RESEARCH ARTICLE

DOI: 10.4274/tjh.galenos.2022.2022.0103
Turk J Hematol 2022;39:222-229

Effectiveness of Mesenchymal Stem Cell Therapy for COVID-19

Patients in the Intensive Care Unit: A Case-Control Study
Yoğun Bakım Ünitesindeki COVID-19 Hastalarında Mezenkimal Kök Hücre Tedavisinin
Etkinliği
Hayri Canbaz1, Ufuk Oğuz İdiz2, Hayriye Cankar Dal3, Fatih Kaçıroğlu4, Seher Taş5, Hikmet Can Çubukçu6,
Attila Beştemir7, Murat Gülşen8, İstemi Taha Polat9, Abubekir Laloğlu10, İbrahim Hakkı Tör11, Halik Ekrem Akkurt12,
Utku Ateş13, İsmail Reisli14, Esin Koç15, Ahmet Çağkan İnkaya16, Musa Karakükçü17, Mustafa Ceylan18,
İbrahim Celalettin Haznedaroğlu19, Haluk Akın20
1Yıldırım Beyazıt University, Yenimahalle Training and Research Hospital, Emergency Service, Ankara, Turkey
2University of Health Sciences Turkey, İstanbul Training and Research Hospital, Clinic of General Surgery, İstanbul, Turkey
3University of Health Sciences Turkey, Ankara City Hospital, Clinic of Intensive Care Unit, Ankara, Turkey
4General Directorate of Health Services, Head of Tissue, Organ Transplantation and Dialysis Services Department, Ankara, Turkey
5General Directorate of Health Services, Department of Tissue, Organ Transplantation and Dialysis Services, Organ Transplantation Unit,

Ankara, Turkey
6Ankara University Stem Cell Institute, Interdisciplinary Stem Cells and Regenerative Medicine, Ankara, Turkey
7İstanbul Bakırköy Dr. Sadi Konuk Training and Research Hospital, Emergency Service, İstanbul, Turkey
8Ankara Dışkapı Yıldırım Beyazıt Training and Research Hospital, Clinic of Pediatrics, Ankara, Turkey
9Horasan State Hospital, Clinic of Anesthesiology and Reanimation, Ağrı, Turkey
10Atatürk University Faculty of Dentistry, Department of Oral, Dental and Maxillofacial Radiology, Erzurum, Turkey
11Erzurum City Hospital, Clinic of Anesthesiology and Reanimation, Erzurum, Turkey
12Konya Numune Hospital, Clinic of Physical Medicine and Rehabilitation, Konya, Turkey
13İstanbul Bilim University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey
14Necmettin Erbakan University Meram Medical Faculty Hospital, Department of Pediatric Immunology and Allergy, Konya, Turkey
15Gazi University Medical Faculty Hospital, Department of Pediatrics, Division of Neonatology, Ankara, Turkey
16Hacettepe University Medical Faculty Hospital, Department of Infectious Diseases, Ankara, Turkey
17Erciyes University Faculty of Medicine, Department of Pediatric Hematology and Oncology, Kayseri, Turkey
18Atatürk University Medical Faculty Hospital, Department of Neurology, Erzurum, Turkey
19Hacettepe University Medical Faculty Hospital, Department of Hematology, Ankara, Turkey
20Ege University Medical Faculty Hospital, Department of Medical Genetics, İzmir, Turkey

©Copyright 2022 by Turkish Society of Hematology

Turkish Journal of Hematology, Published by Galenos Publishing House
Address for Correspondence/Yazışma Adresi: Hayri Canbaz, M.D., Yıldırım Beyazıt University, Yenimahalle Training Received/Geliş tarihi: March 10, 2022
and Research Hospital, Emergency Service, Ankara, Turkey Accepted/Kabul tarihi: October 9, 2022
E-mail : [email protected] ORCID: orcid.org/0000-0001-6989-7854

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Turk J Hematol 2022;39:222-229 Canbaz H. et al: Mesenchymal Stem Cell Therapy for COVID-19

