Effectiveness and Safety of Normoxic Allogenic Umbilical Cord Mesenchymal Stem Cells Administered as Adjunctive Treatment in Patients with Severe COVID-19

Effectiveness and Safety of Normoxic Allogenic Umbilical Cord Mesenchymal Stem Cells Administered as Adjunctive Treatment in Patients with Severe COVID-19 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Effectiveness and Safety of Normoxic Allogenic Umbilical Cord Mesenchymal Stem Cells Administered as Adjunctive Treatment in Patients with Severe COVID-19 Rusdy Ghazali Malueka, Arief Nurudhin, Purwoko Purwoko, Sumardi Sumardi, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2280239/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Aug, 2023 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Inflammatory response in COVID-19 contributes greatly to disease severity. Mesenchymal Stem Cells (MSCs) have the potential to alleviate inflammation and reduce mortality and length of stay in COVID-19 patients. We investigated the safety and effectiveness of normoxic-allogenic umbilical cord (NA-UC)-MSCs as an adjunctive treatment in severe COVID-19 patients. A double-blind, multicentric, randomized, placebo-controlled trial involving severe COVID-19 patients was performed from January–June 2021 in three major hospitals across Java, Indonesia. Eligible participants (n = 42) were randomly assigned to two groups (1:1), namely the intervention (n = 21) and control (n = 21) groups. Either NA-UC-MSCs or NaCl placebo were administered daily. The primary outcome was the duration of hospitalization. Meanwhile, the secondary outcomes were radiographical progression (Brixia score), respiratory and oxygenation parameters, and inflammatory markers, in addition to the safety profile of NA-UC-MSCs. NA-UC-MSC administration did not affect the length of hospital stay of severe COVID-19 patients, nor did it improve the Brixia score or mMRC dyspnoea scale better than placebo. Nevertheless, NA-UC-MSCs led to a better recuperation in oxygenation index (120.80 ± 72.70 baseline vs 309.63 ± 319.30 D + 22, p = 0.038) and oxygen saturation (97.24 ± 4.10% vs 96.19 ± 3.75% in placebo, p = 0.028). Additionally, compared to the placebo group, the treatment group had a significantly smaller increase in PCT level at D + 22 (1.43 vs. 12.76, p = 0.011). No adverse effects, including serious ones, were recorded until D + 91. NA-UC-MSC therapy is a very safe adjunct for COVID-19 patients. It improves the oxygenation profile and carries potential to suppress inflammation. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The emergence of the Coronavirus disease 2019 (COVID-19) pandemic has highlighted the need for streamlined drug development and validation within a condensed timeframe 1,2 . While most COVID-19 patients do not require hospitalization, the frequent outbreak of severe cases and the introduction of new variants compromise the availability of hospital beds and may aggravate mortality. These patients often present with acute respiratory distress syndrome (ARDS), which ultimately deteriorates into multiple organ failure 3 . The latter may be triggered by the attachment of the SARS-CoV-2 virus on the receptors of target organs and also by a cytokine storm response 4,5 . The severity of the disease is not determined by the SARS-CoV-2 viral load but rather by the inflammatory response, which may be quantified in plasma samples 6,7 . The abnormally elevated pro-inflammatory and anti-inflammatory cytokines in severe COVID-19 patients, dubbed the "cytokine storm", suggested that these patients have a dysfunctional immune system 7,8 . These comprise, but are not limited to, VEGF, TNF-α, SCF, LIF, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IL-17A, IL-18, IL-1β, and IFN-γ 9 . The cytokine storm subsequently leads to the cytokine release syndrome (CRS), which, together with chemokine release, forms the basis for multiple organ failure 4,10 . As no approved pharmaceuticals have been demonstrated to reduce viral load, all therapy in COVID-19 is directed towards improving symptoms and immune response 11–13 . Hence, the discovery and investigation of various compounds and biologicals ( e.g., cells ) have been carried out, partly propelled by ongoing confusion and desperation. Mesenchymal stem cells (MSCs), in particular, is a biological with potent angiogenetic, anti-apoptotic, anti-inflammatory, and immunomodulatory properties, all of which are beneficial for the recovery of COVID-19 patients 14,15 . Multiple clinical trials have discovered that MSC therapy reduced mortality and promoted recovery in severe COVID-19, a finding strengthened by a recent meta-analysis 16,17 . For example, one Indonesian trial found that IL-6, a pro-inflammatory cytokine, and ferritin levels were decreased in MSC-administered patients 14 . In another, PaO 2 /FiO 2 ratio and radiological profile in severe COVID-19 patients were drastically improved after umbilical cord (UC)-MSC therapy 15 . Besides these potentials, one notable aspect of allogenic MSC application is its economic efficiency. Firstly, they are prepared by extracting cord blood or cutting up Wharton's Jelly (WJ), readily available in virtually all hospitals with maternity wards, and culturing them inside flasks 18 . They can be passaged for 12–13 cycles before growth deceleration is observed 19 . Secondly, unlike their secretome derivatives, UC-MSCs require less sophisticated equipment to process 14,20 . Based on this, we investigated the safety and effectiveness of normoxic-allogenic (NA)-UC-MSCs as an adjunctive treatment in severe COVID-19 patients. Results Recruitment Forty-eight subjects were recruited from 30 January – 24 June 2021. The screening was performed in the three aforementioned hospitals across Java, Indonesia. Six subjects were excluded from the study due to either having been deceased before the commencement of the trial or having satisfied the exclusion criteria. In total, 42 eligible subjects were randomized into two equal groups: 21 in the intervention group and 21 in the placebo control group. The collection of blood samples and other parameters was performed in accordance with the study methods. A total of 14 patients, seven in each group, died before the end of the observation period. The detailed process of subject recruitment is displayed in Fig. 1 . General subject characteristics The general comparison between the NA-UC-MSC and the placebo groups was summarised in Table 1 . There were no significant disparities in most baseline characteristics of subjects between the two groups. The average age of participants in the intervention and control groups were 56.10 and 55.86 years, respectively. The average body weight were 68.05 and 68.33 in the intervention and control groups, respectively. In addition, subjects were also evenly stratified by gender across the two groups. No difference was observed in past medical history, as indicated by diabetes, hypertension, chronic kidney diseases, congestive heart failures (CHF), chronic liver diseases, chronic obstructive pulmonary disease (COPD), stroke, autoimmune diseases, and active smoking status. Duration of Hospitalisation The average hospital stay in subjects who received NA-UC-MSCs was 20.81 ± 12.25 days compared to control subjects, who were treated for 16.81 ± 5.63 days as shown in Table 2 . No significant difference was observed in the length of hospitalization between the two groups. Group Mean ± S.D Median-Mode Min-Max *p Table 2 Duration of Hospitalisation (Days) Since Admission NA-UC-MSC (n = 21) 20.81 ± 12.25 20–20 6–57 0.427 Control (n = 21) 16.81 ± 5.63 17–20 6–27 * Normal distribution, p-value calculated using Independent T-Test. Radiographical Severity (Brixia Score) Table 3 and Fig. 2 portray the subjects’ mean Brixia scores across both groups and time points. Brixia scores were assessed by evaluating the subjects’ chest x-ray examination on days 0, 15, and 22 of intervention. Although no significant difference between groups was apparent, NA-UC-MSCs successfully alleviated the Brixia score on day 15 and the subsequent day 22. Baseline D + 15 D + 22 **p Table 3 Mean Brixia scores between groups, posthoc tests, and mean Mean Brixia scores NA-UC-MSC 14.10 ± 2.59 11.90 ± 3.22 10.57 ± 4.62 0.016 Control 13.76 ± 4.02 10.48 ± 4.81 9.76 ± 4.93 0.009 *p 0.819 0.179 0.441 * P-value calculated using Mann-Whitney's test. ** P-value calculated using Friedman's test. If p is significant, posthoc tests entail (supplement). MMRC dyspnoea scale, PEF, and 6MW test Table 4 and Fig. 3 present the mMRC dyspnoea scores, while Table 5 and Fig. 4 elaborate on the PEF and 6MW test results. Both the NA-UC-MSC and the control group showed improvement in dyspnoea scores on days 15 and 22 after treatment. However, MSC administration did not seem to relieve or aggravate dyspnoea scores compared to control. A similar pattern is observed in the 6MW test, where no inter-group difference was found at any point in time. Table 5 Mean PEF and 6MW distance (m) between two groups Baseline D + 15 D + 22 **p PEF MSC 56.46 ± 82.18 84.64 ± 105.69 127.14 ± 153.84 0.154 Con 78.57 ± 96.70 146.07 ± 178.88 196.07 ± 168.27 0.026 *p 0.508 0.333 0.268 Walk dist (m) MSC 1.43 ± 2.62 39.48 ± 92.83 52.57 ± 115.24 0.142 Con 3.20 ± 10.72 37.38 ± 83.07 66.08 ± 119.98 0.001 *p 0.556 0.631 0.630 * P-value calculated using Mann-Whitney's test. ** P-value calculated using Friedman's test. If p is significant, posthoc tests entail (supplement). Oxygenation index, duration of oxygenation, and O 2 saturation Table 6 and Fig. 5 depict the oxygenation index, duration of oxygenation, and oxygen saturation across both groups at different time points. Overall, it can be inferred that NA-UC-MSC significantly improved the oxygenation index. This was not observed in the control group. Intriguingly, oxygen saturation by day 22 also favored the intervention group. Table 6 Oxygenation index, duration of oxygenation, and O 2 saturation across