key: cord-292988-q1yz9y8k
authors: Zumla, Alimuddin; Wang, Fu-Sheng; Ippolito, Giuseppe; Petrosillo, Nicola; Agrati, Chiara; Azhar, Esam I; El-Kafrawy, Sherif A; Osman, Mohamed; Zitvogel, Laurence; Locatelli, Franco; Gorman, Ellen; O'Kane, Cecilia; Mcauley, Danny; Maeurer, Markus
title: Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of Mesenchymal Stromal (stem) Cell (MSC) therapy - achieving global consensus and visibility for cellular host-directed therapies
date: 2020-05-17
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.05.040
sha: 
doc_id: 292988
cord_uid: q1yz9y8k

Abstract As of May 11th 2020, the coronavirus disease 2019 (COVID-19) pandemic, caused by the novel, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused 274,361 deaths out of 3,917,366 (7% case fatality rate). As with the two other novel coronavirus zoonotic diseases of humans, SARS and MERS, no specific treatments for reducing mortality or morbidity are yet available. Deaths from COVID-19 will continue to rise globally until effective and appropriate treatments and vaccines are found. With no specific treatments being available for treating COVID-19 patients, the global medical, scientific, pharma and funding communities have rapidly initiated over 500 COVID-19 clinical on a range of antiviral drug regimens, biologics, repurposed drugs in various combinations. We focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease. This is an area which has been eclipsed by the current emphasis the huge number of trials evaluating new anti-viral drugs, repurposed drugs and combinations thereof. MSCs should also be trialed for treatment of severe cases of MERS where mortality rates are upto 34% and MERS-CoV remains a WHO priority Blueprint pathogen. It’s about time funding agencies now invest more into development MSCs per se and other host-directed therapies in combination with other therapeutic interventions. MSC therapy could turn out to be an important contribution to bringing an end to the high COVID-19 and MERS death rates.

caused by the novel, highly contagious zoonotic pathogen, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (Hui D et al, 2020) . By May 11 th 2020, there have been 274,361 deaths out of 3,917,366 (7% case fatality rate) confirmed COVID-19 cases reported from all continents to the World Health Organization (WHO, 2020) . As with the two other novel coronavirus zoonotic diseases of humans, SARS and MERS, no specific treatments for reducing mortality or morbidity are yet available Hui and Zumla, 2020) .

The management of COVID-19 patients remains largely symptomatic and supportive with organ support for severely ill patients. Deaths from COVID-19 will continue to rise globally until effective and appropriate treatments and vaccines are found.

With no specific treatments being available for treating COVID-19 patients, the global medical, scientific, pharma and funding communities have rapidly initiated over 500 COVID-19 related trials (https://clinicaltrials.gov/ct2/who_table). These clinical trials have been fasttracked by ethical committees worldwide and a range of therapeutic interventions registered on clinical trials.gov are taking forward phase 1, 2 and 3 trials of antiviral drug regimens, biologics, repurposed drugs in various combinations, herbal remedies, nutritional supplements, and cellular therapies. The results of ongoing clinical trials of new antiviral regimens, biologics and repurposed drugs (in various combinations) are eagerly awaited. We focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease. This is an area which has been eclipsed by the current emphasis the huge number of trials evaluating new anti-viral drugs, repurposed drugs and combinations thereof.

Defining the underlying pathogenesis and pathology of COVID-19 disease for developing appropriate therapeutic interventions may prevent end organ damage and long-term functional disability in those who survive severe disease. Autopsy and minimally invasive biopsy studies indicate that COVID-19 is a multi-system disease. The lungs in particular manifest significant pathological lesions, such as alveolar exudative inflammation and interstitial inflammation, alveolar epithelium proliferation and hyaline membrane formation (Menter T et al, 2020; Tian S et al, 2020) . Significant proliferation of type II alveolar epithelia and focal desquamation of alveolar and bronchial epithelia and hyaline membrane formation J o u r n a l P r e -p r o o f are seen (Xu et al 2020) ; with predominantly macrophage and monocyte immune cell infiltration in alveoli with multinucleated giant cells; lymphocytes (mostly CD4-positive T cells), and some eosinophils and neutrophils. The blood vessels of alveolar septum were congested, edematous and widened, with modest infiltration of monocytes and lymphocytes.

Hyaline thrombi in microvessels and focal hemorrhage in lung tissue, organization of exudates, and pulmonary interstitial fibrosis have been observed. Furthermore, degeneration and necrosis of parenchymal cells and formation of hyaline thrombus in small vessels were observed in other organs and tissues (Menter T et al, 2020; Tian S et al, 2020) .

