The emergence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) at the end of 2019 in Hubei province China, is now the cause of a global pandemic present in over 150 countries. COVID-19 is a respiratory illness with most subjects presenting with fever, cough and shortness of breath. In a subset of patients, COVID-19 progresses to hypoxic respiratory failure and acute respiratory distress syndrome (ARDS), both of which are mediated by widespread inflammation and a dysregulated immune response.
Mesenchymal stem cells (MSCs), multipotent stromal cells that mediate immunomodulation and regeneration, could be of potential benefit to a subset of COVID-19 subjects with acute respiratory failure. In this review, we discuss key features of the current COVID-19 outbreak, and the rationale for MSC-based therapy in this setting, as well as the limitations associated with this therapeutic approach.
Introduction
The severe acute respiratory syndrome (SARS) corona virus 2 (SARS-CoV-2) disease (COVID-19) emerged in December 2019 in Wuhan, Hubei Province, People’s Republic of China when a cohort of patients with pneumonia of unknown etiology presented to local hospitals1. Since the initial outbreak of COVID-19 in Wuhan, the disease has since spread to over 150 countries with migratory epicenters that include Iran, Italy, Spain, and New York City, USA2. Given the widespread incidence of COVID-19, the World Health Organization (WHO) declared the current outbreak as a Public Health Emergency of International Concern (PHEIC) on January 30th 2020, and subsequently elevated the outbreak to pandemic status on March 11th 20203. As of July 1, 2020, globally, there are about 10 million confirmed cases of COVID-19 and just over 500,000 fatalities have been reported.
The causative agent of COVID-19, SARS-CoV-2, is an enveloped, positive-sense RNA coronavirus. Coronaviruses primarily cause respiratory and intestinal infections, and infect several species from bats to humans. Coronaviruses can have serious implications for public health: in addition to the current COVID-19 pandemic, they have also been responsible for SARS and Middle East respiratory syndrome, significant epidemics in the last two decades5. For the current outbreak of COVID-19, the initial patients who presented with the illness had all visited a local fish and wild animal market in Wuhan, Hubei Province, China1 which is indicative of a possible zoonotic transmission, but the exact mechanism which resulted in the first-in-person infection remains elusive.
Propagation of the virus among humans is thought to occur primarily through three main transmission mechanisms: (I) contact transmission, (II) droplet transmission and (III) aerosol transmission6. The full genome sequence of SARS-CoV-2 has been elucidated, and it shares 79.6% sequence identity with SARS-CoV, and at the whole-genome level is 96% identical to a bat coronavirus. Entry into and subsequent infection of human alveolar epithelial cells by SARS-CoV-2 is mediated by the angiotensin-converting enzyme II (ACE2) receptor.
For most patients with COVID-19 infections, initial symptoms include, but are not limited to fever, shortness of breath, cough and general malaise8,9. In the majority of patients, COVID-19 manifests as a mild-to-moderate disease and with conservative medical management, full recovery from the ailment is expected10,11.
However, in a subset of high-risk patients; the elderly, and those with underlying medical conditions such as hypertension and diabetes, the disease can become critical, and is characterized by severe pneumonia, acute respiratory distress syndrome (ARDS), and multiple organ dysfunction9,12,13,14.
Widespread inflammation, cytokine storm syndrome and a dysregulated immune response mediates the severe clinical manifestations seen in high-risk individuals with COVID-1915,16,17. In this cohort, disease- associated mortality is especially significant9,10.
There is no known cure for COVID-19, but given the prevalence of the disease, and the associated morbidity and mortality, various therapeutic modalities that might be effective against COVID-19 have been evaluated in clinical settings. Therapeutic agents assessed in COVID-19 patients thus far include, convalescent plasma18, antimalarials like Hydroxychloroquine19 and antivirals20. Consideration has also been given to the use of immunoregulatory agents in subjects with severe COVID-1921,22,23, since dysregulated and hyper-activated inflammatory responses tends to be a main driver of COVID-19-induced mortality10.
One such immunoregulatory agent with potential for COVID-19 subjects with critical disease is the mesenchymal stem cell (MSC).
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