groups Baseline D + 15 D + 22 **p Ox. index MSC 120.80 ± 72.70 231.47 ± 184.59 309.63 ± 319.30 0.038 Con 129.17 ± 106.54 298.85 ± 362.09 382.27 ± 431.32 0.214 *p 0.642 0.589 0.930 Duration of O 2 admin*** MSC 13 (61.9%) 8 (38.1%) Con 13 (61.9%) 8 (38.1%) *p 1.000 Finger O 2 sat. MSC 96.86 ± 4.23 96.81 ± 4.06 97.24 ± 4.10 0.313 Con 97.29 ± 2.22 96.81 ± 2.06 96.19 ± 3.75 0.640 *p 0.858 0.259 0.028 * P-value calculated using Mann-Whitney's test. ** P-value calculated using Friedman's test. If p is significant, posthoc tests entail (supplement). *** Defined as oxygen therapy having been terminated by the Dth day of treatment. PCT, ESR, and CRP markers Table 7 and Fig. 6 demonstrate that NA-UC-MSC administration did not alter PCT, ESR, and CRP levels compared to placebo. Despite this, Fig. 5 clearly showed a reduction in PCT levels in the NA-UC-MSC group by day 22, in contrast to the increasing PCT levels in the control group. We then performed an additional analysis by comparing the difference in PCT values between baseline and day 22 in the two groups. As shown in Table 8 , the treatment group had a significantly smaller increase in PCT value than the control group (mean changes 1.43 vs. 12.76, p = 0.011). Table 7 PCT, ESR, and CRP levels across groups Baseline D + 15 D + 22 **p PCT MSC 2.74 ± 10.59 5.55 ± 17.18 4.17 ± 12.38 0.269 Con 0.41 ± 1.30 0.46 ± 1.30 13.17 ± 57.17 0.062 *p 0.184 0.919 0.186 ESR MSC 61.62 ± 27.88 58.67 ± 29.54 61.81 ± 26.33 0.229 Con 55.00 ± 32.25 61.57 ± 19.19 65.24 ± 27.96 0.683 *p 0.554 0.715 0.497 CRP MSC 87.71 ± 62.21 54.53 ± 63.62 53.57 ± 62.35 0.046 Con 66.61 ± 55.57 43.96 ± 48.22 44.54 ± 55.70 0.001 *p 0.273 0.880 0.642 * P-value calculated using Mann-Whitney's test. ** P-value calculated using Friedman's test. If p is significant, posthoc tests entail (supplement). Table 8 Differences in Mean Changes in PCT between groups Group Time Means ± S.D Mean changes (Δ) *p MSC Baseline 2.74 ± 10.59 2.81 0.236 D + 15 5.55 ± 17.18 Con Baseline 0.41 ± 1.30 0.05 D + 15 0.46 ± 1.30 MSC Baseline 2.74 ± 10.59 1.43 0.011 D + 22 4.17 ± 12.38 Con Baseline 0.41 ± 1.30 12.76 D + 22 13.17 ± 57.17 Survival A total of 14 subjects (33.3%) were deceased during the course of therapy. Among those who died, seven (16.7%) were in the NA-UC-MSC group, and the other seven (16.7%) were from the control group. These subjects were then classified as "early terminated" patients. Discussion The intravenous administration of NA-UC-MSCs did not affect the duration of hospitalization in severe COVID-19 patients. This study, however, confirmed the safety of NA-UC-MSC therapy in these subjects. In a previous study involving 30 patients, ten moderate control, ten severe control, and ten severe patients treated with MSCs, the intervention group had a markedly shorter mean ICU stay (31 days) vs. severe controls (41 days) 22 . However, in the mentioned trial, the MSCs were sourced from Wharton's jelly (as opposed to the umbilical cord), which has been shown to promote more scarring than the latter we are incorporating 22,23 . Therefore, further studies involving UC-MSCs should also incorporate the length of intensive care rather than gross hospital stay per se . The Brixia score is a new, potent inventory in determining the current condition and prognosis of pneumonia in COVID-19 patients. It was invented by Borghesi et al. in 2020 and has subsequently been adapted worldwide 24,25 . In our study, NA-UC-MSCs were found to relieve Brixia scores in a similar manner to the NaCl placebo. A similar finding was discovered by Abdullah et al. (2021), where MSC secretomes were administered instead 26 . The similarity between the two groups suggested that NA-UC-MSC therapy is a safe approach for adjunctive treatment. However, the delivery of MSCs or secretomes to the target lung tissues may be compromised 27 . Oxygen saturation, dyspnoea, and oxygen therapy are crucial inventories in managing COVID-19 patients. The former and the middle has been entrenched as an indicator of a patient's survival 28 , while the latter is a relatively simple, heuristic aid that acts as a countermeasure to address the problem 29 . In our study, we failed to show that NA-UC-MSC therapy influenced mMRC dyspnoea scale progression nor shortened the length of oxygenation, which was consistent with findings by Shi et al. (2021), who suggested that UC-MSC administration would only be beneficial to improve these parameters when administered during the acute progressive stage of SARS-CoV-2 infection 30 . Interestingly, peripheral oxygen saturation favored the MSC group by day 22 (97.24% vs. 96.19% in controls), and additionally, the oxygenation index (PaO 2 /FiO 2 ) skyrocketed by 156% the baseline value by day 22 in the intervention group. The latter replicates the results of a trial by Iglesias et al. (2021), whose five participants had their oxygenation index improved from 76 to 154 within a week upon NA-UC-MSC treatment 31 . However, as to how a more downstream parameter is influenced by bypassing the scope of a more upstream variable (dyspnoea and oxygen therapy) is subject to a more profound investigation. Moreover, a more distal variable, the distance traveled for six minutes, did not differ in both groups across the two assessment points. We also tracked the levels of three key inflammatory markers: PCT, ESR, and CRP. Out of the three, only CRP showed a significant reduction in both groups. This suggested no difference in bacterial co-infection between groups since PCT is a powerful biomarker for inflammation of bacterial origin 32 . While no significant differences between groups were observed, we managed to suppress CRP levels in the MSC and control groups (53.57 mg/mL and 44.54 mg/mL) after 22 days, which ultimately translates to the sufficient safety of MSCs. As a comparison, a study by Karyana et al. (2022) in nine patients yielded a median 28-day CRP of 0.45 mg/L in the MSC group, compared to 1.1 mg/L in the placebo group 33 . However, the MSCs used were of embryonic origin, dubbed "DW-MSC", whose procurement and logistics would involve extra steps; and the participants had low-risk COVID-19. Additionally, we found that on the day 22 of the intervention, the treatment group had a significantly smaller increase in PCT value compared to the control group. Procalcitonin is a commonly used diagnostic marker in bacterial infection. However, previous studies showed that in COIV-19, procalcitonin is a biomarker for disease severity rather than bacterial co-infection. High procalcitonin level has been shown to be associated with disease severity, increased intensive unit admission, and mortality in patients with COVID-19. A decrease in PCT level has also been shown as an indication of recovery from COVID-19 (Ahmed S, Jafri L, Hoodbhoy Z, Siddiqui I. Prognostic Value of Serum Procalcitonin in COVID-19 Patients: A Systematic Review. Indian J Crit Care Med. 2021 Jan;25(1):77–84)(Hu R, Han C, Pei S, Yin M, Chen X. Procalcitonin levels in COVID-19 patients. Int J Antimicrob Agents. 2020 Aug; 56(2):106051). Our results raise the possibility that the administration of NA-UC-MSC could probably prevent more severe progression of COVID-19. This, however, warrants further study. Clinically, COVID-19 cases may be classified as asymptomatic, mild, moderate, or severe with respiratory failure, with the lattermost frequently leading to death 34 . In our trial, 14 (33.33%) deaths during the study period were reported, which were evenly stratified across the NA-UC-MSC group (7, 16.67%) and the control group (7, 16.67%). A recent report suggested that this death rate exceeded that in the US, which were 12.7% for oxygenated patients and 47.5% for mechanically-ventilated patients 35 . Nevertheless, it is still comparable to another Indonesian investigation of MSCs in severe COVID-19 patients, where 25% of deaths occurred in the MSC group compared to 45% in the control group 14 . To reinforce this, the Wharton's jelly MSC COVID-19 study noted a 30% death rate in the MSC group and 60% in the control group 22 . The two primary limitations of our study were the relatively small number of participants and the absence of a window period to recruit them. A greater number of subjects would allow a finer distinction between truly significant associations and those that occurred by chance. Complementarily, due to the hospitals' hierarchical status being the highest in each respective region, potential eligible subjects may be screened before receiving referral patients. If a window period had been properly defined (i.e., days 0–3 since positive PCR confirmation) and implemented, more pronounced response to MSC therapy can be expected 30 . The two other crucial limitations were the choice of inflammatory markers and a single delivery route. In numerous other studies, cytokines (e.g., IL-6, TNF-α) and VEGF were quantified in addition to ESR and CRP 16,17,36,37 . Doing so would allow the authors to infer more direct causation and mechanism of MSC therapy in improving both the respiratory and general condition of COVID-19 patients. For example, an elevated IL-6 is putatively triggered as a response to injury in the alveolar epithelial cells 6 , while a high VEGF may indicate a critical illness 9 . The route of MSC delivery may also be varied to better quantify the patient's response to each. It has been established that intramuscular or intra-organ delivery of MSCs provides a more robust response compared to the systemic intravenous route 27 . Since the lung parenchyma is an anatomically inconvenient location for local injection, we would suggest an upcoming investigation on inhalational or intrabronchial MSCs. These two techniques transcend the limits of intravenous delivery and have been safely implemented for COVID-19 patients 38 . While our study did not note any adverse effects or increased mortality and is, therefore, safe, we acknowledge that imprudent use of MSCs may harm patients by promoting