Immunohistochemical staining showed alveolar epithelia and macrophages positive for SARS-CoV-2 antigen. Evidence of SARS-CoV-2 antigens in other organs and tissues has been detected which suggests that host immune responses evoked by SARS-CoV-2 infection are involved in the pathogenesis of multi-organ injury (Yao et al, 2020) .

COVID-19, like MERS and SARS, is a systemic illness with multi-organ involvement. SARS-CoV-2 enters the host cells via the cell surface angiotensin converting enzyme 2 (ACE2) receptor on the target cell surface . ACE2 as a cardio-regulator, so there are numerous cells with ACE2 receptors in blood vessels, alveolar type II cells (AT2) in the lungs and several other organs, such as heart, kidneys. It appears that all three lethal zoonotic coronaviruses, MERS-CoV, SARS-CoV and SARS-CV-2 seem to induce excessive and aberrant host immune responses which are associated with severe lung pathology leading to acute respiratory distress syndrome (ARDS) Li G et al, 2020; Li G et al, 2020) . Characteristic findings on chest imaging in COVID 19 include bilateral ground glass and consolidative changes ). An associated cytokine storm may play a role in pathogenesis. Elevated proinflammatory cytokines and chemokines including tumour necrosis factor (TNF)α, interleukin 1β (IL-1β), IL-6, granulocyte-colony stimulating factor, interferon gamma-induced protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory proteins 1-α were significantly elevated in COVID-19 patients. (Huang C et al, 2020; Liu J et al, 2020) . Patients with evidence of hyperinflammation have an increased risk of mortality (Mehta et al, 2020; Ruan et al, 2020) . In those who survive intensive care, the long-term consequences of these aberrant and excessive immune responses may lead to long term pulmonary damage and fibrosis, with functional disability and reduction of quality of life. It is important that therapeutic interventions which can dampen the excess J o u r n a l P r e -p r o o f inflammation, thus preventing end organ damage and long-term functional disability in those who survive severe disease.

For the past decade the medical and pharma communities have focused on developing therapeutics targeting the pathogen rather than on the role of underlying host factors (Zumla et al 2016a; 2016b) . Human immune defenses are dependent on a complex array of mechanical, innate and acquired immune mechanisms and any disturbance of this internal lung milieu results in serious and fatal consequences. Improved understanding of inflammatory and immune pathways governing protective or deleterious outcomes, provide novel opportunities to target specific pathways that mediate immune pathology (Figure 1 ). (https://ipscell.com/rmat-list). In 2018 the first allogeneic MSC product received marketing approval in the European Union. Since some commercial stem cell clinics are marketing dubious therapies for cardiovascular disease and cancer (Sissung & Figg 2020) there are FDA and CDC cautions regarding their use (https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies) (https://www.cdc.gov/hai/outbreaks/stem-cell-products.html).

Mesenchymal stromal cells interact with most of the cell types of the innate and acquired MSCs also express ATPases and possess ecto-nucleotidase activity through CD73 expression, through which they have the capacity to deplete ATP.. The immunomodulatory effects of MSCs may also be triggered further by the activation of TLR receptor in MSCs, which is stimulated by pathogen-associated molecules such as LPS Importantly, MSCs do not have an ACE2 receptor, which makes them immune to SARS-CoV-2.

Whilst generally regarded as safe (Editorial, 2019), MSCs are not immunologically inert as previously thought (Lohan O et al, 2017; Ankrum JA et al, 2014) . A recent systematic review J o u r n a l P r e -p r o o f and meta-analysis of intravascular MSC therapy reviewed 55 randomised controlled trials of MSC therapy compared to controls (Thompson M, et al, 2020) , MSCs compared to controls were associated with an increased risk of fever but not non-fever acute infusional toxicity, infection, thrombotic/embolic events or malignancy. (1, 5 and 10 x 10 6 cells/kg) recruiting a total of 9 patients (3 patients per dose cohort). MSC infusion was associated with mild adverse reactions in 3 patients however no serious treatment related adverse events were identified.

