The Role of MSC to Treat Coronavirus Pneumonia and ARDS. Part 1: Is the Emperor Wearing Clothes?

Author: Frances Verter, PhD

Introduction

Since the novel coronavirus COVID-19 emerged, everyone in the stem cell industry has been trying to find a way to treat it with stem cells. That is only natural, a combination of applying our industry expertise towards a pressing public health need, plus enlightened self-interest.

Quite a few articles in journals and blogs have discussed the possibility that mesenchymal stromal cells (MSC) might be used to treat the respiratory complications of COVID-19, which include pneumonia and Acute Respiratory Distress Syndrome (ARDS)^1-10.  Years of research have clearly established that MSC are anti-inflammatory and immune-modulatory, so it makes sense that MSC could be beneficial to treat the lung inflammation and cytokine storm caused by COVID-19^11-14.

The idea to treat lung injury with MSC is not new. At CellTrials.org, our database of cell therapy clinical trials shows there were 112 trials for various pulmonary disorders (not including lung cancer) over the years 2011-2019, and 88 (79%) of those trials employed some form of MSC. Our new CellTrials.org database of COVID-19 clinical trials shows that as of 15 April 2020, 44 cell therapy trials have been registered and 70% of them employ some form of MSC.

But, when we delved deeper into the previous research that employed MSC to treat the acute lung injury ARDS, we were dismayed to find that none of the published trial results showed a conclusive benefit from the cell therapy.  Every trial was able to demonstrate the safety of MSC administration, but none was able to demonstrate statistically significant efficacy.

Numerous companies that perform regenerative medicine with MSC are rushing to apply for Emergency Use Authorizations (EUA) from the FDA¹⁵, mostly on the premise that MSC can save COVID-19 patients on ventilators, when there is no hard data to support this belief. It reminds us of the children’s book, “The Emperor’s New Clothes”, where in fact the Emperor is naked, but nobody wants to admit it.

In the remainder of this article we will summarize what we know so far about the pulmonary complications of COVID-19, present the results from published trials of MSC for ARDS, explain why it is so difficult to demonstrate efficacy for ARDS, and conclude with our outlook for the future.

Pulmonary Complications of COVID-19

Diagram from USA Today: A visual guide of coronavirus infection

The novel coronavirus COVID-19 has over 90% genetic similarity to the bat virus that causes SARS^16,17.  Hence it is believed that COVID-19 is a zoonotic virus that originated in bats and crossed over into humans sometime in late 2019 in central China. Like SARS, COVID-19 is notorious for attacking the patient’s lungs. The characteristic symptoms of COVID-19 are fever and dry cough. If it progresses beyond the patient’s upper airways and gets deeper into the lungs, patients will develop pneumonia. Critically ill patients develop a condition called Acute Respiratory Distress Syndrome, or ARDS.

In Feb. 2020, The Chinese Center for Disease Control and Prevention published a report on 72,314 confirmed cases of COVID-19 during the first wave of infection in China, and sorted the cases into these three groups of severity¹⁸:

• 81% uncomplicated: patients can recuperate without medical intervention.
• 14% severe: patients require oxygen support.
• 5% critical: patients require assisted ventilation.

The same report from the Chinese CDC concluded that the overall fatality rate of COVID-19 is 2.3%, about 20 times more deadly than the seasonal flu, which has a fatality rate of about 0.1%¹⁹.

However, more recent research casts doubt on the relative sizes of these patient groups. Systematic surveys of COVID-19 in entire populations are starting to report that the confirmed COVID-19 patients are the tip of the iceberg.  The fraction of patients that were asymptomatic was 43% in one town in Italy²⁰, and so far the fraction of patients that are not detected (this is not the same as asymptomatic) is around 90% in Iceland²¹. In addition, there is a sub-group of COVID-19 patients that present with digestive symptoms only, without respiratory symptoms²².  All of these emerging discoveries make it impossible to accurately forecast what fraction of COVID-19 patients will have severe respiratory symptoms that require breathing support.

Nonetheless, regardless of what exact fraction of patients are critical, we know from experience that the first wave of COVID-19 infection in the United States overwhelmed the hospitals in New York City, and in those hospitals 88% of COVID-19 patients that were placed on ventilators died²³.  Thus, it is common sense that any cell therapy intervention that can provide a benefit to the fraction of COVID-19 patients that are critical will help save lives.

Looking at those COVID-19 patients that required hospitalization, a paper that reviewed all cases in two hospitals in Wuhan, China, found that 31% of COVID-19 patients experienced a cascade of pulmonary complications known as ARDS²⁴. Among the patients that died, the incidence of ARDS was 93%.  Data like this has led many researchers to believe that treating ARDS is crucial to improving the survival of COVID-19 patients.