pro-coagulant AE, which manifests in the form of thrombo-embolic ischemia or disseminated intravascular coagulation 27 . Methodology Study Design This study was a multicentric, double-blinded, randomized, placebo-controlled trial to evaluate NA-UC-MSCs as a complementary treatment in severe COVID-19 patients (clinicaltrials.gov registration number NCT05132972 24/11/2021). This study approved by Health Research Ethics Committee, National Institute of Health Research and Development (HREC-NIHRD) with ethical clearance number LB.02.01/2/KE.573/2020 extended number LB.02.01/2/KE.582/2021. All experiments were conducted in accordance with the relevant guidelines and regulations. Participants Subjects were picked via stratified random sampling, then randomized via a computerized random number generator. The total number of subjects was 42, divided into 21 subjects in the NA-UC-MSC group and 21 in the placebo (NaCl) group. They hail from three major hospitals across the island of Java: dr. Hasan Sadikin General Hospital in Bandung, dr. Moewardi General Hospital in Surakarta, and dr. Sardjito General Hospital in Yogyakarta. Recruitment was done from 30 January – 24 June 2021. All subjects who participated in this trial had satisfied the inclusion and exclusion criteria. The inclusion criteria were: (1) Subjects 18–75 years old, who had been positively diagnosed with COVID-19 based on real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay of either pharyngeal, sputum, or broncho-alveolar lavage swab specimen; (2) Subjects are classified as severe COVID-19 patients; (3) Not mechanically ventilated upon admission; (4) No other adjunctive treatments were administered; (5) Agreed to participate and signed the informed consent. Both the Indonesian Ministry of Health guidelines on COVID-19 and WHO guidelines were consulted for severe COVID-19 categorisation 21 . Severe COVID-19 was defined as COVID-19 pneumonia in addition to at least one of the following: SpO2 ≤ 93% on room air, PaO2/FiO2 ≤ 300 mm Hg, or a respiratory rate ≥ 30 breaths/min. Meanwhile, the exclusion criteria were: (1) Pregnant, lactating women, or women on a contraceptive program; (2) a history or diagnosis of tumors or a history of breast cancer or ovarian cancer in the mother or sister; (3) SGPT/ALT value five times the upper limit of the normal value; (4) eGFR value < 30 mL/min; (5) requires invasive ventilation; (6) shock; (7) complications of organ failure; (8) had enrolled in other clinical trials within the last three months. Randomization and Masking All eligible subjects (n = 42) were randomly assigned into two groups (1:1 ratio) to either the intervention group, who were to receive NA-UC-MSCs (n = 21), or the placebo group, who were administered with NaCl (n = 21). Randomization was performed using blocks (block size = 4), and subjects were assigned to both groups with randomization software (sealedenvelope.com) by an independent statistician. The trial was prepared by a third party with no responsibility for patient care and data collection. All subjects, investigators, and treating physicians were blinded. NA-UC-MSC preparation Human umbilical cords were obtained from the cesarean section in the maternity ward of a hospital in Jakarta from a qualified donor that passed donor screening and testing of infectious disease (HIV, Hepatitis B, Hepatitis C, Syphilis, CMV IgM) and karyotyping. The human umbilical cord was subsequently processed to yield MSCs in Regenic Laboratory PT. Bifarma Adiluhung, Jakarta, Indonesia, with GMP standard. The MSCs were isolated with Alpha MEM (+ GlutaMAX) + Human Serum + Growth Factors and Vitamin + Antibiotic Antimicotic 1% and then passaged to passage 7 with Alpha MEM (+ GlutaMAX) + Human Platelet Lysate. To positively identify MSCs, the markers CD105, CD73, CD90 (> 95%) and CD45, CD34 CD14, CD19 and HLA-DR (< 2%) were used; and also Adipogenic, Osteogenic, Chondrogenic Differentiation were tested. Intervention Before the administration of either MSCs or placebo, history-taking and physical examination [including the Modified Medical Research Council (mMRC) dyspnea scale], routine hematological testing, inflammatory marker testing [procalcitonin (PCT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)], chest X-ray, respiratory testing [peripheral oxygen saturation (SpO2), oxygenation index (PaO 2 /FiO 2 ratio), 6-minute walk (6MW) test, peak expiratory flow (PEF)], and RT-PCR for SARS-COV-2 were performed on all subjects. All subjects received standard COVID-19 therapy according to national guidelines. In addition, NA-UC-MSCs were administered to subjects by intravenous route in the intervention group with the dose of 1x10 6 cells per kilogram of body weight, as opposed to NaCl 0.9% in the placebo group. Outcomes Primary Outcome The primary outcome of this trial was the subjects' duration of hospitalization. Secondary Outcome The secondary outcomes of this trial were radiological and clinical indicators on baseline (day 0–2), 15 (± 2), and 22 (± 2) days: (1) Brixia score for radiographic severity; (2) mMRC Dyspnea scale; (3) oxygenation index; (4) duration of oxygen therapy (days); (5) peripheral oxygen saturation; (6) 6MW test; (7) PEF; (8) PCT; (9) ESR; and (10) CRP levels. In addition, adverse events (AE) and serious adverse events (SAE) were recorded until day 91 (± 2) since randomization. Sample Collection Peripheral venous blood samples were collected for PCT, ESR, and CRP level assessment. Blood was collected on days 0–2 (baseline), 15 (± 2), and 22 (± 2) after the intervention. Following extraction, sample tubes were secured into primary (zip-loc bag), secondary (insulated bottles), and tertiary packs (insulated box with cooler packs), before being ultimately transported. Statistical analysis All data in this trial were analyzed with the software SPSS V.22 (IBM). For categorical variables, analyses were computed using the χ-square or Fisher's exact test. For unpaired continuous quantities, either an independent-sample T-test (normal distribution) or an independent-sample Mann-Whitney U test (non-normal distribution) was used. In addition, the paired T-test (normal distribution) or Wilcoxon test (non-normal distribution) were performed for continuous variables. Conclusion Although we have failed to demonstrate the reduction in the length of stay of severe COVID-19 patients with NA-UC-MSC therapy, we have established that it is a very safe adjunct that yielded no AE, including serious ones, for at least 91 days after the first dose. NA-UC-MSC therapy also did not reduce the Brixia score to values below that of the control group. However, NA-UC-MSCs improved the patients' oxygen saturation by day 22 compared to placebo, in addition to having a significantly smaller increase in PCT value compared to the control group. Thus, we are confident that MSC-based therapies are beneficial in COVID-19 and related diseases but need fine-tuning to reach their pinnacle potential. We aim to expand this study in the near future by introducing novel delivery routes and incorporating MSC products (i.e., secretome, extracellular vesicles (EV)). Declarations Acknowledgments This study was supported by the Grants-in-Aid from The National Research and Innovation Agency (BRIN) Indonesia and PT. Bifarma Adiluhung, Jakarta, Indonesia. Authors ’ contributions B.S., R.G.M., A.N. and A.F. designed the study. B.S. as national coordinator; R.G.M., A.N. and A.F. as PI for each center; R.G.M., J.A.T. and A.F. performed statistical analyses and drafted the manuscript. B.S. and A.N. team in Solo site are Pur., A.A., B.R.A.S., and W.S.; R.G.M. team in Yogyakarta site are Sum., Sud., J.A.T., E.H.H., I.T. and N.R.A.; A.F team in Bandung site are R.W., A.Y.S., T.W.M. and R.W.S. All sites team at least consist of internist, pulmonologist, anesthesiologist, radiologist and clinical pathologist. All sites maintained the study database and contributed to the data analysis. B.S., R.G.M. and A.F. made critical revisions to the manuscript. All sites obtained their own funding of the study. All authors read and approved the final manuscript. All authors are a Member of Indonesian Medical Doctor Association for Tissue Engineering and Cell Therapy (REJASELINDO). Data availability The datasets generated during and/or analysed during the current study are not publicly available due to confidential data of the patients but are available from the corresponding author on reasonable request. Additional Information Competing interests The author(s) declare no competing interests. References Leroux-Roels, G., Bonanni, P., Tantawichien, T. & Zepp, F. Vaccine development. Perspect. Vaccinol 1 , 15–150 (2011). Wang, J., Peng, Y., Xu, H., Cui, Z. & Williams, R. O. 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Dis. 96 , 291–293 (2020). Au-Yong, I. et al. Chest Radiograph Scoring Alone or Combined with Other Risk Scores for Predicting Outcomes in COVID-19. Radiology. 302 , 460–469 (2021). Abdullah, M. et al. Effectiveness and safety profile of mesenchymal stem cell secretome as a treatment for severe cases of COVID-19: a randomized controlled trial [version 1; peer review: awaiting peer review]. doi:10.12688/f1000research.75580.1 (2022). Moll, G. et al. MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy. Front. Immunol. 11 , 1091 (2020). Chatterjee, N. A. et al. Admission respiratory status predicts mortality in COVID-19. Influenza Other Respi. Viruses. 