. 
The investigator verifies that the patient has understood the information. After the information 
session, each patient is given enough time and opportunity to clarify any unanswered 
questions and to decide whether to participate.  
Each patient signs and dates his or her consent to participate in the study in writing on the 
informed consent form. The patient's consent must also explicitly refer to the collection and 
processing of personal data. Therefore, patients are explicitly informed about the purpose and 
scope of the collection and the use of these data, especially health data. 

 
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If a patient is unable to sign the consent form personally, a witness must be present during the 
information process who can confirm the patient's verbal information and consent by signing 
it. In the case of patients who are incapable of giving consent, the consent is given by court-
appointed guardians or other procedures established at the respective testing center. 
One copy of the signed consent form (copy or 2nd original) is given to the patient, the other 
remains at the trial center.  
The patient may withdraw consent at any time and without giving any reason and may 
discontinue treatment or discontinue the study. In such cases, the patient will be asked to state 
the reason for discontinuation (of treatment or participation) but will be advised that he/she 
does not have to do so. The time of withdrawal of consent to treatment or study must be 
documented.  
Randomization: no 
 
Description of the individual visits 
If a suitable patient presents at the outpatient clinic, he/she will be informed about the study 
when the CT is indicated, and the corresponding information will be provided as described as 
before. If consent is given, the EIT is performed for 10 min immediately after the CT. In addition, 
symptoms, concomitant diseases and medication, further examination findings, of the physical 
examination, the CT thorax and, if necessary, further equipment procedures such as lung 
function examination and blood sampling findings are recorded. After completion of the EIT, 
any adverse events are recorded by the measurement and the studies are terminated for the 
patient. 
 
Premature withdrawal of a patient from the study (Discontinuation criteria) 
Participation in the clinical study is voluntary. Each participant has the right to withdraw from 
the study at any time at his own request and without giving reasons (consent is withdrawn) or 
to decide to discontinue treatment (no further treatment) without any disadvantages for his 
further (medical) treatment. 
If a patient withdraws his consent and drops out of the study, this constitutes a discontinuation 
of participation. If it is possible and the patient is willing to give information, an attempt should 
be made to find out the reason for the premature termination of the study. The participant is 
asked to state the reason for discontinuation but is advised that he/she does not have to do 
so. It is documented that, when and, if applicable, why he/she withdrew his/her consent. 
Regular end of study: 
The study participation ends regularly for each study participant after completion of the EIT 
study. 
 
Premature end of study/termination of the entire study 
Reasons for premature termination of the entire study may include: 
- Inadequate recruitment rate. 
- Decision of the study director if new scientific evidence is available. 

 
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The decision to discontinue the study will be made by the decision panel. 
Recording and documentation of adverse events  
No adverse events or procedure-dependent complications are expected. If procedure-related 
adverse events occur, they will be documented and, if requested by the local ethics committee, 
collected and submitted for information after the end of the study.7 
 
Biometry 
 
Planning of the study size (sample size planning) 
In view of the initial investigation of agreement, a general case number estimation according 
to Bland/Altman will be used (Bland, J. M., & Altman, D. (1986). Statistical methods for 
assessing agreement between two methods of clinical measurement. The Lancet, 327(8476), 
307-310). To obtain a 95% confidence interval for the limits of agreement of 1 standard 
deviation of the differences, 50 patients are to be included in the study. It is assumed that 
breath volume data can be collected from all patients (no dropouts). 
Statistical analysis 
The agreement between CT and EIT variables (regional tidal variation in terms of change in 
thoracic impedance within one breath) will be investigated using Bland-Altman method. The 
mean difference of the two methods (CT and EIT) and the limits of agreement are given, 
furthermore 95% confidence intervals for the mean difference as well as the upper and lower 
limits are calculated. The agreement is graphically represented by a Bland-Altman plot. 
 
Data management 
 
Patient identification list  
All patient-related data is recorded in pseudonymized form. For this purpose, a non-speaking 
pseudonym is used, from which alone the identity of the patient cannot be deduced. In order 
to obtain unique patient identification numbers, a combination of a defined test center number 
and a consecutive center-specific patient number is selected. The patient identification number 
is centrally assigned during the internet-based randomization. 
The trial center maintains a patient identification list in which the patient identification numbers 
are linked to the full patient names of the participants, patient identification number and, if 
applicable, date of birth. This list is used for the possibility of later identification of participating 
persons. It is to be treated confidentially and may not leave the test center. It must be archived 
for at least ten years after the end of the study. 
In addition, the participation of the persons concerned in the study is noted in the respective 
patient file.  
List of responsibilities 
At the study site, a signature list with, among other things, the name, function in the study, 
study-related activity and abbreviation of the responsible persons is filed in the study site folder.  

 
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Data collection/documentation forms  
In order to achieve the study objective, it is necessary to collect and process medical data of 
individual patients. Data collection will take place in the trial centers participating in the study. 
Data will be collected using paper-based documentation forms (p-CRF). The corresponding 
staff members in the study centers will receive instructions on how to fill in the paper-based 
documents. 
 
Data processing  
 
Data processing of the pseudonymized data will be performed in SPSS. 
 