Abstract Öz
Objective: Many methods are used in the treatment of coronavirus Amaç: Akut solunum sıkıntısı sendromuna (ARDS) neden olan
disease 2019 (COVID-19), which causes acute respiratory distress koronavirüs hastalığı 2019 (COVID-19) tedavisinde birçok yöntem
syndrome (ARDS), and there are conflicting reports in the literature kullanılmakta olup, literatürde mezenkimal kök hücre (MSC) tedavisinin
regarding the results of mesenchymal stem cell (MSC) therapy, which sonuçları ile ilgili çelişkili yayınlar bulunmaktadır. Çalışmamızın amacı
is one of those methods. The aim of our study is to evaluate the effect standart tedavilerle birlikte uygulanan MSC tedavisinin sağkalım
of MSC treatment applied together with standard treatments on üzerine etkisini değerlendirmektir.
survival.
Gereç ve Yöntemler: Bu retrospektif olgu kontrol çalışması, Mart 2020
Materials and Methods: This retrospective case-control study ile Mart 2021 arasında COVID-19’a bağlı ARDS gelişmesi sonrası yoğun
evaluates the survival effect of MSC treatment administered to
bakımda tedavi edilen hastalara uygulanan MSC tedavisinin sağkalım
patients treated in intensive care after the development of ARDS
etkisini değerlendirmektedir. Çalışmada, standart medikal tedavi (SMT)
due to COVID-19 between March 2020 and March 2021. The age,
alan hastalar ile SMT ile birlikte MSC tedavisi alan hastalar arasında
gender, comorbid disease status, APACHE II score, and overall and
yaş, cinsiyet, komorbid hastalık durumu, APACHE II skoru, genel ve
comorbidity-based survival rates were compared between patients
who received standard medical treatment (SMT) and patients who komorbiditeye dayalı sağkalım oranları karşılaştırıldı.
received MSC treatment together with SMT. Bulgular: Sadece SMT kullanan grupta 62 hasta, SMT ve MSC kullanan
Results: There were 62 patients in the group receiving only SMT and grupta 81 hasta vardı. Gruplar arasında yaş, cinsiyet, eşlik eden hastalık
81 patients in the group receiving SMT and MSC. No difference was varlığı, Apache II skorları açısından fark gözlenmedi. Ayrıca grupların
observed between the groups in terms of age, gender, presence of hayatta kalma durumları için Kaplan-Maier analizine göre herhangi
comorbid diseases, or APACHE II scores. There were also no differences bir farklılık yoktu. Hastalar arasında MSC tedavisine bağlı ciddi bir yan
according to Kaplan-Maier analysis for the survival statuses of the etki görülmedi.
groups. There was no serious adverse effect due to MSC treatment Sonuç: Çalışmamız literatürdeki en geniş olgu serisine sahip olup,
among these patients. literatürdeki birçok çalışmadan farklı olarak MSC tedavisinin hem
Conclusion: Our study presents the largest case series in the literature, genel sağkalıma hem de komorbid hastalık temelli sağkalıma anlamlı
and it was observed that MSC treatment may not significantly affect bir etkisi olmadığı görülmüştür.
overall survival or comorbid disease-based survival, in contrast to
Anahtar Sözcükler: COVID-19, Mezenkimal kök hücre, Acil servis,
many other studies in the literature.
Mortalite, Hayatta kalma
Keywords: COVID-19, Mesenchymal stem cell, Emergency, Mortality,
Survival