Results of previous MSC clinical trials for ARDS

Over the years 2011-2019, CellTrials.org found that 16 clinical trials were registered worldwide that treated ARDS with cell therapy, and all of them employed some form of MSC. In this Table we have summarized those trials and their publications. Among these 16 trials, 7 have completed and 5 have published. Below we briefly describe the outcome of each trial.

The company Athersys has obtained FDA Fast Track designation to treat ARDS with their product MultiStem® that contains bone marrow MSC²⁵.  This achievement was based on the results of a phase 2 randomized, controlled, double-blind clinical trial NCT02611609 that enrolled 36 patients. While the results of this trial have been described on-line²⁶, their statistical significance has not been revealed, a fact that has been a source of controversy¹⁰. Currently, the Athersys collaborator in Japan, Healios K.K., is recruiting patients for a similar phase 2 trial NCT03807804 that plans to recruit 30 patients. The registration data for the ongoing trial says that patients will receive a single intravenous dose of 900 million cells. 

A group at Shaoxing Second Hospital in China published a paper in 2014, which they claimed was the first clinical study of MSC for ARDS²⁷. Their trial NCT01902082 enrolled 12 patients with ARDS into a randomized controlled study. The patients received one infusion of allogeneic adipose MSC, at a dose of 1 million cells/kg. The administration of MSC was safe and feasible but the authors admitted that the clinical effect was “weak”.

In 2015, a group at Karolinska University Hospital in Sweden published 2 case reports that appear to be from trial NCT02215811²⁸. The trial was designed to recruit 10 patients and currently has status Unknown. The 2 cases reported had severe ARDS and were receiving extracorporeal membrane oxygenation (ECMO). The MSC dose was 2 million cells/kg; it was derived from allogeneic bone marrow and divided into 4 infusions. Both patients recovered.

A trial that launched in 2014 to treat patients with ARDS induced by the H7N9 bird flu was just accepted for publication in Feb 2020²⁹. This trial NCT02095444 at the First Affiliated Hospital of Zhejiang University in China enrolled 17 patients to receive allogeneic MSC from menstrual blood, and compared them retrospectively to 44 control patients. The MSC infusion dose was 1 million cells/kg, but the treatment regimen differed across the study in terms of when the MSC were delivered and how many doses were given. The primary outcome measure of this study was that survival was higher in the MSC treatment group²⁹.  A recent paper from the MSC committee of the International Society of Cell & Gene Therapy (ISCT) criticized this study for not providing data on lung performance measures⁹.

The leading team investigating the use of MSC to treat ARDS is led by Michael Matthay, MD, at the University of California in San Francisco. They have completed a phase 1 trial NCT01775774 that enrolled 9 patients, completed a phase 2 trial NCT02097641 that enrolled 60 patients, and in January 2019 they launched a phase 2, multi-center, randomized, controlled, double-blind trial NCT03818854 that plans to recruit 120 patients. These studies have been supported by a consortium of research grants from several US federal agencies. The work by this group is the most scientifically relevant because they have run the most trials, treated the most patients, and published the most detailed analyses of the patient recruitment and outcomes.

Yet even the previous trials by the Matthay group could not establish the efficacy of MSC for ARDS^30,31.  After escalating their dose in the phase 1 trial, the patients in the phase 2 trials receive a single infusion of allogeneic bone marrow MSC at a dose of 10 million cells/kg. The published phase 2 trial screened 1038 patients and found 60 eligible; 40 patients received MSC and 20 received a placebo. They aimed to give the MSC therapy to patients in the exudative phase of ARDS (the only study that made this distinction). Most of the outcome measures that are important for this type of study, like the number of ventilator-free days, positive end-expiratory pressure (PEEP), and other lung function measurements, were not significantly different between the two groups. Sadly, after performing the treatments, the investigators discovered that the viability of their MSC was highly variable, a classic case where the manufacturing aspect of a trial impairs the clinical results.

We suspect that previous controlled trials of MSC for ARDS failed to demonstrate efficacy because they did not accrue enough patients to have the statistical power to reach a clear verdict. The largest study of MSC for ARDS completed so far is the 60 patients in the second publication from the Matthay group³¹.  Going forward, bigger trials of MSC for ARDS are in progress, such as the second phase 2 trial from Matthay’s group NCT03818854 which plans to enroll 120 patients. In the UK, a 2017 trial NCT03042143 of umbilical cord MSC for 75 ARDS patients has been rebranded as a COVID-19 trial, which enabled it to garner designation as a national urgent public health study³².  Athersys has received FDA permission for a new trial (not registered yet) that will be phase 2/3 and plans to enroll 400 patients at multiple centers³³. For comparison, a 2009 review article about ARDS mortality collected 89 ARDS studies in which the median sample size was 134 patients³⁴. 