MSCs are now being used as a potential therapy for treating COVID-19 patients in order to reduce mortality. Although the use of MSCs has been found to be safe when used for treatment of other diseases, it is important to evaluate whether they are safe to use 

The excessive host response seen in patients with COVID-19 appears to have induced a paradigm shift in longstanding focus of drug treatment interventions targeting the pathogen (SARS-CoV-2 in this case) to targeting the host response. Currently, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) report a combined 28 trials exploring the potential of MSCs and their products for treatment or prevention of COVID-19. Table 1 lists clinical trials of MSCs or their products which have been registered on clinicaltrials.gov. Not all of the registered trials will be pursued and in recent weeks, five trials registered on the Chinese Clinical Trial Register ("ChiCTR") and one trial registered on ClinicalTrials.gov have been marked as "Cancelled by the Investigator". xxxxx) is open to any interested parties to join us to help define optimal MSC therapy regimens and change the course of COVID-19 and sustain the growing portfolio of cellular therapies for a range of acute and chronic infectious diseases. 

Viable MSCs rescue injured cells by mitochondrial transfer and produce a broad array of immuno-modulatory cytokines. MSCs may be taken up by phagocytic cells -that may prolong and augment their biological effect after intravenous delivery. Risks include generally reduced immune -competence including anti-viral/bacterial/fungal activity, as well as potential pro-tumorigenic effects. Beneficial reduction of pro-inflammatory cytokines, increased Treg and IL-10 production. 

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Need for a Global consortium for conduct of multicenter clinicals trails of cellular therapies for defining priorities, common protocols, frequent scientific exchange, and long term collaborative efforts. An international consortium between clinical cancer and infectious disease research investigators (Website: xxxxx) (This consortium network is open to any interested parties to join us to help define optimal MSC therapy regimens and change the course of COVID-19 and sustain the growing portfolio of cellular therapies for a range of acute and chronic infectious diseases)

RNAseq data / Proteomics shared or centrally conducted from MSCs products to gauge for better definition of cellular products. Differences in gene expression / proteomics in freshly prepared versus cryopreserved and subsequently thawed MSC? Definition of microRNAs in MSCs. Investigator -initiated studies and commercial products-use different tissue origins and culture methods that may lead to different MSC phenotypes and gene expression patterns. Difference of 'edited', e.g. cytokine-edited MSCs b. Host responses: RNAseq expression pattern, immuno-phenotyping and functional T-cells assays gauging immuno-competence (e.g. anti-CMV responses) in longitudinally sampled blood prior and after MSC infusion to gauge for systemic MSC effects c. Measuring CMV DNA

Tagging or barcoding MSCs. Better understanding of MSC-MoA, e.g. phagocytosis of MSCs by macrophages and systemic effects

Differences in Dendritic Cells and Macrophage responses in vitro and ex vivo using viable MSC or MSC-derived products (e.g. exosomes, apoptotic bodies). Gauging the most suitable and safest MSC profile for COVID-19 treatment

Smart clinical studies to address different modes of MSC delivery, e.g. single or repeated doses, escalating dosing? Improved clinical efficacy by repeated infusions? Role of identical MSC donor in repeated dosing? Increased efficacy and safety if MSCs are used from different donors in the case of repeated infusions ?

Conditioning' patients prior to MSCs delivery. Can MSC-associated effects be improved by using repurposed drugs or biologicals that would augment the desired MSCs effects, e.g. decreasing damaging inflammation

Which patients benefit most from MSC treatment ? Concise clinical documentation needed concerning patients with COVID-19 that allows comparison of trials. Differences associated with MSC products (viable, MSC -apoptotic bodies, exosomes), (COVID-19), disease status or the patients phenotype (e.g. high IL-6 or IL-17 levels) ? Role of lymphopenia in response to MSCs ? Smarter patient selection associated with pathophysiology may aid to offer improved treatment modalities

Attracting pharma and funder attention: Convincing donors that cellular therapies are viable options for the adjunct treatment of patients with COVID-19 and other lethal infectious diseases 6. Gathering trials evidence base on MSC therapy for COVID-19 (the Acronym 'DOSES': D = Donor, O=Origin, S=Separation Method, E= Exhibited Characteristics, S= Site of Delivery has been proposed to define optimal MSCs therapy

Adverse events monitoring and analysis: short term and long-term folllowup of patients, e.g. short term analysis of general immuno-competence (e.g. anti-CMV and anti-SARS-CoV-2 humoral and cellular responses, long term observation concerning infectious complications

Creation of Biobanks and Access to biological material from patients with COVID-19 infection: Creating repository of samples obtained during MSC trials eg blood samples (or BAL) for unbiased gene expression analysis, proteomics and molecular analysis of T-cell responses, e.g defined by deep TCR sequencing to gauge for MSC effects, different reactivity and biology of neutrophils, macrophages and dendritic cells from patients with COVID-19 as compared to non-Covid-19 patients? Synoptic view with other, complementary assays gauging pulmonary recovery

Advancing the Global Consortium activities to f application of MSCs for other infectious diseases