Introduction the term “mesenchymal stem cells” [5,6,7,8]. Today, it is known

that MSCs are pluripotent stem cells that can differentiate into
Coronavirus disease 2019 (COVID-19), which is caused by
both ectodermal and endodermal cells [9,10,11,12].
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection, may lead to acute respiratory distress syndrome MSCs are non-hematopoietic cells that play a role in immune
(ARDS) and even death [1,2,3]. Cytokine storms are responsible modulation and have regeneration and differentiation abilities
for ARDS in COVID-19 and these patients require respiratory [13]. MSC treatment has been found to reduce pathological
support. It has been reported that 67% of critically ill COVID-19 changes and prevent the cell-mediated immunoinflammatory
patients develop ARDS and, among them, patients who are response caused by influenza viruses in the lungs [14,15]. The
older than 65 years or have chronic diseases that cause immune safe application and efficacy of MSC treatments have been
dysfunction have higher mortality rates. An autopsy study evaluated in COVID-19 patients with ARDS [16,17,18,19].
stated that COVID-19 patients with severe pneumonia died as a One study reported that intravenous administration of MSCs
result of severe infection with ARDS [1].
obtained from human umbilical cords may be a safe and
Although many drugs and methods of treatment have been well-tolerated treatment option for patients with moderate and
used for COVID-19, there is currently no effective antiviral severe COVID-19 [20]. However, there are also reports in the
agent. The management of COVID-19 patients remains largely literature that there are limited benefits from MSC treatment
symptomatic and includes standard medical treatment (SMT) and that results of long-term follow-up from larger numbers of
[4]. individuals are still needed [16,19,20].

Friedenstein was the first to describe mesenchymal stem cells The aim of this study is to compare the survival and mortality
(MSCs) from bone marrow in 1968. Caplan proposed that these results of patients who received MSC treatment with SMT and
cells would differentiate into mesodermal cells and he first used those who received only SMT.

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Materials and Methods for the patients who had received SMT plus MSC treatment
were that they had received the standard treatment options
This study was designed retrospectively and involved examining
for COVID-19 as determined by the Science Committee of the
the hospital records of patients who had been treated in
Turkish Ministry of Health and had received MSC treatment as
intensive care units (ICUs) from March 2020 to March 2021 after
well. After evaluating the patients in the SMT plus MSC group
COVID-19 infection. The study was started after obtaining the
according to the inclusion and exclusion criteria, patients who
approval of the Ethics Committee of the University of Health
Sciences Turkey, Ankara City Hospital Clinical Research Center. could be matched in terms of age, gender, and comorbidity
This study was also approved by the Turkish Ministry of Health. to the SMT plus MSC group were selected for the SMT group.
The inclusion criterion for patients receiving SMT treatment
The patients were separated into two main groups according in University of Health Sciences Turkey, Ankara City Hospital’s
to the treatment methods they received: only SMT and SMT ICU was that they had received only the standard treatment
plus MSC treatment. The SMT group included patients who options for COVID-19 as determined by the Science Committee
had been treated for COVID-19 pneumonia in the general ward of the Turkish Ministry of Health. Common exclusion criteria
of University of Health Sciences Turkey, Ankara City Hospital’s were pregnancy, the presence of malignant tumors, a history
ICU and had needed mechanical ventilation. The SMT plus of allergies, and having received additional treatments (i.e.,
MSC treatment group included patients who had been treated
intravenous immunoglobulin, plasmapheresis, or interleukin
with SMT and MSC in any ICU of the university or training and
[IL]-6 receptor antagonists). The flow charts of the patients
research hospitals in Turkey.
included in the study are presented in Figure 1. To demonstrate
The common inclusion criteria were that patients had been the effectiveness of MSC applications, random sampling was
diagnosed with COVID-19 through reverse-transcription performed with regard to the control group to ensure that the
polymerase chain reaction, admitted to emergency medicine, comorbidities, ages, and gender ratios of this group and the
and hospitalized in a third-level ICU with ARDS. Inclusion criteria treatment group were equal.

Figure 1. Inclusion of the patients in the study.

SMT: Standard medical treatment, MSC: mesenchymal stem cell treatment, ICU: intensive care unit, IVIG: intravenous immunoglobulin, ACH: Ankara
City Hospital.

