A Role for MSC to Treat Coronavirus Patients. Part 2: Fibrosis in Survivors

Author: Frances Verter, PhD

Introduction

Currently there is a great deal of enthusiasm in the stem cell industry about the potential of mesenchymal stromal cells (MSC) to treat the respiratory complications of patients that are acutely sick with COVID-19^1-9.  Since the pandemic started, dozens of new clinical trials have been registered which will employ MSC to treat the COVID-19 diagnoses of pneumonia or Acute Respiratory Distress Syndrome (ARDS)¹⁰. Companies that manufacture MSC products are splitting their writing efforts between FDA IND’s for clinical trials, FDA Emergency Use Authorizations (EUA), and press releases, in various proportions¹¹.

We suggest that a more successful role for MSC may not be the acute phase of COVID-19 illness, but the later phase of helping survivors to recover full lung function. Although COVID-19 is a new type of viral illness¹², evidence is accumulating that some survivors of COVID-19 have significant scarring of their lungs that is called fibrosis. Coronavirus survivors may have fibrosis either as a result of the disease itself or from the disease compounded by the use of ventilators to assist their breathing.  We suggest that treating COVID-19 survivors for lung fibrosis in outpatient clinics might be a more feasible and effective application of MSC on behalf of COVID-19 patients.

In the remainder of this blog, we go over the evidence for fibrosis in COVID-19 survivors, we explain the fibrosis paradox encountered during ventilator assisted breathing, we explore the preclinical evidence that MSC can treat pulmonary fibrosis, we review previous clinical trials and publications that used MSC therapy to treat pulmonary fibrosis, we examine the practical considerations of designing MSC therapy for COVID-19 patients, and finally we conclude with a call to action.

Survivor Stories

Photo of James Cai from MedPage Today

James Cai is a physician assistant who had the misfortune of being the first patient in New Jersey to test positive for COVID-19. The story of his experiences at the Hackensack University Medical Center was first broken by MedPage Today¹³, and fully chronicled in the New York Times¹⁴.  When he was first admitted to the hospital, a CT scan of Cai’s lungs showed an area of shading that radiologists describe as “ground glass opacity”. We now know that this is a characteristic feature of the lung CT scans of COVID-19 patients^15,16. When Cai had a repeat CT scan five days later, the opacities had proliferated so rapidly that he had lost nearly 40% of his lung function.

James Cai managed to survive COVID-19 without being intubated on a mechanical ventilator. But when he was finally discharged after 20 days in the hospital, he went home on oxygen. "I have my fingers crossed that my lungs will come back," Cai told the NY Post in a text message because he was too weak to speak on the phone …. Cai said that there’s a chance that lung fibrosis could cause problems for him in the future. His doctors are unable to tell him whether his damaged lungs will ever recover¹⁷.

This type of story, where a patient survives COVID-19 but is left debilitated by lung fibrosis, is not rare. Another high profile patient with a similar experience is the lawyer David Lat, who wrote about the aftermath of his six days on a ventilator for the Washington Post¹⁸. “I used to run marathons; now I can’t walk across a room or up a flight of stairs without getting winded.” Another survivor, Fiona Lowenstein, started an online support group for COVID-19 patients. She says, “A wave of chronically ill and slow-healing survivors is an inevitability we can and must prepare ourselves for.”¹⁹

Ventilator Induced Lung Injury and “The Fibrosis Paradox”

Since the start of the coronavirus pandemic, we have been hearing endless news reports about the desperate need for more ventilators to treat patients experiencing respiratory distress from COVID-19²⁰.  Ironically, the same ventilators that save lives also cause lung damage²¹. “Mechanical ventilation is the most important supportive therapy for patients with ARDS, but it can induce or aggravate lung injury—an entity referred to as ventilator-induced lung injury (VILI).”²²

A research group in Toronto, Canada, coined the phrase “the fibrosis paradox” to describe the conflicting demands of treating patients with Acute Respiratory Distress Syndrome (ARDS). The condition ARDS presents with a mixture of changes to the lining of the lungs, which may or may not include fibrosis. Patients with ARDS often require breathing assistance from a mechanical ventilator. The more fibrosis that patients have, the more prolonged their time on the mechanical ventilator, which leads to more fibrosis from VILI.  “Many patients with ARDS survive the acute phase, but subsequently go on to die, often with evidence of significant pulmonary fibrosis”²².  Studies of ARDS patients find that the presence of fibrosis correlates with poor outcomes^22-24.