15 , 569–572 (2021). Anesi, G. L. COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation). Up to Date https://www.uptodate.com/contents/covid-19-respiratory-care-of-the-nonintubated-hypoxemic-adult-supplemental-oxygen-noninvasive-ventilation-and-intubation (2022). Shi, L. et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct. Target. Ther. 6 , 58 (2021). Iglesias, M. et al. Mesenchymal Stem Cells for the Compassionate Treatment of Severe Acute Respiratory Distress Syndrome Due to COVID 19. Aging Dis. 12 , 360–370 (2021). Ming, D. K. et al. Informing antimicrobial management in the context of COVID-19: understanding the longitudinal dynamics of C-reactive protein and procalcitonin. BMC Infect. Dis. 21 , 932 (2021). Karyana, M. et al. Safety of DW-MSC infusion in patients with low clinical risk COVID-19 infection: a randomized, double-blind, placebo-controlled trial. Stem Cell Res. Ther. 13 , 134 (2022). Wang, Z. et al. Clinical Features of COVID-19 Patients with Different Outcomes in Wuhan: A Retrospective Observational Study. Biomed Res. Int. 2020 , 2138387 (2020). Bradley, M. C. et al. Categorization of COVID-19 Severity to Determine Mortality Risk. in 2021 FDA SCIENCE FORUM (US FDA, 2021). Yao, W., Shi, L., Zhang, Y., Dong, H. & Zhang, Y. Mesenchymal stem/stromal cell therapy for COVID-19 pneumonia: potential mechanisms, current clinical evidence, and future perspectives. Stem Cell Res. Ther. 13 , 124 (2022). Wang L, Li Y, Xu M, et al. Regulation of Inflammatory Cytokine Storms by Mesenchymal Stem Cells. Front Immunol. 12 , 726909 (2021). Fröhlich E. Therapeutic Potential of Mesenchymal Stem Cells and Their Products in Lung Diseases-Intravenous Administration versus Inhalation. Pharmaceutics. 13 , 232 (2021). Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Cite Share Download PDF Status: Published Journal Publication published 02 Aug, 2023 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Major revision 15 Mar, 2023 Reviews received at journal 01 Mar, 2023 Reviewers agreed at journal 22 Feb, 2023 Reviews received at journal 04 Feb, 2023 Reviewers agreed at journal 22 Jan, 2023 Reviewers agreed at journal 22 Jan, 2023 Reviewers invited by journal 18 Jan, 2023 Editor assigned by journal 08 Jan, 2023 Editor invited by journal 23 Dec, 2022 Submission checks completed at journal 23 Dec, 2022 First submitted to journal 16 Nov, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2280239","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":162562515,"identity":"3bea0ca7-633d-4603-9683-985fd3d53658","order_by":0,"name":"Rusdy Ghazali Malueka","email":"","orcid":"","institution":"Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada - Dr. Sardjito General Hospital, Yogyakarta, Indonesia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rusdy","middleName":"Ghazali","lastName":"Malueka","suffix":""},{"id":162562519,"identity":"ce9c9d10-53a0-4778-bfd8-a7267c62355b","order_by":1,"name":"Arief Nurudhin","email":"","orcid":"","institution":"Department of Internal Medicine, Universitas Sebelas Maret - Dr. Moewardi Hospital, Solo, Indonesia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Arief","middleName":"","lastName":"Nurudhin","suffix":""},{"id":162562522,"identity":"46c83f55-b40d-4ff3-8229-bc30af8030ec","order_by":2,"name":"Purwoko Purwoko","email":"","orcid":"","institution":"Department of Anesthesiology and Intensive Therapy, Universitas Sebelas Maret - Dr. Moewardi Hospital, Solo, Indonesia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Purwoko","middleName":"","lastName":"Purwoko","suffix":""},{"id":162562523,"identity":"8edda2dd-529a-4e21-8256-45ac9c0e856a","order_by":3,"name":"Sumardi Sumardi","email":"","orcid":"","institution":"Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada - Dr. Sardjito General Hospital, Yogyakarta, Indonesia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sumardi","middleName":"","lastName":"Sumardi","suffix":""},{"id":162562527,"identity":"f28e0d24-07a1-4197-b8f4-7672b4f722a2","order_by":4,"name":"Rudi Wisaksana","email":"","orcid":"","institution":"Department of Internal Medicine, Universitas Padjadjaran - Dr. Hasan Sadikin Hospital, Bandung","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rudi","middleName":"","lastName":"Wisaksana","suffix":""},{"id":162562532,"identity":"6ffd77db-6a80-48f6-94bc-92e44a65dd47","order_by":5,"name":"Artrien Adhiputri","email":"","orcid":"","institution":"Department of Pulmonology and Respiratory Medicine, Universitas Sebelas Maret - Dr. Moewardi Hospital. 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A marked reduction in CRP levels was seen in both groups.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-2280239/v1/76eaf1554a22cb6113f738d6.png"},{"id":44734727,"identity":"e7262350-352d-45ef-bfd1-6e7d064c897c","added_by":"auto","created_at":"2023-10-16 22:20:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":606295,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2280239/v1/7dd39d3a-f46d-4efd-9365-267165e4d302.pdf"},{"id":30898969,"identity":"a3f385e3-2df8-4939-a9ae-e001eaae2fd8","added_by":"auto","created_at":"2022-12-29 18:27:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17331,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2280239/v1/32585eaaa0c3bb07a0383fd6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effectiveness and Safety of Normoxic Allogenic Umbilical Cord Mesenchymal Stem Cells Administered as Adjunctive Treatment in Patients with Severe COVID-19","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe emergence of the Coronavirus disease 2019 (COVID-19) pandemic has highlighted the need for streamlined drug development and validation within a condensed timeframe\u003csup\u003e1,2\u003c/sup\u003e. While most COVID-19 patients do not require hospitalization, the frequent outbreak of severe cases and the introduction of new variants compromise the availability of hospital beds and may aggravate mortality. These patients often present with acute respiratory distress syndrome (ARDS), which ultimately deteriorates into multiple organ failure\u003csup\u003e3\u003c/sup\u003e. The latter may be triggered by the attachment of the SARS-CoV-2 virus on the receptors of target organs and also by a cytokine storm response\u003csup\u003e4,5\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe severity of the disease is not determined by the SARS-CoV-2 viral load but rather by the inflammatory response, which may be quantified in plasma samples\u003csup\u003e6,7\u003c/sup\u003e. The abnormally elevated pro-inflammatory and anti-inflammatory cytokines in severe COVID-19 patients, dubbed the \"cytokine storm\", suggested that these patients have a dysfunctional immune system\u003csup\u003e7,8\u003c/sup\u003e. These comprise, but are not limited to, VEGF, TNF-α, SCF, LIF, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IL-17A, IL-18, IL-1β, and IFN-γ\u003csup\u003e9\u003c/sup\u003e. The cytokine storm subsequently leads to the cytokine release syndrome (CRS), which, together with chemokine release, forms the basis for multiple organ failure\u003csup\u003e4,10\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs no approved pharmaceuticals have been demonstrated to reduce viral load, all therapy in COVID-19 is directed towards improving symptoms and immune response\u003csup\u003e11\u0026ndash;13\u003c/sup\u003e. Hence, the discovery and investigation of various compounds and biologicals (\u003cem\u003ee.g., cells\u003c/em\u003e) have been carried out, partly propelled by ongoing confusion and desperation. Mesenchymal stem cells (MSCs), in particular, is a biological with potent angiogenetic, anti-apoptotic, anti-inflammatory, and immunomodulatory properties, all of which are beneficial for the recovery of COVID-19 patients\u003csup\u003e14,15\u003c/sup\u003e. Multiple clinical trials have discovered that MSC therapy reduced mortality and promoted recovery in severe COVID-19, a finding strengthened by a recent meta-analysis\u003csup\u003e16,17\u003c/sup\u003e. For example, one Indonesian trial found that IL-6, a pro-inflammatory cytokine, and ferritin levels were decreased in MSC-administered patients\u003csup\u003e14\u003c/sup\u003e. In another, PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratio and radiological profile in severe COVID-19 patients were drastically improved after umbilical cord (UC)-MSC therapy\u003csup\u003e15\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBesides these potentials, one notable aspect of allogenic MSC application is its economic efficiency. Firstly, they are prepared by extracting cord blood or cutting up Wharton's Jelly (WJ), readily available in virtually all hospitals with maternity wards, and culturing them inside flasks\u003csup\u003e18\u003c/sup\u003e. They can be passaged for 12\u0026ndash;13 cycles before growth deceleration is observed\u003csup\u003e19\u003c/sup\u003e. Secondly, unlike their secretome derivatives, UC-MSCs require less sophisticated equipment to process\u003csup\u003e14,20\u003c/sup\u003e. Based on this, we investigated the safety and effectiveness of normoxic-allogenic (NA)-UC-MSCs as an adjunctive treatment in severe COVID-19 patients.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec3\"\u003e\n \u003ch2\u003eRecruitment\u003c/h2\u003e\n \u003cp\u003eForty-eight subjects were recruited from 30 January \u0026ndash; 24 June 2021. The screening was performed in the three aforementioned hospitals across Java, Indonesia. Six subjects were excluded from the study due to either having been deceased before the commencement of the trial or having satisfied the exclusion criteria. In total, 42 eligible subjects were randomized into two equal groups: 21 in the intervention group and 21 in the placebo control group. The collection of blood samples and other parameters was performed in accordance with the study methods. A total of 14 patients, seven in each group, died before the end of the observation period. The detailed process of subject recruitment is displayed in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec4\"\u003e\n \u003ch2\u003eGeneral subject characteristics\u003c/h2\u003e\n \u003cp\u003eThe general comparison between the NA-UC-MSC and the placebo groups was summarised in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. There were no significant disparities in most baseline characteristics of subjects between the two groups. The average age of participants in the intervention and control groups were 56.10 and 55.86 years, respectively. The average body weight were 68.05 and 68.33 in the intervention and control groups, respectively. In addition, subjects were also evenly stratified by gender across the two groups. No difference was observed in past medical history, as indicated by diabetes, hypertension, chronic kidney diseases, congestive heart failures (CHF), chronic liver diseases, chronic obstructive pulmonary disease (COPD), stroke, autoimmune diseases, and active smoking status.