Treating severe COVID-19 in patients has been a reason of concern since the pandemic started. This article highlights a very important study by a group of Indonesian researchers that can help treat critically ill patients with non-altered stem cells from the umbilical connective tissue.

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Boosting the survival of critically ill COVID-19 patients is possibly not an easily achievable goal. Not anymore. Researchers in Indonesia led by Professor Ismail Hadisoebroto Dilogo of the University of Indonesia, Chipt Mangunkusmo Central Hospital, found that critically ill COVID-19 patients treated with non-altered stem cells from umbilical connective tissue were more than twice as likely to survive as those who did not have the treatment. The journal STEM CELLS Translational Medicine published the study online on June 8, 2021.

This clinical trial carried out at four hospitals also showed that administering the treatment to COVID-19 patients with an added chronic health condition such as diabetes, hypertension or kidney disease increased their survival more than fourfold. Currently, the management of COVID-19 is based on empirical and supportive therapy. The physicians have not yet found a curative regimen. Some unfortunate patients with COVID-19 do not respond to all the combination treatments. The researchers found that still there is very limited research about the new potential therapeutic agents for treating patients, critically ill with COVID-19.

Therefore, the present study exclusively involved intubated critically ill patients with COVID-19 in the intensive care unit. In contrast to the existing studies, the present study used regular umbilical cord mesenchymal stem cells without a special manipulation procedure aimed to achieve angiotensin-converting enzyme-2 (ACE-2)-negative mesenchymal stem cell. That is why the researchers specifically referred to the use of unaltered birth cord cells in their study. The researchers noted that acute respiratory distress syndrome (ARDS) is the leading cause of death in COVID-19 patients. One of the main causes of ARDS in SARS-CoV-2 infection is cytokine storm, although this topic is still controversial.

“In interactions with dendritic cells, mesenchymal stromal cells (MSCs) cause pro-inflammatory Th2 cells to shift to anti-inflammatory Th2 cells, including changes in cytokine profiles toward anti-inflammatory. Human umbilical cord mesenchymal stromal cells (hUC-MSCs) have a high proliferative capacity for sustaining paracrine effects and low risk of body rejection due to absent Human Leukocyte Antigen (HLA) expression," the researchers clarified. Clinical trials in China have shown that patients with COVID-19-related pneumonia treated with umbilical cord mesenchymal cells (UC-MSCs) were more likely to survive and have a faster recovery than patients without MSC therapy.

This is the context in which Indonesian researchers investigated whether administration of allogenic UC-MSCs as adjuvant therapy for critically ill patients with COVID-19 who are unresponsive to conventional supportive treatment can improve the survival rate of critically ill patients with COVID-19-related pneumonia in Indonesia.

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The study design

The study is a multi-centred, double-blind, randomised clinical trial, carried out between May 1 and October 10, 2020, at four COVID-19 referral hospitals in Jakarta (Sulianti Saroso Infection Disease Hospital, Persahabatan Central General Hospital, Cipto Mangunkusumo National Central General Hospital, and Indonesia University Hospital). Researchers selected the study subjects using stratified random sampling and randomised using a computerised random number generator. They included 40 subjects with 20 in the control group and 20 in the experimental group. They determined the number of subjects for this study based on references to previous studies. This is a double-blinded study. That means neither the subjects nor the care providers and those assessing the outcomes were aware of the treatment assignment.

The researchers achieved this by making the packaging of MSCs and the placebo in an identical way. Besides that, a third party, unrelated to clinical decision-making or data collection determined all patient allocations.

The criteria of critical patients included the following:

1. Respiratory failure that progressed into ARDS, defined as the partial pressure of oxygen in arterial blood (PaO2)/the fraction of inspired oxygen (FiO2) lower than 300 mmHg and supported by mechanical ventilation.
2. Shock, such as septic shock (persistent hypotension following fluid resuscitation and requiring vasopressor to maintain mean arterial pressure of ≥65 mmHg and serum lactate of >2 mmol/L).
3. Multiple organ failure and monitored in the ICU.

The participants included were:

• Between 18-95 years
• Critically ill with RT-PCR-confirmed COVID-19, obtained from a nasopharyngeal swab or bronchoalveolar lavage if intubated
• Leukopenia and lymphopenia in peripheral blood and differential count
• Presenting with pneumonia on chest x-ray and/or ground-glass opacity on thorax computed tomography (CT) scan, and signed informed consent by subjects or family members

Exclusion criteria in this study were:

• Any history of malignancy
• Pregnant women or women who showed a positive pregnancy test
• Any history of or currently taking part in another clinical trial in the last 3 months

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The study procedure

The researchers harvested the mesenchymal stem cells (MSCs) from the human umbilical cord produced by Stem Cells Medical Technology Integrated Service Installation, Cipto Mangunkusumo Central National General Hospital, Faculty of Medicine, University of Indonesia. They were cultured and harvested from passage 5 or 6 to ensure the best quality of the cells.

After carrying out baseline assessments, researchers gave the subjects admitted to the study a single intravenous infusion of 1 × 106/kg body weight UC-MSCs in 100 ml saline (0.9%) solution for the experimental group or with placebo (100 ml saline [0.9%] solution) for the control group on day 8 (ranged from day 2-30) of treatment in the ICU.

They assessed baseline parameters including routine blood count, differential count, C - reactive protein (CRP), D-dimer, fibrinogen, and procalcitonin and specific markers, including vascular endothelial growth factor (VEGF), ferritin, cytokine IL-6, IL-10, flow cytometry leukaemia inhibitory factor (LIF), and lymphocyte subpopulation CX-CR3 CD4, CD8, and CD56, before the application was done.

During the 15 days of observation, researchers conducted laboratory evaluations on day 0 and day 1 and then once every 3 days for routine laboratory examination whereas specific markers were evaluated on day 0 and day 7 only. Adverse events (AEs) were closely observed in the MSCs group.

In brief, all 40 patients who took part in the double-blind, controlled, randomised study were adults in intensive care who had been intubated due to COVID-19-induced pneumonia. Half were given intravenous infusions containing umbilical mesenchymal stromal cells, or stem cells derived from the connective tissue of a human birth cord, and half were given infusions without them.

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Conclusions (verbatim) from AlphaMed press release

The survival rate of those receiving the stem cells was 2.5 times higher and climbed even more - 4.5 times - in the COVID-19 patients who had other chronic health conditions, said Ismail Hadisoebroto Dilogo, professor of medicine at Cipto Mangunkusumo Central Hospital-Universitas Indonesia and research team member. The stem cell infusion also was found to be safe and well-tolerated with no life-threatening complications or acute allergic reactions in seven days of post-infusion monitoring, he added.

Previous clinical trials have shown that treating COVID-19 pneumonia patients with stem cells from umbilical cord connective tissue may help them survive and recover more quickly, but the Indonesian study is the first to treat intubated, critically ill COVID-19 pneumonia patients with a naive, or non-genetically manipulated, a form of the stem cells.

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Limitations of the study

1. Firstly, the limited subject in this study holds up to acquire a statistically significant result. The number of patients studied is too small.
2. Secondly, the researchers did not perform further supplementary tests to check for endotheliitis.
3. Another limitation is that they did not apply exact criteria about how long the critically ill patient with COVID-19 had been treated in the ICU.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with a specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.