MSC Can Help Heal Lung Injuries in Animals

Can MSC therapy break the cycle of the fibrosis paradox?  When MSC are delivered intravenously, they are trapped quickly in the lungs^25,26. The hope is that MSC can attenuate the cytokine storm in the lungs, mitigate inflammation, and induce the lining of the lungs to heal without fibrotic scarring. Any form of lung inflammation can lead to fibrosis, whether the inflammation starts with an acute lung injury such as pneumonia and ARDS, or is caused by a chronic lung condition such as COPD and asthma²⁷. Regardless of the cause of inflammation, “inappropriate immune response and/or aberrant repair process causes irreversible damage in lung tissue and most usually results in the development of fibrosis”.²⁷

Numerous studies have shown that in animal models of lung disease, MSC therapy yields a statistically significant benefit against controls. Both mice and sheep with pneumonia had a significant benefit from MSC therapy^28,29. Several sources of MSC can improve lung function in rodents with ARDS^27,30-34. A meta-analysis of 21 experiments found that treatment with MSC (of any origin) significantly improved survival in animal models of ARDS³⁰. One animal study of ARDS published in 2019 also noted a promising decrease in fibrosis³⁴. Finally, MSC can significantly enhance recovery from VILI in rodents^35,36.  One study notably found that MSC were beneficial even if there was a delay between the injury and the cell therapy³⁶.  This suggests that the mechanism of the MSC therapy is not solely anti-inflammatory. “The finding that MSCs are effective at later time points enhances their therapeutic potential, in that it is rarely feasible to administer a therapy in the clinical setting in the earliest stages after the injurious event has occurred.”³⁶

Previous Cell Therapy Trials and Publications Treating Fibrosis in Humans

Going through the archives of CellTrials.org, we have found 12 trials from the years 2011 to 2019 that employed cell therapy to treat a pulmonary disorder which is dominated by fibrosis. We were able to find five publications corresponding to these trials and one relevant publication that did not cite a trial³⁷: four papers tested MSC for idiopathic pulmonary fibrosis^37-39,42, one paper tested MSC for radiation-induced fibrosis⁴⁰, and one paper tested MSC for bronchiolitis obliterans after a stem cell transplant⁴¹.  

Most of these prior publications were not able to establish that MSC therapy has a statistically significant efficacy for pulmonary fibrosis^37-41. To be fair, these fibrosis studies suffered from the same weakness we saw in our blog about MSC therapy for ARDS: patient groups were not large enough to power the study to determine efficacy¹⁰.  One study in Moscow that showed a statistically significant improvement, for idiopathic pulmonary fibrosis (IPF), achieved that result by giving repeated doses of 200 million MSC, up to a cumulative dose of 1.6 billion cells⁴².  The ability to give repeated doses of MSC over a prolonged period of time was crucial to their success; at the 3 month point their patient response was very similar to a previous IPF study in Miami, and it was only at the end of a year that they could demonstrate that MSC patients had improved while placebo patients continued to decline^39,42.

Pulmonary fibrosis in survivors of COVID-19 is a new diagnosis and these previous studies may not be relevant. Idiopathic pulmonary fibrosis has received the most research because it is the most commonly occurring form of scarring in the lungs^43,44.  But IPF is called “idiopathic” precisely because it does not follow the standard pathway from lung inflammation to fibrosis^45,46. Instead, IPF results when a patient that has a genetic susceptibility is subjected to environmental triggers that cause the epithelial cells and fibroblasts in the lungs to become overactive⁴⁶. Hence, IPF has a distinctly different pathogenesis from fibrosis that is induced by viral illness, and the previous clinical trials of MSC for IPF are not predictive of how MSC might benefit COVID-19 survivors.

Practical Considerations

Coronavirus survivors that Google the keywords “pulmonary fibrosis” will be horrified to find numerous search results predicting an average survival of 3-5 years after diagnosis.  This is misleading, because that statistic is for idiopathic pulmonary fibrosis^43-46.  The various websites about lung disorders need to update their educational materials to reflect the fact that the prognosis for fibrosis post-COVID-19 is unknown. Survivors should not receive a default message that their fibrosis is a death sentence.