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The standard treatment for COVID-19 was administered Results

according to the Science Committee of the Turkish Ministry of
Health. The recommended hydroxychloroquine regimen for all The mean age of the 143 patients who were included in this
hospitalized patients was a loading dose of 400 mg twice on study was 62.81 (27-92) years and the female/male ratio was
day 1, followed by 400 mg daily for 4 additional days. Favipiravir 41/102. There were 61 patients in the group that received only
was initiated at a loading dose of 1600 mg twice on day 1, SMT and 82 patients in the group that received SMT and MSC
followed by 600 mg twice daily for a further 4 days for patients therapy.
with severe pneumonia or persistent fever in spite of treatment No differences were observed between the groups in terms of
with hydroxychloroquine. Unless there was a contraindication,
the demographic parameters that were examined, including
doses of 1x40 mg/day of enoxaparin were started as prophylaxis
age, gender, and the presence of comorbid diseases, as shown
for all patients subcutaneously. In cases of severe pneumonia,
in Table 1. The distributions of comorbid diseases in Group
D-dimer levels of 1000 ng/mL, body mass indexes of 40 kg/m2,
1 and Group 2 were as follows: diabetes mellitus (28 and 16
and acute venous thromboembolism, subcutaneous enoxaparin
patients, respectively), hypertension (37 and 24 patients,
was administered at a therapeutic dose of 2x40 mg/day.
respectively), chronic obstructive pulmonary disease (8 and 8
MSCs were prepared from umbilical cords or adipose tissues, and patients, respectively), and coronary artery disease (8 and 6
the MSC treatments were applied with 1x106 or 10x106 cells/kg patients, respectively). No differences were observed between
each time, administered intravenously or intratracheally once the groups in terms of the APACHE II scores of the patients
or twice throughout the treatment, based on the decisions of (Table 1). Additionally, no patients had serious adverse effects
ICU directors. The patients received 10 mL of MSCs at doses of caused by MSC treatment.
0.5 million/kg (55x106 cells) administered into an endotracheal
tube by interrupting the mechanical ventilator application Kaplan-Meier analysis showed no differences in survival
twice every 5-7 days, given only to intubated patients as between patients in the group that received SMT plus MSC and
intratracheal MSC administration. The ages, genders, comorbid those in the group that received only SMT (p>0.05) (Figure 2).
diseases, and 75-day follow-up results for mortality were noted In addition, no differences in survival were found between the
for all patients. two groups in Kaplan-Meier analyses performed for patients
with comorbid diseases (p>0.05) (Figure 3) and for those with
Statistical Analysis coronary artery disease (p>0.05) (Figure 4).
The Jamovi program (version 1.6.18) was used in the statistical
analysis of the data that were obtained. The distribution of the Discussion
data was evaluated using the Shapiro-Wilk test. Continuous During the COVID-19 pandemic, which has had high mortality
variables with nonparametric and parametric distributions rates due to pneumonia and thromboembolic events in the
were compared with the Mann-Whitney U test and t-test, lungs, many treatment modalities such as immunosuppressive
respectively. The chi-square test was used in the analysis of drugs and anti-IL-6 treatments have been used in the acute
qualitative independent data. Survival analyses were performed phase for symptomatic patients and for post-COVID pulmonary
using Kaplan-Meier survival analysis regarding receiving sequelae [21].
MSC treatment, and values of p<0.05 were considered to be
significant.

Table 1. The demographic parameters and comorbid diseases of the patients.

SMT + MSC group (n: 82) SMT group (n: 61) p
Age, mean (SD) 61.2 (12.5) 65 (14.8) 0.098a
Gender (female/male) 22/60 19/42 0.572b
Presence of comorbid diseases (+/-) 52/30 39/22 0.949b
Hypertension (n) (+/-) 37/45 24/37 0.490b
Diabetes mellitus (n) (+/-) 28/54 16/45 0.310b
Chronic obstructive pulmonary disease (n) (+/-) 8/74 8/53 0.529b
Coronary artery disease (n) (+/-) 8/74 6/55 0.987b
APACHE II scores, median (IQR) 19 (19) 17 (17) 0.085c
a
: t-test, : chi-square test, : Mann-Whitney U test, IQR: interquartile range, SD: standard deviation, APACHE: Acute Physiology and Chronic Health Evaluation, SMT: standard medical
b c

treatment, MSC: mesenchymal stem cell.