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec5\"\u003e\n \u003ch2\u003eDuration of Hospitalisation\u003c/h2\u003e\n \u003cp\u003eThe average hospital stay in subjects who received NA-UC-MSCs was 20.81\u0026thinsp;\u0026plusmn;\u0026thinsp;12.25 days compared to control subjects, who were treated for 16.81\u0026thinsp;\u0026plusmn;\u0026thinsp;5.63 days as shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. No significant difference was observed in the length of hospitalization between the two groups.\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMedian-Mode\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMin-Max\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e*p\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDuration of Hospitalisation (Days) Since Admission\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA-UC-MSC (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.81\u0026thinsp;\u0026plusmn;\u0026thinsp;12.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u0026ndash;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u0026ndash;57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.427\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eControl (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.81\u0026thinsp;\u0026plusmn;\u0026thinsp;5.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u0026ndash;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u0026ndash;27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e* Normal distribution, p-value calculated using Independent T-Test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec6\"\u003e\n \u003ch2\u003eRadiographical Severity (Brixia Score)\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e portray the subjects\u0026rsquo; mean Brixia scores across both groups and time points. Brixia scores were assessed by evaluating the subjects\u0026rsquo; chest x-ray examination on days 0, 15, and 22 of intervention. Although no significant difference between groups was apparent, NA-UC-MSCs successfully alleviated the Brixia score on day 15 and the subsequent day 22.\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD\u0026thinsp;+\u0026thinsp;15\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD\u0026thinsp;+\u0026thinsp;22\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e**p\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMean Brixia scores between groups, posthoc tests, and mean \u003cem\u003eMean Brixia scores\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNA-UC-MSC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.10\u0026thinsp;\u0026plusmn;\u0026thinsp;2.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.90\u0026thinsp;\u0026plusmn;\u0026thinsp;3.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.57\u0026thinsp;\u0026plusmn;\u0026thinsp;4.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.76\u0026thinsp;\u0026plusmn;\u0026thinsp;4.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.48\u0026thinsp;\u0026plusmn;\u0026thinsp;4.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.76\u0026thinsp;\u0026plusmn;\u0026thinsp;4.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.819\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.441\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e* P-value calculated using Mann-Whitney\u0026apos;s test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e** P-value calculated using Friedman\u0026apos;s test. If p is significant, posthoc tests entail (supplement).\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003eMMRC dyspnoea scale, PEF, and 6MW test\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e present the mMRC dyspnoea scores, while Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e elaborate on the PEF and 6MW test results. Both the NA-UC-MSC and the control group showed improvement in dyspnoea scores on days 15 and 22 after treatment. However, MSC administration did not seem to relieve or aggravate dyspnoea scores compared to control. A similar pattern is observed in the 6MW test, where no inter-group difference was found at any point in time.\u003c/p\u003e\n \u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab5\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMean PEF and 6MW distance (m) between two groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD\u0026thinsp;+\u0026thinsp;15\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD\u0026thinsp;+\u0026thinsp;22\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e**p\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePEF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56.46\u0026thinsp;\u0026plusmn;\u0026thinsp;82.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84.64\u0026thinsp;\u0026plusmn;\u0026thinsp;105.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e127.14\u0026thinsp;\u0026plusmn;\u0026thinsp;153.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78.57\u0026thinsp;\u0026plusmn;\u0026thinsp;96.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e146.07\u0026thinsp;\u0026plusmn;\u0026thinsp;178.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e196.07\u0026thinsp;\u0026plusmn;\u0026thinsp;168.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.026\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.508\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.333\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.268\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eWalk dist (m)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.43\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.48\u0026thinsp;\u0026plusmn;\u0026thinsp;92.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.57\u0026thinsp;\u0026plusmn;\u0026thinsp;115.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.20\u0026thinsp;\u0026plusmn;\u0026thinsp;10.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.38\u0026thinsp;\u0026plusmn;\u0026thinsp;83.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66.08\u0026thinsp;\u0026plusmn;\u0026thinsp;119.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.556\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.631\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.630\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003e* P-value calculated using Mann-Whitney\u0026apos;s test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003e** P-value calculated using Friedman\u0026apos;s test. If p is significant, posthoc tests entail (supplement).\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eOxygenation index, duration of oxygenation, and O\u003csub\u003e2\u003c/sub\u003e saturation\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e depict the oxygenation index, duration of oxygenation, and oxygen saturation across both groups at different time points. Overall, it can be inferred that NA-UC-MSC significantly improved the oxygenation index. This was not observed in the control group. Intriguingly, oxygen saturation by day 22 also favored the intervention group.\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab6\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eOxygenation index, duration of oxygenation, and O\u003csub\u003e2\u003c/sub\u003e saturation across groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD\u0026thinsp;+\u0026thinsp;15\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD\u0026thinsp;+\u0026thinsp;22\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e**p\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOx. index\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e120.80\u0026thinsp;\u0026plusmn;\u0026thinsp;72.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e231.47\u0026thinsp;\u0026plusmn;\u0026thinsp;184.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e309.63\u0026thinsp;\u0026plusmn;\u0026thinsp;319.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.038\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e129.17\u0026thinsp;\u0026plusmn;\u0026thinsp;106.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e298.85\u0026thinsp;\u0026plusmn;\u0026thinsp;362.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e382.27\u0026thinsp;\u0026plusmn;\u0026thinsp;431.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.214\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.642\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.930\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration of O\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e \u003cstrong\u003eadmin***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (61.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (38.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (61.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (38.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eFinger O\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e \u003cstrong\u003esat.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.86\u0026thinsp;\u0026plusmn;\u0026thinsp;4.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.81\u0026thinsp;\u0026plusmn;\u0026thinsp;4.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97.24\u0026thinsp;\u0026plusmn;\u0026thinsp;4.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.313\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.81\u0026thinsp;\u0026plusmn;\u0026thinsp;2.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.19\u0026thinsp;\u0026plusmn;\u0026thinsp;3.