There is a public health need for clinical trials that specifically target the pulmonary fibrosis induced by COVID-19. This is a whole new ballgame, as the saying goes, although the previous pre-clinical and clinical studies of MSC therapy do provide some guidelines. We know from preclinical animal studies that there are mechanisms of action by which MSC can be therapeutic for both acute and chronic lung injury. We know from prior clinical trials for other pulmonary conditions that the safety of intravenous MSC is well established, including the safety of high doses and multiple doses. To our knowledge, only one cell and gene therapy trial has launched so far that targets fibrosis in COVID-19 survivors: Healeon Medical of Montana registered NCT04326036 on 30 March 2020.

We believe that the manufacturers of MSC products and the clinics that provide MSC therapy should mobilize trials for COVID-19 fibrosis as enthusiastically as they have tackled COVID-19 ARDS. Whereas studies of MSC therapy for the acute phase of COVID-19 infection require immediate access to patients that are hospitalized on ventilators, the treatment of fibrosis in COVID-19 survivors can be conducted over time in an outpatient setting. Nearly every aspect of conducting a clinical trial with MSC is more feasible for survivor fibrosis, as we have outlined in the table below.

Conclusions

We see a new opportunity for MSC therapy: treating COVID-19 survivors for lung fibrosis in outpatient clinics. This environment affords the opportunity to give patients multiple doses of MSC over time and to collect detailed records of lung function performance.  So far most of the stem cell industry has been designing treatments for patients that are acutely sick with COVID-19. But access to acute COVID-19 patients in hospitals is complex and there are many confounding effects going on at the same time, which make it difficult to deliver MSC therapy or to measure the impact of the MSC therapy. As the first wave of this pandemic passes, there is a growing awareness that many COVID-19 survivors are suffering from prolonged sequelae, including pulmonary fibrosis. It is our hope that more hospitals and clinics will take up our suggestion to develop treatment programs for COVID-19 survivors.