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Before the COVID-19 pandemic, MSC treatments had been shown to increase the survival of the mice and the amounts of
used for ARDS in many clinical studies. However, most of these lipocalin-2, which plays a role in bacterial growth [23]. MSC
studies have not yet been completed [22]. We found only three treatment for lung infections caused by influenza has been
phase 1 and 2 studies that have been published about MSC shown to decrease proinflammatory cytokine release, decrease
treatments for ARDS [16,18,19]. inflammatory cells in the lungs, and reduce lung damage by
increasing alveolar macrophages [14,24,25]. One study found
In one preclinical study, MSCs were used in the treatment of that MSC treatment significantly reduced the mortality among
gram-negative pneumonias in mice, and MSC treatment was a group of patients with ARDS resulting from H7N9 influenza
compared to a control group (17.6% and 54.5%, respectively)
[15].

Numerous studies have reported reductions in the main

inflammatory biomarkers (C-reactive protein [CRP], IL-6,
IL-8, and tumor necrosis factor-α) due to MSC treatment [26].
Although many clinical trials involving MSC treatment have
reported regulation of the inflammatory response in COVID-19
patients, it is unclear how MSCs achieve this effect [27,28].
However, some published studies have shown that MSCs are
capable of reducing the release of proinflammatory cytokines
from cells in the immune system [29]. In preclinical studies,
MSCs were shown to release the cytokines (transforming
growth factor-β, IL-10, IL-4, and prostaglandin E2) that play
anti-inflammatory roles in ARDS and sepsis [29,30]. MSCs also
Figure 2. Kaplan-Meier survival analysis of the groups for all protect endothelial cells from inflammation and oxidative stress,
patients. Blue line and red dotted line represent SMT and SMT restore the epithelial permeability for tissue repair, and reduce
plus MSC treatment. Number at risk corresponds to the days pulmonary edema in the event of intratracheal administration
given on the x-axis, showing surviving patients. Faded colored [31,32,33].
areas represent 95% confidence interval.
SMT: Standard medical treatment, MSC: mesenchymal stem cell In the first case report of MSC treatment used for COVID-19,
treatment. a 65-year-old female patient who had been diagnosed with
the disease was transferred to the ICU in spite of having

Figure 3. Kaplan-Meier survival analysis of the patients who had Figure 4. Kaplan-Meier survival analysis of the patients who had
comorbid diseases. Blue line and red dotted line represent SMT coronary artery disease. Blue line and red dotted line represent
and SMT plus MSC treatment. Number at risk corresponds to SMT and SMT plus MSC treatment. Number at risk corresponds to
the days given on the x-axis, showing surviving patients. Faded the days given on the x-axis, showing surviving patients. Faded
colored areas represent 95% confidence interval. colored areas represent 95% confidence interval.
SMT: Standard medical treatment, MSC: mesenchymal stem cell SMT: Standard medical treatment, MSC: mesenchymal stem cell
treatment. treatment.

