The Disillusioned Comfort with COVID-19 and the Potential of Convalescent Plasma and Cell Therapy

Abstract

Coronavirus disease 2019 or COVID-19 is highly infectious, which can lead to acute and chronic debilitating symptoms, as well as mortality. The advent of safe and effective vaccines or antiviral drugs remains distant in the future. Practical public health measures, such as social distancing, hand washing, and wearing a face mask, are the current recommended guidelines by the Centers for Disease Control and Prevention for limiting the spread of the virus. Weakened immune system and aberrant inflammation represent a major pathological symptom of COVID-19 patients. Based on the unique immunomodulatory properties of both convalescent plasma and stem cells, we discuss here their potential use for treating COVID-19.

Keywords

virus mesenchymal stem cells vaccine immunoglobulin convalescent plasma

The Disillusioned Comfort

Three common vices to avoid: smoking, gambling, and riding a motorcycle! The dire statistics in the United States prove staggering, in that these vices lead to life-threatening diseases, financial losses, and bodily injuries.

Smoking stands as the main cause of lung cancer, contributing to 80% and 90% of lung cancer deaths in men and women, respectively¹. Men and women who smoke are 23 times and 13 times, respectively, more likely to develop lung cancer compared to never smokers¹.

The average debt generated by a man addicted to gambling ranges from $55,000 to $90,000, while women gamblers average $15,000 of debt². In extreme cases, gambling can result in serious legal problems or financial ruin. Indeed, more than 20% of compulsive gamblers end up filing for bankruptcy because of gambling losses².

In the United States, motorcyclists are about 26 times more likely to die in a crash than someone riding in a passenger car and are five times as likely to be injured³. The lack of any substantial protective barriers between a motorcycle and the road, as well as the difficulty that other motorists may have in anticipating and seeing a motorcycle, leave riders prone to serious injury in the event of an accident³.

Currently, the world, which is under virus attack, has added another form of vice that can be as devastating as these three vices. This new vice refers to “disillusioned comfort,” defined as our ignorance of the dangers of the virus, giving us a false blanket of security that we can continue to live life as it is. As of July 20, 2020, according to data collected by Johns Hopkins University, there are about 15 million confirmed coronavirus cases and close to 615,000 deaths worldwide⁴. The United States now leads the world with about 3.8 million confirmed COVID-19 cases, and more than 140,000 deaths. The US numbers have reached the estimates made by Dr Anthony Fauci of the National Institute of Allergy and Infectious Diseases, who projected in late March 2020 that there will be at least 100,000 deaths in America even in a best-case scenario compared to the originally reported 14 American cases on February 26, 2020⁵!

The projected deaths seemed initially unfathomable with only a few known cases in early 2020⁵. Many scenarios may contribute to the rapid uncontained virus spread, but the majority of the multifold increments in infections and deaths may be likely accounted for by human behavior, especially those who do not take seriously the Centers for Disease Control and Prevention (CDC)-recommended public health practices of social distancing and proper hygiene, i.e., washing of hands with soap and water. Moreover, the virus-associated microdroplets can stay airborne for up to 3 h⁶, necessitating the need for wearing a face mask to protect ourselves and others. The combination of 6-feet social distancing, 20-s hand washing, and wearing N-95 or other CDC-recommended face masks has been reported to curve the spread of virus^7,8, but quantifying the risk of reducing these strategies remains debatable. Notwithstanding, the CDC continues to stress practicing social distancing, hand washing, and wearing a face mask in order to inhibit future deaths from the virus. Otherwise, we are living in our “disillusioned comfort,” similar to the misguided security blanket we afford to negative consequences of smoking, gambling, and riding a motorcycle.

The Spanish Flu

A historical review of virus-related pandemics reminds us of the 1918 Spanish flu, which infected 500 million and estimated to have killed about 17 million to 50 million people⁹. The Spanish flu resembles COVID-19: both are respiratory viruses with the precursor viruses mutating in animals thereafter infecting humans, and with fast-progressive cases from infection to symptom onset with viral consolidation in the lung and eventually mortality primarily from pneumonia^9

–12. Eerily enough, the key promoters of such high mortality rate of Spanish flu were overcrowding and poor hygiene—the same two factors that define our disillusioned comfort for COVID-19. Human behavior to the Spanish flu outbreak stands as the major determinant for the pattern of the pandemic’s high mortality rate¹³. Again, the same human response, or lack thereof, that faces COVID-19.

A Spanish flu vaccine was not available during the 1918 pandemic, with the virus remaining largely unknown for almost a century when the molecular underpinnings of the virus were finally characterized in 2005¹⁴. Similar to COVID-19, the 1918 Spanish flu was first detected in the month of January, but after the second wave in August of that year, the number of cases dropped significantly and almost disappeared by the year’s end. Without a vaccine, the rapid decline in infection and mortality after the second of the two lethal waves of Spanish flu was attributed to better treatment of pneumonia and the virus mutating to a less dangerous strain.

