Stem cell therapy in COVID: is it safe?

International Journal of Medical Science in Clinical Research and Review Online ISSN: 2581-8945 Available Online at http://www.ijmscrr.in Volume 03|Issue 06 (November-December)|2020|. Stem cell therapy in COVID: is it safe? *Corresponding author: Santiago Saldarriaga-Gómez, MD, MSc. phone number: +573007765266 25th street, 1a south – 45, Medellin, Colombia. Authors Informations : Saldarriaga-Gómez S1*†, Hernández-Ruíz A2†,Quintero-Gil C1, Ortega-Arellano H. Fernandez-Viña M3,Correa D4,5, Halpert K1 1 BioXcellerator 2 Clinical Somer research center. 3 Stem Cell Therapy Argentina. 4 Department of Orthopedics, U Health Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL, USA. 5 Diabetes Research Institute & Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA. † Both authors contributed equally to this study.. Article Received 06-10-2020 , Accepted 06-11-2020 , Published 12-11-2020 ABSTRACT. Mesenchymal stem cells (MSC) have emerged as a promising therapy for various conditions including neurologic, cardiovascular, autoimmune and musculoskeletal diseases due to their immuno modulatory and regenerative effects. SARS-CoV- 2 severe infection has been associated with a cytokine storm leading to multiple clinical manifestations including Acute Respiratory Distress Syndrome (ARDS) and sepsis. Due to a global lack of specific therapy for the virus and its complications, several strategies have been used to try to limit disease severity and hospital length of stay. Among these strategies, MSC have shown good results in phase I clinical trials, rising hope for physicians and patients around the world. Given this is a novel therapy, safety concerns about acute and long-term side effects limit their widespread use. Taking into account the everyday growing evidence of MSC therapy, a narrative review of its safety was conducted and discussion was made about current and possible future directions in MSC therapy and research. Keywords: COVID 19, coronavirus, stem cells, regenerative medicine. INTRODUCTION. World Health Organization, for June the 7th. COVID-19 SUMMARY The emergence of. of 2020, 6’912.751 people had been. SARS-CoV 2, COVID 19 etiologic agent,. diagnosed around the world, with 400.469. has become a worldwide challenge since. deaths and 216 countries affected (2).. pandemic declaratory (1). According to the. Recent estimates show that each infected Page | 476. person may infect other 2.2 people, with. illness, 5.2% had severe infection and only. case duplication rates of approximately 7. 0.6% had critical disease.. days (3). SARS-CoV-2 belongs to Corona. POTENTIAL. viridae family and Betacoronavirus genus.. INVESTIGATION To date there is no. It is a single stranded positive sense RNA. specific treatment. Antimalarial medication. virus with a spiked envelop projecting in. emerged. the viral surface (4) that mediate virus entry. strategy(4,14) but lack of efficacy and. into the cell via the Angiotensin Converter. safety. Enzyme receptor 2 (ACE 2). Its main. reported(15–17). Remdesivir has shown. tropism is for type 2 pneumocytes and. promising. ciliated cells. reports have found that 68% of patients. (5), but extrapulmonary. manifestations. such. as. diarrhea,. TREATMENTS. as. a. possible. concerns. showed. have. results.. UNDER. therapeutic. been. recently. Preliminary. improvements. in. cohort. ventilatory. lymphopenia and hepatic failure suggest. parameters, including extubation in 17 out. tropism for non-pulmonary tissues with. of 30 patients(18). Another randomized. ECA 2 receptor expression(6).. clinical trial report preliminary faster. The. vast. majority. are. recovery (11 vs. 15 days), with no impact. mild. neither mortality yet, but with a clear. of. trend(19). Interferons (mainlyβ y γ) have. patients may progress to severe disease with. been studied, but their use is limited by. pneumonia,. their. asymptomatic. or. presentations,. but. of. have. cases only. between16-17%. ARDS. or. sepsis(7,8).. adverse. reactions. Suggested mechanism involves a cytokine. Recently,. storm of factors such as interleukin (IL)-1,. Administration. IL-6, IL-8 or Tumoral necrosis factorα. convalescent plasma therapy in critically ill. (TNF-. α)(9,10).. In. patients. requiring. the. Food. profile(20). and. (FDA),. Drug approved. patients under clinical trials, given the lack. Intensive Care Unit admission, elevations of. of an effective treatment to date(21).. IL-2, IL-7, granulocyte colony stimulating. WHY MSC In this context, experimental. factor, interferon gamma induced protein. therapies such as Mesenchymal Stem Cells. 