Reports of 83% survival in ventilator-dependent COVID-19 patients following mesenchymal stem cell therapy
Australian stem cell company Mesoblast Ltd. announced an 83% survival rate in ventilator-dependent COVID-19 patients with moderate to severe acute respiratory distress syndrome (ARDS) treated at New York’s Mount Sinai Hospital with allogeneic mesenchymal stem cells.
Nine of the 12 treated patients (75%) have successfully come off ventilator support within 10 days following two infusions of remestemcel-L.
“Once you’re ventilated when you have acute respiratory distress syndrome in the lungs, your likelihood of coming off a ventilator is 9%, and your survival is 12%,” Mesoblast CEO Silviu Itescu told BioWorld.
In contrast, only 9%, or 38 of 445 ventilator-dependent COVID-19 patients at a major hospital network in New York were able to come off ventilator support when treated with standard of care during the same March to April period.
Moreover, there was 88% mortality with only 12% survival (38/320) among ventilator-dependent COVID-19 patients at a second major hospital network in New York during the same period.
Those poor outcomes are consistent with earlier published data from China where mortality rates of over 80% were reported in patients with COVID-19 and moderate to severe ARDS.
At this time, 7 of the 12 treated patients have been discharged from the hospital. Patients received a variety of experimental agents prior to remestemcel-L. All patients were treated under an emergency IND or expanded access protocol at Mount Sinai.
Under the protocol, patients come into intensive care and received standard-of-care treatment. Once they were intubated on a ventilator, they were treated within 72 hours with two infusions of Mesoblast’s remestemcel-L cells within five days.
A bright light among dismal options
“What’s exciting is that our patients in the same epicenter of this disease with the same treatment everyone else is getting, suddenly 75% are coming off of ventilators within 10 days, and we’ve got 83% survival,” Itescu said.
The compassionate use treatment experience has informed the design of the clinical protocol for a randomized, placebo-controlled phase II/III trial of remestemcel-L in ventilator-dependent COVID-19 moderate to severe ARDS patients across North America.
The FDA has approved the same protocol for the phase II/III trial, and it will be powered so that results will be “self-evident,” Itescu said, noting that the trial will begin “imminently” in 20 to 30 sites across the U.S..
“We’ll know very fast if we’re seeing the same survival benefit in a randomized trial,” the CEO said.
“What people are dying of is acute respiratory distress syndrome, which is the body’s immune response to the virus in the lungs, and the immune system goes haywire, and in its battle with the virus it overreacts and causes severe damage to the lungs,” he said.
The stem cell therapy is currently being reviewed by the FDA for potential approval in the treatment of children with steroid-refractory acute graft-vs.-host disease (aGVHD). The clinical data submitted with the BLA showed a survival rate of 79% compared to an expected 30% survival rate in the pediatric phase III trial in aGVHD.
FDA Green-Lights Clinical Trial For COVID-19 Coronavirus Treatment That ‘Flattens The Curve’ In Patients
Celularity founder Robert Hariri
CELULARITY
Therapeutics startup Celularity announced Thursday morning that it has received FDA clearance to begin a clinical trial of a proposed stem-cell treatment for COVID-19. The approval of the New Jersey-based company’s IND application enables the company to begin a clinical trial with patients who have the disease. The company’s therapy, called CYNK-001 for now, uses “Natural Killer” (NK) cells, a form of white blood cells that wage war against cancer and viral infection, derived from placental stem cells. The company’s been developing similar treatments for several years against cancer and Crohn’s disease, several of which are being tested as well.
The idea behind the therapy is that for patients who are starting to show symptoms, or who may be at risk for a more severe form of the disease, can receive an intravenous infusion of NK cells to bolster their immune response to the virus, says founder and CEO Robert Hariri. That’s because the additional NK cells help slow down the viruses’ ability to replicate within the body. It’s an approach he likens to social distancing—slowing the spread of COVID-19 so hospitals don’t get even more overwhelmed—within patients themselves.‘’By administering our NK cells to patients, we are acting to ‘flatten the viral titer curve,’ so the patient’s adaptive immune system can get in gear and do the job of clearing the virus,” he says.Celularity was cofounded by Hariri and X Prize Foundation chair Peter Diamandis in 2016 as a spinout of pharmaceutical company Celgene. About a decade before, the company had found itself in the business of collecting and storing umbilical cord blood from placentas after birth. The undifferentiated stem cells found in that blood offer a universal way to generate NK cells that potentially reduce risk of rejection or other complications.It’s a strategy that’s earned the company support from investors like Bill Maris at Section 32, Sorrento Therapeutics, and former Apple CEO John Sculley. According to Pitchbook, the company has raised over $327 million in backing to date. The primary thrust of the company’s therapeutic efforts have been to leverage these treatments against forms of cancer such as myelomas and leukemia. But because NK cells are often involved in protecting the body against viruses, Hariri says he’s always looked to the company one day going after infectious disease.According to Hariri, it may take only a matter of days to see results from the first clinical trial of COVID-19 patients. That test will involve use of the treatment in a patient group of up to 86 people. If that’s successful, Hariri hopes those results will mean accelerating to a larger trial, and then, if all goes well, out to market.