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received SMT because she needed mechanical ventilation. After Although many publications in the literature show that MSCs
intravenous administration of umbilical cord MSCs at a dose of are beneficial in the treatment of ARDS and COVID-19, there
50x106 cells, the general condition of the patient improved [34]. are also studies that state that MSCs do not have significant
effects on mortality. Zheng et al. [19] evaluated the efficacy
Most of the initial case reports of MSC administration due to of MSCs obtained from adipose tissue in patients with ARDS
COVID-19 involved male patients over 50 years of age and and stated that although MSC treatment can be applied
were reported from China. The source of the MSCs that were safely, they did not observe any superiority with regard to this
administered was reported as being Wharton’s jelly, umbilical treatment in terms of duration of hospitalization, length of ICU
cord blood, and bone marrow, and the intravenous route was stay, need for mechanical ventilators, or improvement in blood
preferred for the administration of MSCs in all cases except parameters on the 28th day of hospitalization. Matthay et al.
one. Because intravenously administered MSCs usually attach [16] compared MSCs derived from bone marrow, administered
to the pulmonary vessels, and the lungs are the most frequently at 10x106 cells/kg, to a placebo in ARDS patients in a phase 2
affected organs in COVID-19, the intravenous administration study and determined that MSC treatment had no effect on
of the infusion is the most logical option. In these cases, all 28-day mortality. In a phase 1 study, Meng et al. [20] evaluated
of the patients also received other treatment methods, such the effectiveness of MSCs prepared from umbilical cords in
as antivirals, antibiotics, and/or corticosteroids, in addition to the treatment of COVID-19 patients in two groups, with nine
MSC treatment. In all cases, no side effects were observed as patients in each group, with four severe and five moderate
a result of the MSC treatment and the symptoms of COVID-19 cases, who either received or did not receive MSC treatment.
disappeared completely [35]. MSC treatment was administered intravenously in three doses
at 3x107 cells per dose, no serious adverse events were observed
Subsequent case report series have generally included a in any patients, and there was no mortality among the patients.
limited number of patients while evaluating the applicability However, these authors emphasized that although MSCs can
and effectiveness of MSC treatment. Leng et al. [27] used be applied safely, phase 2/3 studies should be performed to
ACE-2-negative MSCs obtained from an unknown source to determine their contributions to treatment [20].
treat COVID-19 pneumonia and reported that all seven patients
Our study is the largest case series report to date in the literature
included in their study recovered. However, all the patients
of the use of MSCs in COVID-19. We observed that MSC
in that study had over 90% oxygen saturation levels when treatment did not improve overall survival rates or comorbid
breathing room air. Sánchez-Guijo et al. [36] reported that there disease-based survival in the 75-day follow-up of critically
were two deaths among 13 patients (15%) in 16 days of median ill COVID-19 patients who were treated in ICUs. This may be
follow-up after patients received MSCs obtained from allogenic because the MSC administrations in this study were prepared at
adipose tissue. Another study reported that the mortality rate different doses and with different methods.
was 45% in the 60-day follow-up of 11 COVID-19 patients who
were monitored in the ICU [26]. The main limitation of our study is that it does not involve
a standardized MSC treatment method. The absence of
According to the results of non-randomized phase 1 clinical immunological tests before and after treatment is another
research involving 18 patients with moderate and severe important limitation. Missing data on the sources, doses, and
COVID-19, transient flushing and fever developed in two patients administration routes of MSCs limited further inferences about
and transient hypoxia was seen in one patient who underwent different treatment modalities’ effects.
umbilical cord MSC treatment, but no serious adverse events
were reported [20]. MSC infusions from umbilical cords are safe Conclusion
and have significantly improved the survival and shortened Many methods are used in the treatment of COVID-19 and there
the recovery time of patients according to the results of a are conflicting reports in the literature about MSC treatment. A
double-blind, phase 1/2a study that included 24 patients with common feature among these publications is that the studies
COVID-19 [37]. In another study by Shu et al. [38], umbilical were performed with small case groups. To our knowledge, the
cord MSCs administered to a group of 12 patients resulted in present study has the largest case series in the literature to date.
significantly shorter recovery times, rapid disappearance of Although increasing evidence has indicated the therapeutic
symptoms, and rapid reductions in lung inflammation compared potential of MSC treatment, according to the present study’s
to a control group. MSCs derived from adipose tissue were given limited findings MSC treatment might not contribute to the
to 13 patients who had severe COVID-19 and needed mechanical improvement of overall or comorbid disease-based survival.
ventilation, and improved clinical statuses and radiological Further studies with more comprehensive data may clarify
healing were observed. The need for mechanical ventilation was the effects of different MSC treatment modalities on discrete
also reduced [36]. subgroups of COVID-19 patients.

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