10, monocyte chemotactic protein (MCP) 1,. (MSC) have been used in critically ill. MCP1α, TNFαand D dimer have been. patients. identified (11,12). Pediatric population. modulatory activity, as it has been shown. tends. that they are capable of releasing a great. to. have. milder. symptoms.. (22)due. for. to. growth. their. Ludvigsson(13), reported that almost 90%. variety. factors. children had asymptomatic or non-severe. hepatocyte,. epidermic,. transforming. growth. immuno. such. platelet factorβ.. as and. Under. @2020 IJMSCRR All Rights Reserved (Vol 03, Issue 06 November – December) 2020 Page | 477. inflammatory stimuli, they are also capable. METHODS. of enhancing their intrinsically present. MSC-based IV therapy: Safety analysis. immuno modulatory and anti-inflammatory. A narrative literature review was made that. effects, including indoleamine dioxygenase. included systemic (intravenous or intra. (IDO). of. arterial) administration and conditions to. prostaglandin E2 (PGE2) and interleukin 10. determine safety of MSC application in. (IL-10) among other factors (23,24) that. adult humans. Efficacy endpoints were. may contribute to decrease inflammatory. excluded as they were beyond review. response and repair damaged tissue (25–. objectives. Systematic reviews and meta-. 27). For this reason, some authors have. analysis were taken into account. These. suggested its compassionate use in these. should include clinical trials in adults, both. patients (28).. genderswith any condition and in which. CELL THERAPY EFFICACY IN ARDS. MSC therapy was the intervention, no. IS STILL CONTROVERSIAL. matter the administration way. Primary and. Despite. activity,. promising. and. synthesis. results. in. several. secondary outcomes must include adverse. conditions, MSC therapy for ARDS has yet. and. to show clinical efficacy. In a study. Language was limited to English and. including 9 ARDS patients treated with. Spanish and only full texts were included.. umbilical cord MSC, mortality rate was. Study selection. 33.3%, but no infusion related adverse. At first, title exclusion was made. Abstracts. events (AE) were identified. Cytokine. and full text were then reviewed to check. profile improved in these patients (29).. for inclusion criteria. Main Mesh search. Zheng et al. and Matthay et al. had similar. terms were:(Safety [Title/Abstract]) AND. results with 12 and 60 patients treated with. Mesenchymal Stem Cells [Title/Abstract]. adipose derived and bone marrow MSC. OR. respectively, with improved inflammatory. Analysis; Systematic Reviews; Humans;. parameters, but no clinical correlation. No. Adult: 19+ years.. serious AE were reported in these studies. RESULTS. (30,31). MOTIVATION TO USE MSC Given their potential use, a safety review of the MSC therapy was made to provide evidence in different conditions, including SARS-CoV-. severe. Adult. adverse. Stem. events. reports.. Cells. Filters: Meta. 50 citations were identified. After excluding for different topics or inclusion criteria, 20 papers were left, of which 9 complied with all criteria. Included meta-analysis are summarized in table 1.. 2 sequelae.. @2020 IJMSCRR All Rights Reserved (Vol 03, Issue 06 November – December) 2020 Page | 478. Table 1. Systematic review and meta-analysis summary in safety of cellular therapy.. Author, country,. Condition.. publication date.. n studies/. Administration. participants. route/MSC source Intravenous or. Safety outcome. Conclusion. Studies showed relation between. There were no. Lalu(32) ,. Stroke,. 36studies/. Canada, 2.012.. Crohn’s. 1.012partici intra arterial. fever and MSC therapy (MD. differences in. disease,. pants. 16.82 CI 95% 5.33-23.10) but not. adverse events. myocardial. in other Adverse events (AE). between. infarction,. including acute infusional. groups, results. graft versus. toxicity, infections, death, tumor-. should provide. host disease. malignancy, cardiac, renal and. some. and healthy. gastric dysfunction.. assurance to. application.. volunteers.. researchers that this therapy appears safe.. Kim (33),. Cirrhosis. Korea, 2.015.. 14 studies/. Autologous MSC,. No study reported severe AEs, nor According to. 448. 8. statistically significant difference. these results,. participants. peripheralapplicat. in adverse events reports among. MSC are. ion, 3. groups.. considered. intrasplenic, 2. safe for. hepaticarteries y 1. chronic. portal vein.. cirrhosis.. El-Badawy(34),. Type 1 and 2. 22 studies/. 6 studies used. Only 21.72% of patients reported. Compared to. Egypt, 2.016. Diabetes. 