“This is a very easy product to deploy,” says Hariri. “We’re hopeful that if we get compelling enough data, the agency and the CDC and the NIH will work with us to scale up production.”
Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia
Zikuan Leng1,5,#, Rongjia Zhu2,#, Wei Hou3,#, Yingmei Feng3,#, Yanlei Yang4, Qin Han2, Guangliang Shan2, Fanyan Meng1, Dongshu Du1, Shihua Wang2, Junfen Fan2, Wenjing Wang3, Luchan Deng2, Hongbo Shi3, Hongjun Li3, Zhongjie Hu3, Fengchun Zhang4, Jinming Gao4, Hongjian Liu5*, Xiaoxia Li6, Yangyang Zhao2, Kan Yin6, Xijing He7, Zhengchao Gao7, Yibin Wang7, Bo Yang8, Ronghua Jin3*, Ilia Stambler9,10,11, Lee Wei Lim9,10,12, Huanxing Su9,10,13, Alexey Moskalev9,10,14, Antonio Cano9,10,15, Sasanka Chakrabarti16, Kyung-Jin Min9,10,17, Georgina Ellison-Hughes9,10,18, Calogero Caruso9,10,19, Kunlin Jin9,10,20*, Robert Chunhua Zhao1,2,9,10* 1School of Life Sciences, Shanghai University, Shanghai, China. 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China. 3Beijing YouAn Hospital, Capital Medical University, Beijing, China. 4Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 5Department of Orthopaedics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 6Institute of Stem Cell and Regeneration Medicine, School of Basic Medicine, Qingdao University, Shandong, China. 7Department of Orthopaedics, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. 8Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 9The Executive Committee on Anti-aging and Disease Prevention in the framework of Science and Technology, Pharmacology and Medicine Themes under an Interactive Atlas along the Silk Roads, UNESCO, Paris, France. 10International Society on Aging and Disease, Fort Worth, Texas, USA. 11The Geriatric Medical Center "Shmuel Harofe", Beer Yaakov, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 12School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China. 13Institute of Chinese Medical Science, University of Macau, Taipa, Macau, China. 14Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russia. 15Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain. 16Maharishi Markandeshwar Deemed University, Mullana-Ambala, India. 17Department of Biological Sciences, Inha University, Incheon, South Korea. 18Faculty of Life Sciences & Medicine, King's College London, London, UK. 19Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy. 20University of North Texas Health Science Center, Fort Worth, TX76107, USA.
[Received February 25, 2020; Revised February 28, 2020; Accepted February 28, 2020] Aging and Disease Vol 11,N02; 216-228
ABSTRACT: A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.
Key words: COVID-19, ACE2 negative, mesenchymal stem cells, cell transplantation, immunomodulation, function recovery
Advanced Therapy Medicinal Products under investigation (n=24) (wording taken from the titles of the registered studies)
10 out of 24 products that have been employeed in clinical trials for the treatment of Covid 19 are from perinatal tissues, mostly from cord tissue.