The elusive goal of improving ARDS survival

Diagram from MedPage Today: COVID-19: Not Your Typical ARDS? 

There is a huge medical literature on ARDS, and some researchers have dedicated their entire careers to seeking better outcomes for patients with ARDS. Despite this effort, for the past two decades the pooled mortality of patients with ARDS has remained at 44%^34,35. This is the mortality rate when patients receive expert care in studies. Cell therapy companies that want to do battle against ARDS during a pandemic, armed with MSC, need to appreciate that the enemy is a complex beast.

During ARDS, damage to the lining of the lungs goes through three phases: Exudative, Proliferative, and Fibrotic^36,37.  However, these phases represent a continuum and not a chronology³⁷. Each patient diagnosed with ARDS may present with differing mixtures of these three phases.

The clinical management of ARDS differs depending on whether the underlying cause is a direct insult to the lungs, such as pneumonia, versus an indirect cause such as sepsis³⁶.  Breaking news comes from critical care doctors who report that many COVID-19 patients exhibit an unusual form of ARDS that differs from the standard combination of symptoms seen in severe pneumonia^38,39.  There are now calls to develop new protocols guiding the use of ventilators for COVID-19 patients³⁹.

Given that ARDS is a complex disorder, and that ARDS induced by COVID-19 is a new phenomenon, it will be challenging to demonstrate clinical efficacy with any intervention for COVID-19 ARDS. Patients that go onto ventilators may fall on different parts of the spectrum of ARDS phases, and they may have multiple comorbidities. In order to know whether an intervention is effective, the patients have to be carefully sorted so that intervention versus control is compared for patients that are matched on all other factors.  

Conclusions

We share the community hope that MSC will play a useful role in treating the respiratory complications from COVID-19. But as the scientists that manage CellTrials.org, the most complete database of cell therapy clinical trials, we have an ethical responsibility to point out that the past performance of MSC in this arena is being hyped by most of the companies that are proposing to offer MSC therapy for COVID-19.

The five published clinical trials of MSC therapy for ARDS were not able to establish statistically significant efficacy. Another six trials of MSC therapy for ARDS that were registered before the COVID-19 pandemic are currently recruiting.

Since the start of the COVID-19 pandemic through 15 April 2020, our CellTrials.org database of registered COVID-19 clinical trials counts 44 cell therapy trials, and 31 (70%) of them employ some form of MSC. Due to the speed with which investigators are launching COVID-19 trials, the trial descriptions may have been written in haste, and we have to be cautious not to over-interpret them. With that caveat, we find that 4 of the MSC trials have already been withdrawn, 21 MSC trials state that they will treat pneumonia, 5 MSC trials indicate they will treat ARDS, and 1 trial is tracking MSC impact on viral titers. The 5 new MSC trials for ARDS registered as of 15 April 2020 have a mean target enrollment of 41 patients (range from 16 to 60) and will take place in China, France, Denmark, and the United States.

What can we forecast about the outcomes of the many MSC trials for COVID-19 pneumonia? We can confidently predict that extravagant claims will be made in press releases: "100% of a handful of patients who received MSC survived!" But without control groups, and without statistical significance, such claims are scientifically meaningless.

The magnitude of the COVID-19 pandemic offers an opportunity to give MSC therapy to large numbers of patients with pneumonia or ARDS. But if that therapy is offered to everybody as a compassionate use with no control groups, which has been called for on a humanitarian basis⁴, it will be very difficult to interpret the outcomes. We anticipate that researchers may have to conduct retrospective studies of hospital records to tease out the statistical significance of MSC impact on lung function measurements in COVID-19 patients. We hope that these efforts are successful.

References:

1. Liang B, Chen J, Li T, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells. ChinaXiv preprint server 2020-02-27
2. Knoepfler P. ‘We Cannot Stick to the Rules’: claims of stem cells saving COVID-19 patients. THE NICHE 2020-03-03
3. Lim M. Can MSCs Treat Patients with COVID-19? RoosterBio Blog 2020-03-18
4. Atluri S, Manchikanti L, and Hirsch JA. Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use. Pain Physician (accepted 2020-03-20) 2020; 23(2):E71-E83.
5. Hildreth C. MSCs, The Most Suitable Cells for COVID-19? BioInformant blog 2020-03-22
6. Brown K. and Skiles M. Wondering why there are so many stories in the news about stem cells and COVID-19 respiratory conditions? The CBR Blog 2020-03-31
7. Lim M, Carson J, and Rowley JA. hMSCs: A Secret(ome) Weapon Against ARDS RoosterBio Blog 2020-04-03
8. Williams R. Are Mesenchymal Stem Cells a Promising Treatment for COVID-19? The Scientist 2020-04-09
9. Khoury M, Rocco PRM, Phinney DG, et al. Cell-Based Therapies for COVID-19: Proper Clinical Investigations are Essential. Cytotherapy (accepted 2020-04-13) 2020; PREPRINT
10. Feuerstein A. Athersys pivots a stem cell therapy to Covid-19, but prior data offer little confidence. STAT 2020-04-14
11. Nauta AJ and Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110(10):3499-506.
12. Caplan AI and Correa D. The MSC: an injury drugstore. Cell Stem Cell 2011; 9(1):11-5.
13. Aernardo ME, and Fibbe WE. Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation. Cell Stem Cell 2013; 13(4):392–402.
14. Harrell CR, Sadikot R, Pascual J, Fellabaum C, Jankovic MG, Jovicic N, Djonov V, Arsenijevic N, and Volarevic V. Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives. Stem Cells International 2019; 2019:4236973
15. FDA. Emergency Use Authorizations. web page
16. Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579:270-273.
17. Paraskevis D, Kostaki EG, Magiorkinis G, Panayiotakopoulos G, Sourvinos G, and Tsiodras S. Full-genome evolutionary analysis of the novel corona virus (2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event. Infection, Genetics and Evolution 2020; 79:104212
18. Wu Z, and McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China; Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020; 323(13):1239-42.
19. USA Center for Disease Control and Prevention (CDC) Disease Burden of Influenza web page sourced 2020-04-01
20. Lavezzo E, Franchin E, Ciavarella C, et al. Suppression of COVID-19  outbreak in the municipality of Vo', Italy. PREPRINT 2020;
21. Stock JH, Aspelund KM, Droste M, and Walker CD. Estimates of the Undetected Rate among the SARS-CoV-2 Infected using Testing Data from Iceland. PREPRINT 2020;
22. Han C, Duan C, Zhang S, et al. Digestive Symptoms in COVID-19 Patients with Mild Disease Severity: Clinical Presentation, Stool Viral RNA Testing, and Outcomes. Amer. J. Gastroenterology 2020; 115(4):preprint
23. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020;
24. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study The Lancet 2020; 395(10229):1054-1062.
25. Athersys. Athersys Announces Fast Track Designation From FDA for MultiStem® Program for Acute Respiratory Distress Syndrome. Press Release 2019-05-14
26. Athersys. COVID-19 and other Viral Induced ARDS. web page sourced 2020-04-23
27. Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respiratory Research 2014; 15:39
28. Simonson OE, Mougiakakos D, Heldring N, et al. In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome. Stem Cells Translational Med. 2015; 4(10):1199-1213.
29. Chen J, Hu C, Chen L, et al. Clinical Study of Mesenchymal Stem Cell Treatment for Acute Respiratory Distress Syndrome Induced by Epidemic Influenza A (H7N9) Infection: A Hint for COVID-19 Treatment. Engineering 2020; IN_PRESS
30. Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Resp. Med. 2015; 3(1):24-32.
31. Matthay MA, Calfee CS, Zhuo H, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomized phase 2a safety trial. Lancet Respiratory Med 2019; 7(2):154-162.
32. Hospital Healthcare Europe. REALIST COVID-19 trial initiated. Newsletter 2020-04-07
33. Athersys.  FDA Authorizes Athersys to Initiate a Pivotal Clinical Trial Evaluating MultiStem® Cell Therapy in Patients With COVID-19 Induced Acute Respiratory Distress Syndrome. Press Release 2020-04-13
34. Phua J, Badia JR, Adhikari NK, et al.  Has Mortality from Acute Respiratory Distress Syndrome Decreased over Time? A Systematic Review Am. J. Resp. Crit. Care Med. 2009; 179(3):220-227.
35. Zambon M, and Vincent J-L. Mortality Rates for Patients With Acute Lung Injury/ARDS Have Decreased Over Time. Chest 2008; 133(5):1120-1127.
36. Kenny JES. An Illustrated Guide to the Phases of ARDS: Implications for management. PulmCCM 2017-08-30
37. Butt Y, Kurdowska A, and Allen TC. Acute Lung Injury: A Clinical and Molecular Review. Archives of Pathology & Lab. Med. 2016; 140(4):345-350.
38. Fiore K. COVID-19: Not Your Typical ARDS? MedPage Today 2020-04-20
39. Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Medicine Editorial 2020-04-14