524. hematopoietic. AEs, and no death occurred. whole organ or. Mellitus.. participants. stem cells, 5 used. during follow ups.. islet. bone marrow. transplantation. mononuclear. , MSC therapy. stemcells, 5 used. appears to be. umbilical cord. safe and. blood MSC, 2. effective for. used UCMSC, 2. type 1 and 2. Page | 479. used a. diabetes. combination of. mellitus. stem cells, 1 used. patients.. BMMSC and 1 used placental MSC. 14 used IV adminsitration. Lalu (35),. Acute. 23 studies:. 7 out 11 AMI. Acute (<24 hours) cardiac AEs. There was no. Canada, 2.018.. myocardial. 11 AMI:. studies used. were similar between groups(OR. association. infarction. 470. autologous MSC,. 3,20, CI 95% 0,70– 14,61). 3. with acute. (AMI)and. participants. 7, and 9 out of the. MSC treated patients presented. EAs. Results. ischemic. , 12 IHF:. 12 IHF studies. rhythm abnormalities, 2 AMI, 1. support MSC. heart failure. 639particip. also did. 18. vessel obstruction during. therapy safety. (IHF).. ants. studies used BM-. procedure and 1 pericardial. in AMI and. MSC, 4 used. effusion. Late onset AEs included. IHF.. umbilical cord. fever, respiratory tract infections,. MSC (UC-MSC). hematologic, cardiac,. and 1 used AD-. gastrointestinal, and neurologic. MSC. 12 studies. AEs, with only neurologic ones. used. presenting statistical significance. intracoronary. compared to controls (OR 3,79,. administration, 3. CI 95% 1,26–11,41). No details. intravenous and 4. were provided. Late AEs related. intramyocardic. 2. to therapy were infrequent.. used endocardic administration and other 2 used epicardic.. @2020 IJMSCRR All Rights Reserved (Vol 03, Issue 06 November – December) 2020 Page | 480. Lalu (36),. Cerebro-. 10 studies/. IV in 7 studies,. MSC treated patient had lower. Authors. Canada, 2.019.. Vascular. 339. intracerebral in. mortality risk compared to. conclude MSC. disease.. participants. 2and intra-arterial. controls (Peto OR 0,43; CI 95%:. therapy. in 1. 5 used. 0,20-0,90). Only fever was. appears to be. autologous MSC,. associated with MSC therapy (OR. safe, without. 4 allogenic, 1 not. 6,88; CI 95% 2,48–19,08). No. increasing AEs. reported. 7 studies. differences were found in other. other than. used BM-MSC, 2. AEs.. fever.. used UC-MSC and 1 did not report source.. Xu(37), China,. Spinal cord. 11 studies,. Intravenous and. Results showed MSC treated. Treatment. 2.019.. injury.. 449. subarachnoid.. patients had more infusion. proved safe. participants. Three studies. toxicity than control (RR: 20,34;. and effective. .. used MSC and. CI del 95%: 8,09-51,18, P. to improve. other three used. <0,001). Main EAs were fever,. sensitivity and. chondrocytes. 5. headache, back pain, tringling,. bladder. used expanded. abdominal distension, that. function. Main. cells and the other. resolved without treatment.There. AEs were mild. one was. were no severe AEs.. and related to. unexpanded.. spinal tap. No severe AEs were observed, favoring safety.. Jayaraj(38),. Advanced. 6 studies,. Intravenous,. There were no differences in. Authors. USA,. heart failure.. 569. intracoronary,. mortality risk between groups(OR. conclude MSC. participants. intramyocardic,. 0,97 CI 95% 0,52-1,78). The. therapy. .. transendocardic.. majority of studies did not report. appears safe as. Main sources. EAs during application. Authors. there was no. were BM-MSC. highlight that heterogeneity could. difference in. 2.019.. @2020 IJMSCRR All Rights Reserved (Vol 03, Issue 06 November – December) 2020 Page | 481. and UC-MSCS.. not be assessed due to low of. mortality and. Some studies just. studies.. no severe Aes. specified. were reported.. “human”. Sang(39),. Cirrhosis.. 14 RCTs,. 8 studies used IV. 4 studies did not describe AEs.. MSC therapy. China,. 717. route, 5 used. The others reported just fever for. appears to be. 2.018.. participants. hepatic artery y 1. MSC therapy, that subsided. safe as no. .. did not specify.. naturally in 24 hours.. deaths no serious Aes were reported in studies.. Thompson (40),. Cardiac,. 47studies,. Intravascular. Only fever was associated with. With this. Canada, 2.020.. neurologic,. 2.696. (arterial or. therapy (RR 2.48 CI 95% 1.27-. updated. liver,. participants. venous). 