· Aerosol inhalation of vMIP: viral macrophage inflammatory protein
· Ankylosaurus; M1 macrophages target
· Anti-2019-nCoV inactivated convalescent plasma
· Anti-SARS-CoV-2 inactivated convalescent plasma
· Biological preparation of human placenta
· Convalescent plasma treatment
· Cord blood mesenchymal stem cells
· Human menstrual blood-derived stem cells
· Immunoglobulin from cured patients
· Inactivated Mycobacterium vaccine
· Infusion of convalescent plasma
· Mesenchymal stem cells
· Mesenchymal stem cells exosomes atomization
· mRNA-1273
· NK cells
· Plasma treatment
· Recombinant cytokine gene-derived protein injection
· Regulating intestinal flora
· Therapeutic antibody from recovered novel coronavirus pneumonia patients
· Umbilical cord blood mononuclear cells
· Umbilical cord mesenchymal stem cells (hucMSCs)
· Umbilical cord Wharton’s Jelly derived mesenchymal stem cells
· Umbilical Cord(UC)-derived mesenchymal stem cells
· Washed microbiota transplantation
Carl Heneghan is the Editor in Chief BMJ EBM and Professor of EBM, Centre for Evidence-Based Medicine in the Nuffield Department of Primary Care Health Sciences, University of Oxford Oxford https://www.cebm.net/covid-19/registered-trials-and-analysis/
Τhe American College of Obstetrician and Gynecologists Practice Advisory: Novel Coronavirus 2019 (COVID-19)
March 13, 2020
The American College of Obstetricians and Gynecologists (ACOG) is closely monitoring the COVID-19 pandemic. Imported cases of COVID-19 infection in travelers have been detected in the United States, and person-to-person spread of COVID-19 also has been seen among close contacts of returned travelers from Wuhan. Community spread of COVID-19 has also been reported in several states.
The Centers for Disease Control and Prevention (CDC) has released Interim Clinical Guidance for Management of Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) Infection and guidance for Evaluating and Reporting Persons Under Investigation (PUI).
Travel
Due to the current risk of COVID-19, CDC is continually updating travel recommendations. Please see CDC’s Coronavirus Disease 2019 Information for Travel page for the most up to date information on travel recommendations and restrictions.
Additional travel advisories or restrictions may be implemented globally and locally within the United States depending on community spread. Ob-gyns and other health care practitioners should check with their local and/or state health department for guidance on travel restrictions in their area.
Testing
Testing is currently occurring at state and local public health laboratories in 50 states and the District of Columbia. Ob-gyns and other health care practitioners should contact their local and/or state health department for guidance on testing persons under investigation.
Pregnant Women
The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have developed an algorithm to aid practitioners in assessing and managing pregnant women with suspected or confirmed COVID-19. View the algorithm.
At this time, very little is known about COVID-19, particularly related to its effect on pregnant women and infants, and there currently are no recommendations specific to pregnant women regarding the evaluation or management of COVID-19.
Currently available data on COVID-19 does not indicate that pregnant women are at increased risk. However, pregnant women are known to be at greater risk of severe morbidity and mortality from other respiratory infections such as influenza and SARS-CoV. As such, pregnant women should be considered an at-risk population for COVID-19. Adverse infant outcomes (eg, preterm birth) have been reported among infants born to mothers positive for COVID-19 during pregnancy. However, this information is based on limited data and it is not clear that these outcomes were related to maternal infection. Currently it is unclear if COVID-19 can cross through the transplacental route to the fetus. In limited recent case series of infants born to mothers infected with COVID-19 published in the peer-reviewed literature, none of the infants have tested positive for COVID-19 (1).
While travel history is always an essential component of medical history intake, obstetrician–gynecologists and other health care practitioners should be vigilant in obtaining a detailed travel history as well as a history of exposure to people with symptoms of COVID-19 for all patients, including pregnant women presenting with fever or acute respiratory illness and should follow the CDC’s Interim Clinical Guidance for Management of Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) Infection and guidance for Evaluating and Reporting Persons Under Investigation (PUI). Of note, health care practitioners should immediately notify infection control personnel at their health care facility and their local or state health department in the event of a PUI for COVID-19.
Community Mitigation Efforts
Community mitigation efforts to control the spread of COVID-19 are being implemented across the United States. While these efforts are important, ob-gyns and other health care practitioners should be aware of the unintended impact they may have, including limiting access to routine prenatal care. Ob-gyns and other prenatal care practitioners should ensure that patients with certain high-risk conditions are provided necessary prenatal care and testing when needed. Ob-gyns and other prenatal care practitioners should also consider creating a plan to address the possibility of a decreased health care workforce, potential shortage of personal protective equipment, limited isolation rooms, and should maximize the use of telehealth across as many aspects of prenatal care as possible.
Infection Prevention and Control in Inpatient Obstetric Care Settings
The CDC has published Interim Considerations for Infection Prevention and Control of Coronavirus Disease 2019 (COVID-19) in Inpatient Obstetric Healthcare Settings. These considerations apply to health care facilities providing obstetric care for pregnant patients with confirmed COVID-19 or pregnant persons under investigation (PUI) in inpatient obstetric health care settings including obstetrical triage, labor and delivery, recovery and inpatient postpartum settings.