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. Williams R. Are Mesenchymal Stem Cells a Promising Treatment for COVID-19? The Scientist 2020-04-09
• 8. 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
• 9. Turner L. Preying on Public Fears and Anxieties in a Pandemic: Businesses Selling Unproven and Unlicensed “Stem Cell Treatments” for COVID-19. Cell Stem Cell 2020; PREPRINT available 2020-05-07
• 10. Verter F. The Role of MSC to Treat Coronavirus Pneumonia and ARDS. Part 1: Is the Emperor Wearing Clothes? CellTrials.org Blog 2020-04-26
• 11. CellTrials.org Team. Cell Therapy Companies Making Media Claims to Treat COVID-19. CellTrials.org Blog 2020-04-29
• 12. USA Center for Disease Control and Prevention (CDC) > Coronavirus Disease 2019 (COVID-19) > CDC’s Response > Situation Summary web page sourced 2020-05-05
• 13. Fiore K. Physician Assistant With COVID-19 Speaks Out — "I don't know how many days I can last". MedPage Today 2020-03-10
• 14. Dominus S. How New Jersey’s First Coronavirus Patient Survived. NYTimes Magazine 2020-04-05
• 15. Pan Y, Guan H, Zhou S, et al. Initial CT findings and temporal changes in patients with the novel coronavirus pneumonia (2019-nCoV): a study of 63 patients in Wuhan, China. Eur Radiology 020; 2020:1–4.
• 16. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020; 323(11):1061-1069.
• 17. Salo J. New Jersey’s first coronavirus patient released from hospital on oxygen. New York Post 2020-03-22
• 18. Lat D. I spent six days on a ventilator with covid-19. It saved me, but my life is not the same. Washington Post 2020-04-09
• 19. Lowenstein F. We Need to Talk About What Coronavirus Recoveries Look Like. NYTimes 2020-04-13
• 20. Begley S. New analysis recommends less reliance on ventilators to treat coronavirus patients. STAT 2020-04-21
• 21. Slutsky AA, and Ranieri VM. Ventilator-Induced Lung Injury. NEJM 2013; 369:2126-2136.
• 22. Cabrera-Benitez NE, Laffey JG, Parotto M,  Spieth PM, Villar J, Zhang H, and Slutsky AS. Mechanical Ventilation–associated Lung Fibrosis in Acute Respiratory Distress Syndrome A Significant Contributor to Poor Outcome. Anesthesiology 2014; 121(1):189–198.
• 23. Meduri GU, Headley S, Kohler G et al. Persistent Elevation of Inflammatory Cytokines Predicts a Poor Outcome in ARDS: Plasma IL-1β and IL-6 Levels Are Consistent and Efficient Predictors of Outcome Over Time. Chest 1995; 107(4):1062-1073.
• 24. Ichikado K, MuranakaH, Gushima Y, et al. Fibroproliferative changes on high-resolution CT in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study. BMJ Open 2012; 2:e000545. 
• 25. Harting MT, Jimenez F, Xue H, et al. Intravenous mesenchymal stem cell therapy for traumatic brain injury. J Neurosurg. 2009; 110(6):1189-97.
• 26. Park SE, Lee NK, Lee J, et al. Distribution of human umbilical cord blood-derived mesenchymal stem cells in the Alzheimer's disease transgenic mouse after a single intravenous injection. Neuroreport. 2016; 27(4):235-41.
• 27. 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; 2019:423697.
• 28. Gupta N, Krasnodembskaya A, Kapetanaki M, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax 2012; 67(6):533-539.
• 29. Asmussen S, Ito H, Traber DL, et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax 2014; 69(9):819-25.
• 30. McIntyre LA, Moher D, Fergusson DA, et al. Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review. PLoS One. 2016; 11(1): e0147170.
• 31. Curley GF, Jerkic M, Dixon S, et al. Cryopreserved, Xeno-Free Human Umbilical Cord Mesenchymal Stromal Cells Reduce Lung Injury Severity and Bacterial Burden in Rodent Escherichia coli–Induced Acute Respiratory Distress Syndrome. Critical Care Medicine 2017; 45(2):e202-e212.
• 32. Silva JD,  Lopes-Pacheco M, Paz AHR, et al. Mesenchymal Stem Cells From Bone Marrow, Adipose Tissue, and Lung Tissue Differentially Mitigate Lung and Distal Organ Damage in Experimental Acute Respiratory Distress Syndrome. Critical Care Medicine 2018; 46(2):e132-e140.
• 33. He H-L, Liu L, C Q-H, et al. MSCs Modified With ACE2 Restore Endothelial Function Following LPS Challenge by Inhibiting the Activation of RAS. J Cellular Phsiology 2015; 230:691-701.
• 34. Jung YJ, Park YY, Huh JW, and Hong SB. The effect of human adipose-derived stem cells on lipopolysaccharide-induced acute respiratory distress syndrome in mice. Ann. Transl. Med. 2019; 7(22):674.
• 35. Hayes M, Masterson C, Devaney J, et al. Therapeutic Efficacy of Human Mesenchymal Stromal Cells in the Repair of Established Ventilator-induced Lung Injury in the Rat. Anesthesiology 2015; 122:363-373.
• 36. Hayes M, Curley GF, Masterson C, et al.  Mesenchymal stromal cells are more effective than the MSC secretome in diminishing injury and enhancing recovery following ventilator-induced lung injury. Intensive Care Med. Exp. 2015; 3:29
• 37. Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J. Transl. Med. 2013; 11:171
• 38. Chambers DC, Enever D, Ilic N, et al. A phase 1b study of placenta‐derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology 2014; 19(7):1013-1018.
• 39. Glassberg MK, Minkiewicz J, Toonkel RL, et al. Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial. Chest 2017; 151(5):971-981.
• 40. Qiao Z, Zhang D, and Xiong W. Efficacy and safety of clinical-grade umbilical cord mesenchymal stem cell therapy for treatment of radiation-induced pulmonary fibrosis: analysis of 8 cases. J. Third Military Medical Univ. 2017; 39(10):1013-1018.
• 41. Chen S, Zhao K, Lin R, et al. The efficacy of mesenchymal stem cells in bronchiolitis obliterans syndrome after allogeneic HSCT: A multicenter prospective cohort study. EBioMedicine 2019; 49:213-222.
• 42. Averyanov A, Koroleva I, Konoplyannikov M, et al. First‐in‐human high‐cumulative‐dose stem cell therapy in idiopathic pulmonary fibrosis with rapid lung function decline. Stem Cells Trans. Med. 2020; 9(1):6-16.
• 43. American Lung Association. Here's a look at some of the different categories of PF. web page accessed 2020-05-23
• 44. Malcolm E. 12 Facts About Pulmonary Fibrosis Prognosis and Life Expectancy. Pulmonary Fibrosis News 2019-08-16
• 45. King Jr TE, Pardo A, and Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378(9807):1949-1961.
• 46. Kropski JA, and Blackwell TS. Progress in Understanding and Treating Idiopathic Pulmonary Fibrosis. Annual Review of Medicine 2019; 70:211-224.