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.640\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.858\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.259\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.028\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003e* P-value calculated using Mann-Whitney\u0026apos;s test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003e** P-value calculated using Friedman\u0026apos;s test. If p is significant, posthoc tests entail (supplement).\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003e*** Defined as oxygen therapy having been terminated by the Dth day of treatment.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec9\"\u003e\n \u003ch2\u003ePCT, ESR, and CRP markers\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e demonstrate that NA-UC-MSC administration did not alter PCT, ESR, and CRP levels compared to placebo. Despite this, Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e clearly showed a reduction in PCT levels in the NA-UC-MSC group by day 22, in contrast to the increasing PCT levels in the control group. We then performed an additional analysis by comparing the difference in PCT values between baseline and day 22 in the two groups. As shown in Table \u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003e, the treatment group had a significantly smaller increase in PCT value than the control group (mean changes 1.43 vs. 12.76, p\u0026thinsp;=\u0026thinsp;0.011).\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab7\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePCT, ESR, and CRP levels across groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD\u0026thinsp;+\u0026thinsp;15\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eD\u0026thinsp;+\u0026thinsp;22\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e**p\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePCT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2.74\u0026thinsp;\u0026plusmn;\u0026thinsp;10.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.55\u0026thinsp;\u0026plusmn;\u0026thinsp;17.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.17\u0026thinsp;\u0026plusmn;\u0026thinsp;12.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.17\u0026thinsp;\u0026plusmn;\u0026thinsp;57.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.062\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.919\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eESR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e61.62\u0026thinsp;\u0026plusmn;\u0026thinsp;27.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58.67\u0026thinsp;\u0026plusmn;\u0026thinsp;29.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.81\u0026thinsp;\u0026plusmn;\u0026thinsp;26.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.229\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e55.00\u0026thinsp;\u0026plusmn;\u0026thinsp;32.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.57\u0026thinsp;\u0026plusmn;\u0026thinsp;19.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.24\u0026thinsp;\u0026plusmn;\u0026thinsp;27.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.683\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.715\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.497\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e87.71\u0026thinsp;\u0026plusmn;\u0026thinsp;62.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.53\u0026thinsp;\u0026plusmn;\u0026thinsp;63.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53.57\u0026thinsp;\u0026plusmn;\u0026thinsp;62.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.046\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e66.61\u0026thinsp;\u0026plusmn;\u0026thinsp;55.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.96\u0026thinsp;\u0026plusmn;\u0026thinsp;48.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44.54\u0026thinsp;\u0026plusmn;\u0026thinsp;55.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cspan class=\"BoldItalic\" name=\"Emphasis\" type=\"BoldItalic\"\u003e*p\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.273\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.880\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.642\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003e* P-value calculated using Mann-Whitney\u0026apos;s test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003e** P-value calculated using Friedman\u0026apos;s test. If p is significant, posthoc tests entail (supplement).\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u0026nbsp;\u003ctable border=\"1\" id=\"Tab8\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDifferences in Mean Changes in PCT between groups\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTime\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMeans\u0026thinsp;\u0026plusmn;\u0026thinsp;S.D\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean changes (\u0026Delta;)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003e*p\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMSC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.74\u0026thinsp;\u0026plusmn;\u0026thinsp;10.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e2.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e0.236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eD\u0026thinsp;+\u0026thinsp;15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.55\u0026thinsp;\u0026plusmn;\u0026thinsp;17.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCon\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eD\u0026thinsp;+\u0026thinsp;15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMSC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.74\u0026thinsp;\u0026plusmn;\u0026thinsp;10.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e1.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eD\u0026thinsp;+\u0026thinsp;22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.17\u0026thinsp;\u0026plusmn;\u0026thinsp;12.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCon\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e12.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eD\u0026thinsp;+\u0026thinsp;22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.17\u0026thinsp;\u0026plusmn;\u0026thinsp;57.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003eSurvival\u003c/h2\u003e\n \u003cp\u003eA total of 14 subjects (33.3%) were deceased during the course of therapy. Among those who died, seven (16.7%) were in the NA-UC-MSC group, and the other seven (16.7%) were from the control group. These subjects were then classified as \u0026quot;early terminated\u0026quot; patients.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe intravenous administration of NA-UC-MSCs did not affect the duration of hospitalization in severe COVID-19 patients. This study, however, confirmed the safety of NA-UC-MSC therapy in these subjects. In a previous study involving 30 patients, ten moderate control, ten severe control, and ten severe patients treated with MSCs, the intervention group had a markedly shorter mean ICU stay (31 days) vs. severe controls (41 days)\u003csup\u003e22\u003c/sup\u003e. However, in the mentioned trial, the MSCs were sourced from Wharton's jelly (as opposed to the umbilical cord), which has been shown to promote more scarring than the latter we are incorporating\u003csup\u003e22,23\u003c/sup\u003e. Therefore, further studies involving UC-MSCs should also incorporate the length of intensive care rather than gross hospital stay \u003cem\u003eper se\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eThe Brixia score is a new, potent inventory in determining the current condition and prognosis of pneumonia in COVID-19 patients. It was invented by Borghesi et al. in 2020 and has subsequently been adapted worldwide\u003csup\u003e24,25\u003c/sup\u003e. In our study, NA-UC-MSCs were found to relieve Brixia scores in a similar manner to the NaCl placebo. A similar finding was discovered by Abdullah et al. (2021), where MSC secretomes were administered instead\u003csup\u003e26\u003c/sup\u003e. The similarity between the two groups suggested that NA-UC-MSC therapy is a safe approach for adjunctive treatment. However, the delivery of MSCs or secretomes to the target lung tissues may be compromised\u003csup\u003e27\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOxygen saturation, dyspnoea, and oxygen therapy are crucial inventories in managing COVID-19 patients. The former and the middle has been entrenched as an indicator of a patient's survival\u003csup\u003e28\u003c/sup\u003e, while the latter is a relatively simple, heuristic aid that acts as a countermeasure to address the problem\u003csup\u003e29\u003c/sup\u003e. In our study, we failed to show that NA-UC-MSC therapy influenced mMRC dyspnoea scale progression nor shortened the length of oxygenation, which was consistent with findings by Shi et al. (2021), who suggested that UC-MSC administration would only be beneficial to improve these parameters when administered during the acute progressive stage of SARS-CoV-2 infection\u003csup\u003e30\u003c/sup\u003e. Interestingly, peripheral oxygen saturation favored the MSC group by day 22 (97.24% vs. 96.19% in controls), and additionally, the oxygenation index (PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e) skyrocketed by 156% the baseline value by day 22 in the intervention group. The latter replicates the results of a trial by Iglesias et al. (2021), whose five participants had their oxygenation index improved from 76 to 154 within a week upon NA-UC-MSC treatment\u003csup\u003e31\u003c/sup\u003e. However, as to how a more downstream parameter is influenced by bypassing the scope of a more upstream variable (dyspnoea and oxygen therapy) is subject to a more profound investigation. Moreover, a more distal variable, the distance traveled for six minutes, did not differ in both groups across the two assessment points.