The American College of Obstetricians and Gynecologists encourages physicians and other obstetric care practitioners to read and familiarize themselves with the complete list of recommendations.
Key highlights from the recommendations include:
· Health care practitioners should promptly notify infection control personnel at their facility of the anticipated arrival of a pregnant patient who has confirmed COVID-19 or is a PUI.
· Patients with known or suspected COVID-19 should be cared for in a single-person room with the door closed. Airborne Infection Isolation Rooms should be reserved for patients undergoing aerosol-generating procedures.
· Facemasks are an acceptable alternative when the supply chain of respirators cannot meet the demand. During this time, available respirators should be prioritized for procedures that are likely to generate respiratory aerosols. When the supply chain is restored, facilities with a respiratory protection program should return to use of respirators for patients with known or suspected COVID-19.
· Infants born to mothers with confirmed COVID-19 should be considered PUIs. As such, these infants should be isolated according to the Infection Prevention and Control Guidance for PUIs.
· To reduce the risk of transmission of the virus that causes COVID-19 from the mother to the newborn, facilities should consider temporarily separating (eg, separate rooms) the mother who has confirmed COVID-19 or is a PUI from her baby until the mother’s transmission-based precautions are discontinued.
· Discharge for postpartum women should follow recommendations described in the Interim Considerations for Disposition of Hospitalized Patients with COVID-19.
Due to the limited data on COVID-19, these recommendations are largely based on infection prevention and control considerations for other respiratory viruses such as influenza, SARS-CoV and MERS-CoV and are intentionally cautious as experts learn more about this new virus.
Breastfeeding
The CDC has developed Interim Guidance on Breastfeeding for a Mother Confirmed or Under Investigation for COVID-19. There are rare exceptions when breastfeeding or feeding expressed breast milk is not recommended. Whether and how to start or continue breastfeeding should be determined by the mother in coordination with her family and health care practitioners. Currently, the primary concern is not whether the virus can be transmitted through breastmilk, but rather whether an infected mother can transmit the virus through respiratory droplets during the period of breastfeeding. A mother with confirmed COVID-19 or who is a symptomatic PUI should take all possible precautions to avoid spreading the virus to her infant, including washing her hands before touching the infant and wearing a face mask, if possible, while breastfeeding. If expressing breast milk with a manual or electric breast pump, the mother should wash her hands before touching any pump or bottle parts and follow recommendations for proper pump cleaning after each use. If possible, consider having someone who is well feed the expressed breast milk to the infant.
In limited case series reported to date, no evidence of virus has been found in the breast milk of women infected with COVID-19; however, it is not yet known if COVID-19 can be transmitted through breast milk (ie, infectious virus in the breast milk).
Precautions for Health Care Personnel
The CDC recommends that all health care personnel who enter the room of a patient with known or suspected COVID-19 (persons under investigation) should adhere to Standard, Contact, and Airborne Precautions. See the CDC’s Interim Infection Prevention and Control Recommendations for Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) or Persons Under Investigation for 2019-nCoV in Healthcare Settings for detailed recommendations.
Pregnant healthcare personnel (HCP) should follow risk assessment and infection control guidelines for HCP exposed to patients with suspected or confirmed COVID-19. Facilities may want to consider limiting exposure of pregnant HCP to patients with confirmed or suspected COVID-19, especially during higher risk procedures (e.g., aerosol-generating procedures) if feasible based on staffing availability.
Additional Information
Currently, health officials are emphasizing that seasonal influenza remains a persistent concern for the U.S. population. Influenza activity continues to be high across the United States, and health care practitioners are encouraged to continue offering influenza vaccine to their unvaccinated patients, particularly pregnant women. For more information on seasonal influenza and recommendations for pregnant women see the CDC’s website and ACOG’s Clinical Guidance.
The American College of Obstetricians and Gynecologists will continue to closely monitor the evolution of the 2019 novel coronavirus (COVID-19) in collaboration with the CDC. New and updated information will be shared as it becomes available.
This Practice Advisory was developed by the American College of Obstetricians and Gynecologists’ Immunization, Infectious Disease, and Public Health Preparedness Expert Work Group in collaboration with Laura E. Riley, MD; Richard Beigi, MD; Denise J. Jamieson, MD, and Brenna L. Hughes MD.
References
1. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020; DOI: 10.1016/S0140-6736(20)30360-3. Available at: http://www.sciencedirect.com/science/article/pii/S0140673620303603. Retrieved Feb 21, 2020.
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