31 used. 4.86). Infection,. review, the. respiratory,. .. BMMSC, 16 used. thrombotic/embolic events and. only. renal and. UCMSC, 4 used. malignancy were no different. associated EA. hematologic. ADMSC, 2 used. among groups. Death appeared to. is fever. No. diseases.. placenta derived. be inferior in MSC treated group. other serius. MSC and 2 had. (RR 0.78 CI 0.65-0.94).. Aes appear to. unclear source.. be related.. Discussion. second. Increasing amount of evidence is emerging to back up MSC therapy safety in a wide variety of conditions, not finding serious AE related to systemic infusion. Concerning COVID 19, there is still a paucity of evidence but some case reports and preliminary data from clinical trials have emerged, showing experimental efficacy and safety in these population.. lymphopenia, neutropenia and computed. MSC evidence in COVID 19. were. The first published paper was by Liang et al.. reported no ACE 2 receptor expression by. with a case report of a 65yearold critically ill. MSC,. female patient with no previous response to. susceptible to SARS-CoV-2 infection. The. standard. same. treatment. and. multiorgan. dose,. C. reactive. protein,. tomography showed improvements (41). Preliminary reports from a Chinese clinical trial (ChiCTR2000029990) showed that all 7 patients treated with MSC (1x106cells per kilogram of body weight) improved between 1 and 4 days after receiving therapy and 3 discharged.. suggesting. trial. Additionally,. that. reported. they. authors. are. decrease. not-. in. compromise. Patient received 3 intravenous. proinflammatory cytokines such as TNFα. infusions of 5x107 cells and, and after the. whereas anti inflammatory interleukin 10. @2020 IJMSCRR All Rights Reserved (Vol 03, Issue 06 November – December) 2020 Page | 482. increased (42). A Spanish proof of concept. important to highlight that heterogeneity. study reported results of 13 COVID 19. continues to be a main issue, and strategies. patients with mechanical ventilation and no. such as longer follow up periods and AE. response to previous treatment (including. standardized reports should be adopted.. antivirals, steroids, tocilizumab) showing no. Some case reports have described worsening. treatment related adverse events and clinical. of visual impairment in advanced macular. improvements in 70% of patients after the. degeneration(47)and. first dose (43). No author reported treatment. calcification. related adverse events. Sample sizes are still. (48).These infrequent reactions need to be. small to accurately inform about MSC safety. assessed with larger samples that allow. profile, but preliminary data is encouraging. identification of uncommon manifestations.. in. this. Regarding late AEs and malignancy risk,. population. As showed by Zhao et al., MSC. most of the studies report follow ups of 3. therapy in pulmonary diseases also appears. years or less, without reporting tumor. to be safe (44), thus encouraging its use as. formation. Fehringeret al. published reports. research product.. from a cohort with a follow up of de 12,5. Systematic review and meta-analysis evidence. years without finding increased risk of. discussion. tumor formation. Related to cell harvesting, studies show. therapy(49). Nevertheless, as recommended. autologous source may produce pain and. Volare Vic et al. in their review,it is. slightly increase infection risk. In this. important to keep reporting long term follow. context, sources as placenta or umbilical. up data to confirm these findings(50).. cord may have advantages as they are. CONCLUSION. usually discard tissues posing no risks for. Based on evidence reported in systematic. the patient(45). MSC may be applied locally. reviews, meta-analysis and clinical trials. or systemically, with different expected. including systemic or locally applied MSC,. adverse. this therapy appears to be safe in different. both. safety. and. reactions.. systemically,. meta. efficacy. When analysis. in. applied shows. myocardial. injuries. after. after. MSC. use. receiving MSC. no. conditions and situations and could prove a. increased risk of severe AE, with just mild. useful strategy for COVID 19 patients given. symptoms as fever arising from therapy and,. their immuno modulatory properties. While. in general, being the only statistically. more data is necessary to accurately define. significant associated AE. Authors agree. safety in this condition, future clinical trials. that therapy is in general safe. This. (56. conclusion is similar to that of Betemanet al.. clinicaltrials.gov. clinical. trials. were. under. registered COVID. in and. (46)in their MSC safety review. It is @2020 IJMSCRR All Rights Reserved (Vol 03, Issue 06 November – December) 2020 Page | 483. “mesenchymal” terms as of the writing date. pathogenesis of the emerging human. of this review) will contribute valuable. pathogenic coronaviruses SARS‐CoV,. safety and efficacy information for these. MERS‐CoV, and 2019‐nCoV. 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