\u003c/p\u003e \u003cp\u003eWe also tracked the levels of three key inflammatory markers: PCT, ESR, and CRP. Out of the three, only CRP showed a significant reduction in both groups. This suggested no difference in bacterial co-infection between groups since PCT is a powerful biomarker for inflammation of bacterial origin\u003csup\u003e32\u003c/sup\u003e. While no significant differences between groups were observed, we managed to suppress CRP levels in the MSC and control groups (53.57 mg/mL and 44.54 mg/mL) after 22 days, which ultimately translates to the sufficient safety of MSCs. As a comparison, a study by Karyana et al. (2022) in nine patients yielded a median 28-day CRP of 0.45 mg/L in the MSC group, compared to 1.1 mg/L in the placebo group\u003csup\u003e33\u003c/sup\u003e. However, the MSCs used were of embryonic origin, dubbed \"DW-MSC\", whose procurement and logistics would involve extra steps; and the participants had low-risk COVID-19.\u003c/p\u003e \u003cp\u003eAdditionally, we found that on the day 22 of the intervention, the treatment group had a significantly smaller increase in PCT value compared to the control group. Procalcitonin is a commonly used diagnostic marker in bacterial infection. However, previous studies showed that in COIV-19, procalcitonin is a biomarker for disease severity rather than bacterial co-infection. High procalcitonin level has been shown to be associated with disease severity, increased intensive unit admission, and mortality in patients with COVID-19. A decrease in PCT level has also been shown as an indication of recovery from COVID-19 (Ahmed S, Jafri L, Hoodbhoy Z, Siddiqui I. Prognostic Value of Serum Procalcitonin in COVID-19 Patients: A Systematic Review. Indian J Crit Care Med. 2021 Jan;25(1):77\u0026ndash;84)(Hu R, Han C, Pei S, Yin M, Chen X. Procalcitonin levels in COVID-19 patients. Int J Antimicrob Agents. 2020 Aug; 56(2):106051). Our results raise the possibility that the administration of NA-UC-MSC could probably prevent more severe progression of COVID-19. This, however, warrants further study.\u003c/p\u003e \u003cp\u003eClinically, COVID-19 cases may be classified as asymptomatic, mild, moderate, or severe with respiratory failure, with the lattermost frequently leading to death\u003csup\u003e34\u003c/sup\u003e. In our trial, 14 (33.33%) deaths during the study period were reported, which were evenly stratified across the NA-UC-MSC group (7, 16.67%) and the control group (7, 16.67%). A recent report suggested that this death rate exceeded that in the US, which were 12.7% for oxygenated patients and 47.5% for mechanically-ventilated patients\u003csup\u003e35\u003c/sup\u003e. Nevertheless, it is still comparable to another Indonesian investigation of MSCs in severe COVID-19 patients, where 25% of deaths occurred in the MSC group compared to 45% in the control group\u003csup\u003e14\u003c/sup\u003e. To reinforce this, the Wharton's jelly MSC COVID-19 study noted a 30% death rate in the MSC group and 60% in the control group\u003csup\u003e22\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe two primary limitations of our study were the relatively small number of participants and the absence of a window period to recruit them. A greater number of subjects would allow a finer distinction between truly significant associations and those that occurred by chance. Complementarily, due to the hospitals' hierarchical status being the highest in each respective region, potential eligible subjects may be screened before receiving referral patients. If a window period had been properly defined (i.e., days 0\u0026ndash;3 since positive PCR confirmation) and implemented, more pronounced response to MSC therapy can be expected\u003csup\u003e30\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe two other crucial limitations were the choice of inflammatory markers and a single delivery route. In numerous other studies, cytokines (e.g., IL-6, TNF-α) and VEGF were quantified in addition to ESR and CRP\u003csup\u003e16,17,36,37\u003c/sup\u003e. Doing so would allow the authors to infer more direct causation and mechanism of MSC therapy in improving both the respiratory and general condition of COVID-19 patients. For example, an elevated IL-6 is putatively triggered as a response to injury in the alveolar epithelial cells\u003csup\u003e6\u003c/sup\u003e, while a high VEGF may indicate a critical illness\u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe route of MSC delivery may also be varied to better quantify the patient's response to each. It has been established that intramuscular or intra-organ delivery of MSCs provides a more robust response compared to the systemic intravenous route\u003csup\u003e27\u003c/sup\u003e. Since the lung parenchyma is an anatomically inconvenient location for local injection, we would suggest an upcoming investigation on inhalational or intrabronchial MSCs. These two techniques transcend the limits of intravenous delivery and have been safely implemented for COVID-19 patients\u003csup\u003e38\u003c/sup\u003e. While our study did not note any adverse effects or increased mortality and is, therefore, safe, we acknowledge that imprudent use of MSCs may harm patients by promoting pro-coagulant AE, which manifests in the form of thrombo-embolic ischemia or disseminated intravascular coagulation\u003csup\u003e27\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis study was a multicentric, double-blinded, randomized, placebo-controlled trial to evaluate NA-UC-MSCs as a complementary treatment in severe COVID-19 patients (clinicaltrials.gov registration number NCT05132972 24/11/2021). This study approved by Health Research Ethics Committee, National Institute of Health Research and Development (HREC-NIHRD) with ethical clearance number LB.02.01/2/KE.573/2020 extended number LB.02.01/2/KE.582/2021. All experiments were conducted in accordance with the relevant guidelines and regulations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eSubjects were picked via stratified random sampling, then randomized via a computerized random number generator. The total number of subjects was 42, divided into 21 subjects in the NA-UC-MSC group and 21 in the placebo (NaCl) group. They hail from three major hospitals across the island of Java: dr. Hasan Sadikin General Hospital in Bandung, dr. Moewardi General Hospital in Surakarta, and dr. Sardjito General Hospital in Yogyakarta. Recruitment was done from 30 January \u0026ndash; 24 June 2021.\u003c/p\u003e \u003cp\u003eAll subjects who participated in this trial had satisfied the inclusion and exclusion criteria. The inclusion criteria were: (1) Subjects 18\u0026ndash;75 years old, who had been positively diagnosed with COVID-19 based on real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay of either pharyngeal, sputum, or broncho-alveolar lavage swab specimen; (2) Subjects are classified as severe COVID-19 patients; (3) Not mechanically ventilated upon admission; (4) No other adjunctive treatments were administered; (5) Agreed to participate and signed the informed consent. Both the Indonesian Ministry of Health guidelines on COVID-19 and WHO guidelines were consulted for severe COVID-19 categorisation\u003csup\u003e21\u003c/sup\u003e. Severe COVID-19 was defined as COVID-19 pneumonia in addition to at least one of the following: SpO2\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;93% on room air, PaO2/FiO2\u0026thinsp;\u0026le;\u0026thinsp;300 mm Hg, or a respiratory rate\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;30 breaths/min. Meanwhile, the exclusion criteria were: (1) Pregnant, lactating women, or women on a contraceptive program; (2) a history or diagnosis of tumors or a history of breast cancer or ovarian cancer in the mother or sister; (3) SGPT/ALT value five times the upper limit of the normal value; (4) eGFR value\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min; (5) requires invasive ventilation; (6) shock; (7) complications of organ failure; (8) had enrolled in other clinical trials within the last three months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eRandomization and Masking\u003c/h2\u003e \u003cp\u003eAll eligible subjects (n\u0026thinsp;=\u0026thinsp;42) were randomly assigned into two groups (1:1 ratio) to either the intervention group, who were to receive NA-UC-MSCs (n\u0026thinsp;=\u0026thinsp;21), or the placebo group, who were administered with NaCl (n\u0026thinsp;=\u0026thinsp;21). Randomization was performed using blocks (block size\u0026thinsp;=\u0026thinsp;4), and subjects were assigned to both groups with randomization software (sealedenvelope.com) by an independent statistician. The trial was prepared by a third party with no responsibility for patient care and data collection. All subjects, investigators, and treating physicians were blinded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eNA-UC-MSC preparation\u003c/h2\u003e \u003cp\u003eHuman umbilical cords were obtained from the cesarean section in the maternity ward of a hospital in Jakarta from a qualified donor that passed donor screening and testing of infectious disease (HIV, Hepatitis B, Hepatitis C, Syphilis, CMV IgM) and karyotyping. The human umbilical cord was subsequently processed to yield MSCs in Regenic Laboratory PT. Bifarma Adiluhung, Jakarta, Indonesia, with GMP standard. The MSCs were isolated with Alpha MEM (+\u0026thinsp;GlutaMAX)\u0026thinsp;+\u0026thinsp;Human Serum\u0026thinsp;+\u0026thinsp;Growth Factors and Vitamin\u0026thinsp;+\u0026thinsp;Antibiotic Antimicotic 1% and then passaged to passage 7 with Alpha MEM (+\u0026thinsp;GlutaMAX)\u0026thinsp;+\u0026thinsp;Human Platelet Lysate. To positively identify MSCs, the markers CD105, CD73, CD90 (\u0026gt;\u0026thinsp;95%) and CD45, CD34 CD14, CD19 and HLA-DR (\u0026lt;\u0026thinsp;2%) were used; and also Adipogenic, Osteogenic, Chondrogenic Differentiation were tested.