Data management 
The collection and management of the pseudonymized data will be done by Ms. Ilona Timmler 
(Coordinator Central Emergency Department) and Ms. Isabelle Utech (Research Assistant 
post-COVID Outpatient Clinic). 
Study documents and their retention (archiving) 
The originals of all essential study documents are kept by the study director for at least ten 
years after preparation of the final report.  
At each study site, accrued administrative documents (e.g., correspondence with ethics 
committee(s), study director), patient identification list, signed informed consent forms, and 
general study documentation (study protocol, amendments) are retained for the period. All 
documentation must be kept in a safe place and treated confidentially. The patient identification 
list should be kept separate from the documentation records.  
Original study patient data (e.g., medical records) or essential study documents must be 
retained in accordance with the archiving period applicable to the trial sites, but not less than 
ten years). The trial site or the investigator-in-charge must take precautions to prevent the 
accidental or premature destruction of these documents. 
Data Protection  
Within the scope of the study, the EIT data, diagnoses, data regarding the treatment and the 
course of the disease (e.g. medical findings) are recorded, electronically stored, processed 
and evaluated in pseudonymized form (i.e. without direct reference to the patient's name). 
In the event of revocation of consent to the study by the patient, including further data 
collection, no further data will be collected from the time of revocation. The data collected so 
far will continue to be used and evaluated within the study. If a patient only discontinues the 
study treatment, the data required for the study can continue to be collected and used. 
quality assurance 
 
Create chapter in cooperation with quality management, e.g. with the following structure 

 
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Standardization 
The investigations evaluated in this observational study are subject to guidelines and standard 
operating procedures (SOP). These defined investigation schemes standardize the decision 
paths and thus ensure the quality of the triage and the respective investigation procedures. 
Audits  
In the event of an audit or inspection, auditors and inspectors have a right to inspect the data 
and personal medical records due to legal regulations. These persons are also bound to 
secrecy. Inspection and disclosure will only take place within the scope of the legally regulated 
tasks of the inspectors, namely for the purpose of verifying the data. 
 
Ethical concerns, legal and administrative regulations  
 
Declaration of Helsinki and Good Clinical Practice 
The study will be conducted in accordance with the ethical principles originating in the 
Declaration of Helsinki. The latest version of the Declaration will be observed.  
The recommendations of the Good Clinical Practice, valid since 17.1.1997, will be considered, 
if applicable. 
Ethics Committees 
The study protocol is submitted with the required additional documents to the responsible lead 
ethics committee of the study director with a request for evaluation. The study can only begin 
after the ethics committee has given its approval. 
The ethics committees of the participating study centers will receive a copy of the approving 
evaluation of the first ethics committee and the documents required for granting the "second 
vote" in each case. Each participating trial site will receive copies of the positive evaluation of 
the first ethics committee and its responsible ethics committee for the trial site file. 
Subsequent Changes 
The study protocol must be followed. Any deviation from the planned examination and 
treatment measures or times for which the investigator is responsible must be documented 
and justified (e.g. emergency measures).  
Changes or additions to the study protocol can only be initiated and authorized by the study 
management. The lead ethics committee and the ethics committees of the participating study 
centers are informed about changes to the study protocol. If necessary, the approval of the 
ethics committee will be obtained again. Changes requiring evaluation may not be 
implemented prior to the decision of the Ethics Committee.  
Changes to the study evaluated by the ethics committee with approval that are likely to  
affect the safety of the persons concerned, 
additional data collection or analysis that require a change in patient information and/or 
consent,  
the interpretation of the scientific documents on which the study is based, or to affect the 
scientific validity of the study results,  
substantially change the manner in which the study is conducted or performed,  
may only be made if these changes have been approved by the Ethics Committee. 

 
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Legal regulations 
This study is an observational study according to professional regulations. The legal 
regulations of the Thuringian Hospital Act (ThürKHG) § 27 para. 4 apply. 
Registration 
The study shall be registered in the following public register: www.clinicaltrial.gov. 
Mrs. Yvonne Gremme and Mrs. Ilona Timmler are responsible for the registration in the register 
and the maintenance of the register data. 
Funding  
The study will be funded by budgetary resources. 
Final report and publication 
The publication of the study results will take place regardless of the outcome of the study 
 
Note: We plan to extend the study with a lung-healthy comparison group, which does not 
require an additional ethics vote (stand: 8.02.2022). 
 
Literature: 
[1] Taboada M, Cariñena A, Moreno E, et al. Post-COVID-19 functional status six-months 
after hospitalization. J Infect 2021; 82: e31–e33. doi:10.1016/j.jinf.2020.12.022 
[2] Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med 
2021; doi:10.1038/s41591-021-01292-y 
[3] Augustin M, Schommers P, Stecher M, et al. Post-COVID syndrome in non-hospitalised 
patients with COVID-19: a longitudinal prospective cohort study. The Lancet Regional 
Health - Europe 2021; 6: 100122. doi:10.1016/j.lanepe.2021.100122 
[4] NICE Guideline No 188. COVID-19 rapid guideline: managing the long-term effects of 
COVID-19. London: National Institute for Health and Care Excellence (UK); 2020