Novel Coronavirus (2019nCoV) or Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) that causes Coronavirus Disease 2019, or known as Covid-19 has recently become a global health emergency since it was first detected in Wuhan, the People Republic of China in December 2019. Since then, the prevalence has rapidly increased worldwide. In Indonesia, by the end of April 2020, around 10,000 patients have been tested positive for Covid-19 infection, with a case fatality rate of around 8%. The pathogenesis of Covid-19 is still under investigation and to our understanding, ACE2 receptors in the alveoli serve as the binding site of the S-protein of envelope spike virus of SARS-CoV-2. TMPRSS2 enzyme aids the fusion between cell membrane and capsid of the virus, allowing penetration of virus into the cell. Vesicles containing virion fuse with cell membrane and released as new virions. Cytopathic effect of the virus and its ability to overcome immune response determines the degree of infection. Differences in immunological profile among degrees of severity of Covid-19 may vary especially for the number of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-6, IL-8, leukemia-inhibiting factors (LIF), immunological markers such as CXCR3+CD4+, CXCR3+CD8+ T cell and CXCR3+ NK cells, implying the ongoing cytokine storm. The previous studies also found increasing number for infection markers such as procalcitonin, ferritin, and C-reactive protein. The decreasing number of anti-inflammatory cytokines in such as IL-10 also supports this finding. Previous studies have shown immunomodulating and anti-inflammatory capacity of the mesenchymal stem cells (MSCs). MSCs contributed to the shifting of pro-inflammatory Th2 into anti-inflammatory Th2. One of the most recent study on the usage of MSCs on Covid-19 patients showed increased expression of leukemia inhibitory factor (LIF), which give rise to inhibitory effect of T lymphocyte and natural killer (NK) cell population. Vascular epithelial growth factor (VEGF) is found increasing following MSCs administration, which indicates the ability to improve the disrupted capillaries due to SARS-Cov-2 infection. The ability of MSCs in differentiating to alveolar cells is proven by the presence of SPM and SPC2, surfactant proteins produced by type II alveolar cells. MSCs are unable to be infected by SARS-CoV-2 since they don't have ACE2 receptors and TMPRSS2 enzyme.
This study is a double blind, randomized control trial (RCT). This study will be concluded in
2 months, from May to July 2020, from subject selection to the end of follow up. Research
subjects are obtained consecutively from Covid-19 patients who receive care in the intensive
care unit (ICU) across four Covid-19 referral hospitals, including Persahabatan Hospital,
Sulianti Saroso Center for Infectious Disease, Cipto Mangunkusumo General Hospital, and
Universitas Indonesia Hospital, with 10 subjects obtained from each hospital and total 40
subjects for this RCT. Subjects from each hospitals are divided into control and experimental
groups. Subject belongs to the control group will receive standardized therapy (consisting of
oseltamivir and azithromycin), whereas subjects in the experimental group will receive MSCs
infusion, in addition to standardized therapy.
Subject Criteria Inclusion Criteria for MSC Donor from Umbilical Cord:
Umbilical cord is collected from elective caesarean section from a fullterm pregnancies
without any complication and free from HIV, Hepatitis B, C, D virus, Cytomegalovirus, Rubella
Virus, and free from fungal and bacterial contamination.
Informed consent all of the subjects must be filled and signed up before ruled in this study.
As soon as after delivery, the umbilical cord is collected and processed in sterile specimen
0,9% NaCl at 4oC for 8 hours. The umbilical cord transported to the laboratory and cultured
in GMP lab, at Stem Cells Medical Technology Integrated Service Unit Cipto Mangunkusumo
Hospital. Cellular viability and proliferation are evaluated after cell characterization test
by flow cytometer.
Sterility tests are done three times to ensure cellular sterility. Subjects will receive MSCs
through infusion through intravenous for 1 hour, following the administration of
diphenhydramine and anticoagulant to prevent clotting.
Following the MSCs administration, monitoring at the patients is carried out every day,
whereas laboratory testing for basic parameters (complete blood count, differential count,
blood gas analysis, C-reactive protein, SGOT/SGPT (AST/ALT), Ureum/Creatinine, eGFR,
electrolyte, procalcitonin, albumin, total bilirubin, D-Dimer, fibrinogen, troponin I and
proBNP) are carried out every three days. Cytokine levels are measured before the
administration and 7th day after the administration. Chest radiography is carried out every
three days.
Drug: Oseltamivir
Current standardized treatment for Covid-19
Drug: Azithromycin
Current standardized treatment for Covid-19
Biological: Umbilical Cord Mesenchymal Stem Cells
Adjuvant therapy on top of current standardized treatment (Oseltamivir + Azithromycin)
Inclusion Criteria:
- Patients aged 18-95 years old
- Confirmed for diagnosis of Covid-19 through RT-PCR from nasopharyngeal swab and/or
bronchoalveolar lavage for patients under intubation
- Laboratory results showed leukopenia and lymphopenic
- Chest radiography shows pneumonia appearance and/or ground-glass opacity on chest
CT-Scan
- Patients/their families are willing to sign the informed consent
Exclusion Criteria:
- History of malignancy
- Pregnant, or show positive result on pregnancy test
- Patients was/are currently participating in other clinical trials within the last 3
months
Cipto Mangunkusumo General Hospital
Jakarta Pusat, DKI Jakarta, Indonesia
Persahabatan General Hospital
Jakarta, DKI Jakarta, Indonesia
Sulianti Saroso Center for Infectious Disease
Jakarta, DKI Jakarta, Indonesia
Universitas Indonesia Hospital
Depok, West Java, Indonesia
Ismail H Dilogo, MD, PhD
+621500135
ismailortho@gmail.com
Tri Kurniawati, BSc
+621500135
selpuncarscm@yahoo.co.id
Ismail H Dilogo, MD, PhD, Principal Investigator
Indonesia University