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eIntervention\u003c/h2\u003e \u003cp\u003eBefore the administration of either MSCs or placebo, history-taking and physical examination [including the Modified Medical Research Council (mMRC) dyspnea scale], routine hematological testing, inflammatory marker testing [procalcitonin (PCT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)], chest X-ray, respiratory testing [peripheral oxygen saturation (SpO2), oxygenation index (PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e ratio), 6-minute walk (6MW) test, peak expiratory flow (PEF)], and RT-PCR for SARS-COV-2 were performed on all subjects. All subjects received standard COVID-19 therapy according to national guidelines. In addition, NA-UC-MSCs were administered to subjects by intravenous route in the intervention group with the dose of 1x10\u003csup\u003e6\u003c/sup\u003e cells per kilogram of body weight, as opposed to NaCl 0.9% in the placebo group.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcome\u003c/h2\u003e \u003cp\u003eThe primary outcome of this trial was the subjects' duration of hospitalization.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcome\u003c/h2\u003e \u003cp\u003eThe secondary outcomes of this trial were radiological and clinical indicators on baseline (day 0\u0026ndash;2), 15 (\u0026plusmn;\u0026thinsp;2), and 22 (\u0026plusmn;\u0026thinsp;2) days: (1) Brixia score for radiographic severity; (2) mMRC Dyspnea scale; (3) oxygenation index; (4) duration of oxygen therapy (days); (5) peripheral oxygen saturation; (6) 6MW test; (7) PEF; (8) PCT; (9) ESR; and (10) CRP levels. In addition, adverse events (AE) and serious adverse events (SAE) were recorded until day 91 (\u0026plusmn;\u0026thinsp;2) since randomization.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eSample Collection\u003c/h2\u003e \u003cp\u003ePeripheral venous blood samples were collected for PCT, ESR, and CRP level assessment. Blood was collected on days 0\u0026ndash;2 (baseline), 15 (\u0026plusmn;\u0026thinsp;2), and 22 (\u0026plusmn;\u0026thinsp;2) after the intervention. Following extraction, sample tubes were secured into primary (zip-loc bag), secondary (insulated bottles), and tertiary packs (insulated box with cooler packs), before being ultimately transported.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll data in this trial were analyzed with the software SPSS V.22 (IBM). For categorical variables, analyses were computed using the χ-square or Fisher's exact test. For unpaired continuous quantities, either an independent-sample T-test (normal distribution) or an independent-sample Mann-Whitney U test (non-normal distribution) was used. In addition, the paired T-test (normal distribution) or Wilcoxon test (non-normal distribution) were performed for continuous variables.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlthough we have failed to demonstrate the reduction in the length of stay of severe COVID-19 patients with NA-UC-MSC therapy, we have established that it is a very safe adjunct that yielded no AE, including serious ones, for at least 91 days after the first dose. NA-UC-MSC therapy also did not reduce the Brixia score to values below that of the control group. However, NA-UC-MSCs improved the patients' oxygen saturation by day 22 compared to placebo, in addition to having a significantly smaller increase in PCT value compared to the control group. Thus, we are confident that MSC-based therapies are beneficial in COVID-19 and related diseases but need fine-tuning to reach their pinnacle potential. We aim to expand this study in the near future by introducing novel delivery routes and incorporating MSC products (i.e., secretome, extracellular vesicles (EV)).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the\u0026nbsp;Grants-in-Aid\u0026nbsp;from\u0026nbsp;The National Research and Innovation Agency (BRIN) Indonesia and PT. Bifarma Adiluhung, Jakarta, Indonesia.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eB.S., R.G.M., A.N.\u0026nbsp;and A.F. designed the study. B.S. as national coordinator;\u0026nbsp;R.G.M., A.N.\u0026nbsp;and A.F. as PI for each center;\u0026nbsp;R.G.M., J.A.T.\u0026nbsp;and A.F. performed statistical analyses and drafted the manuscript.\u0026nbsp;B.S. and A.N. team in Solo site are Pur., A.A., B.R.A.S., and W.S.; R.G.M. team in Yogyakarta site are Sum., Sud., J.A.T., E.H.H., I.T. and N.R.A.; A.F team in Bandung site are R.W., A.Y.S., T.W.M. and R.W.S. All sites team at least consist of internist, pulmonologist, anesthesiologist, radiologist and clinical pathologist. All sites maintained the study database and contributed to the data analysis. B.S.,\u0026nbsp;R.G.M.\u0026nbsp;and A.F. made critical revisions to the manuscript. All sites obtained their own funding of the study. All authors read and approved the final manuscript. All authors\u0026nbsp;are a Member of Indonesian Medical Doctor Association for Tissue Engineering and Cell Therapy (REJASELINDO).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are not publicly available due to confidential data of the patients but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLeroux-Roels, G., Bonanni, P., Tantawichien, T. \u0026amp; Zepp, F. Vaccine development. \u003cem\u003ePerspect. 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Regulation of Inflammatory Cytokine Storms by Mesenchymal Stem Cells. \u003cem\u003eFront Immunol. \u003c/em\u003e\u003cstrong\u003e12\u003c/strong\u003e, 726909 (2021).\u003c/li\u003e\n\u003cli\u003eFr\u0026ouml;hlich E. Therapeutic Potential of Mesenchymal Stem Cells and Their Products in Lung Diseases-Intravenous Administration versus Inhalation. \u003cem\u003ePharmaceutics. \u003c/em\u003e\u003cstrong\u003e13\u003c/strong\u003e, 232 (2021).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2280239/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2280239/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eInflammatory response in COVID-19 contributes greatly to disease severity. Mesenchymal Stem Cells (MSCs) have the potential to alleviate inflammation and reduce mortality and length of stay in COVID-19 patients. We investigated the safety and effectiveness of normoxic-allogenic umbilical cord (NA-UC)-MSCs as an adjunctive treatment in severe COVID-19 patients. A double-blind, multicentric, randomized, placebo-controlled trial involving severe COVID-19 patients was performed from January\u0026ndash;June 2021 in three major hospitals across Java, Indonesia. Eligible participants (n\u0026thinsp;=\u0026thinsp;42) were randomly assigned to two groups (1:1), namely the intervention (n\u0026thinsp;=\u0026thinsp;21) and control (n\u0026thinsp;=\u0026thinsp;21) groups. Either NA-UC-MSCs or NaCl placebo were administered daily. The primary outcome was the duration of hospitalization. Meanwhile, the secondary outcomes were radiographical progression (Brixia score), respiratory and oxygenation parameters, and inflammatory markers, in addition to the safety profile of NA-UC-MSCs. NA-UC-MSC administration did not affect the length of hospital stay of severe COVID-19 patients, nor did it improve the Brixia score or mMRC dyspnoea scale better than placebo. Nevertheless, NA-UC-MSCs led to a better recuperation in oxygenation index (120.80\u0026thinsp;\u0026plusmn;\u0026thinsp;72.70 baseline vs 309.63\u0026thinsp;\u0026plusmn;\u0026thinsp;319.30 D\u0026thinsp;+\u0026thinsp;22, p\u0026thinsp;=\u0026thinsp;0.038) and oxygen saturation (97.24\u0026thinsp;\u0026plusmn;\u0026thinsp;4.10% vs 96.19\u0026thinsp;\u0026plusmn;\u0026thinsp;3.75% in placebo, p\u0026thinsp;=\u0026thinsp;0.028). Additionally, compared to the placebo group, the treatment group had a significantly smaller increase in PCT level at D\u0026thinsp;+\u0026thinsp;22 (1.43 vs. 12.76, p\u0026thinsp;=\u0026thinsp;0.011). No adverse effects, including serious ones, were recorded until D\u0026thinsp;+\u0026thinsp;91. NA-UC-MSC therapy is a very safe adjunct for COVID-19 patients. It improves the oxygenation profile and carries potential to suppress inflammation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"Effectiveness and Safety of Normoxic Allogenic Umbilical Cord Mesenchymal Stem Cells Administered as Adjunctive Treatment in Patients with Severe COVID-19","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-29 18:26:54","doi":"10.21203/rs.3.rs-2280239/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-03-15T13:25:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-03-01T10:19:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"38e3f916-4fbf-4678-9bb1-67ed3de25166","date":"2023-02-22T11:51:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-02-04T20:36:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8235913a-0a0a-4a05-8961-74a440442e66","date":"2023-01-22T14:21:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"c3052d05-fd6f-4108-8e43-e53e900eecdc","date":"2023-01-22T05:34:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-01-18T21:01:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-01-09T02:36:45+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-12-23T20:10:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-12-23T19:38:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2022-11-16T11:52:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e9c496e6-b18b-43ab-b2e2-c53dedd6fde7","owner":[],"postedDate":"December 29th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T22:02:54+00:00","versionOfRecord":{"articleIdentity":"rs-2280239","link":"https://doi.org/10.1038/s41598-023-39268-2","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2023-08-02 21:51:41","publishedOnDateReadable":"August 2nd, 2023"},"versionCreatedAt":"2022-12-29 18:26:54","video":"","vorDoi":"10.1038/s41598-023-39268-2","vorDoiUrl":"https://doi.org/10.1038/s41598-023-39268-2","workflowStages":[]},"version":"v1","identity":"rs-2280239","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2280239","identity":"rs-2280239","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}