Three key lessons from the Spanish flu pandemic are worthy of consideration. First, those who survived the first wave developed immunity against the virus; thus, these individuals were immune to the second wave of the Spanish flu, providing us a glimpse on the future of passive immunity-based treatment against the virus. Indeed, clinical trials have recently been initiated using plasma collected from recovered COVID-19 patients based on the concept that these individuals have likely harbored strong immune responses such as antibodies that target the proteins found on COVID-19¹⁵. Second, that the end of Spanish flu cases by 1920 might have signaled the eradication of the pandemic may not be completely true. Evidence of slow-progressive cases of Spanish flu has been linked to secondary bacterial pneumonia, possibly affecting the brain, which results in neurological disorders, in particular encephalitis lethargica, that recorded its outbreak in the 1920s, in children¹⁶, which was suggested to manifest in adulthood as Parkinson’s disease¹⁷ but such a pathological link being merely coincidental has been debated¹⁸. Similarly, the potential long-term consequences of COVID-19 to brain disorders, and other comorbid diseases, warrant critical research avenues as we tackle this pandemic and its associated not-so-apparent mini outbreaks. Third, that overcrowding in military camps and lack of sanitation due to poverty during World War I contributed to Spanish flu pandemic draws our attention to the key pressing issue of human behavior.

The Potential of Convalescent Plasma

Regenerative medicine may play a key role in treating COVID-19. The ongoing clinical trials of infusing convalescent plasma stand as a potent cell therapy for COVID-19 patients. This investigational treatment uses plasma that contains antibodies to severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2, the virus that causes COVID-19. Plasma therapy entails the use of plasma or specific, fractioned, antibodies, along with other immunoglobulins (IGs) and possibly other therapeutic molecules harvested from immunized individuals or convalescent persons¹⁹. Plasma therapy has a long history of safety, and even efficacy, since the Spanish flu in 1917–1918^19,20. While the mechanism of action of plasma therapy remains not fully understood, the functional benefits have been largely ascribed to the purified neutralizing antibodies of the convalescent plasma^19,20. A meta-analysis of English-language journals from 1918 to 1925 reveals that the overall mortality rate was 16% among treated patients compared to 37% among controls, indicating difference in fatality between the treatment and control groups at 8% to 26%²⁰. Note that the meta-analysis study²⁰ was based on only eight studies with many methodologic limitations, including lack of blinding, randomization, or placebo-controlled arm. Subsequent to the Spanish flu pandemic, the treatment with convalescent plasma has been studied in similar outbreaks of respiratory infections, such as the 2003 SARS-CoV-1 epidemic, the 2009–2010 H1N1 influenza virus pandemic, and the 2012 MERS-CoV epidemic^19,20. Whereas small clinical trials and anecdotal accounts of convalescent plasma suggest safety and efficacy of plasma treatment in these previous outbreaks²¹, its potency in COVID-19 requires carefully designed and rigorous assessment of these clinical trials as discussed subsequently.

The still limited evidence but massively accumulating interest in the safety and efficacy of convalescent plasma treatments may provide the basis for compassionate use of these therapies for COVID-19 in the United States. Indeed, a review of the literature from 2020 alone shows that there are already 152 publications, although most are review and commentary articles, and protocol descriptions, on the theme of convalescent plasma treatments for COVID-19. Notable clinical research reports include: (1) The small study on six Chinese patients diagnosed with COVID-19, who subsequently received ABO-compatible convalescent plasma, demonstrating immediate increase of antibody titers in two patients and elimination of the virus in two other patients²². (2) Another small study on ten severe COVID-19 Chinese patients revealed that nine patients displayed increased neutralizing antibody titers, and the viral load in seven patients becoming undetectable by day seven post-infusion of convalescent plasma, but only 3 exhibited improved respiratory function²³. (3) Another study on five critically ill COVID-19 patients revealed viral loads decreased and became negative by day 12, and three patients were discharged by about 50 days, while 2 patients remained in stable condition at 37 days after convalescent plasma infusion²⁴. (4) In six end-stage COVID-19 patients, convalescent plasma effectively induced viral shedding with the SARS-CoV-2 RNA undetectable by day 3 post-infusion of convalescent plasma, but five patients eventually died²⁵; (5) In South Korea, two severe COVID-19 patients treated with convalescent plasma with both showing favorable outcomes including being weaned from mechanical ventilators and/or extubated with SARS-CoV-2 negative after days 20–26 of convalescent plasma infusion²⁶.

From these five small clinical case reports, the following protocol specifics may require optimization in order to further assess the safety and efficacy of convalescent plasma treatment for COVID-19. (1) The small number of patients is clearly a limiting factor in all these studies. (2) Once the number of patients to be enrolled is increased, there is a need for proper control and randomization of treatments, as well as blinding of the treating physicians. (3) The timing of convalescent plasma infusion and its doses and the need for booster shots will require careful considerations. For example, in Duan’s study²³, patients were infused with convalescent plasma at around 16 days of symptom onset, while in Shen’s study²⁴, patients received convalescent plasma at around 21 days after symptom onset. The recognition of positive outcomes may depend on the early initiation of convalescent plasma infusion and may be the need for subsequent booster treatment. Additionally, in Duan’s study²³, one dose of 200 ml of convalescent plasma with the neutralizing antibody titers above 1:640 was specified. In Shen’s study²⁴, it was 400 ml of convalescent plasma with the neutralizing antibody titer set at 1:1000. Finding the optimal timing and dose will improve the safety and efficacy of convalescent plasma. (4) Related to the timing of convalescent plasma infusion, the severity of the disease is likely to impact on the treatment outcomes. In all these five clinical studies, it is understandable that because convalescent plasma treatment remains experimental, the target population is initially the severe or critically ill patients, who have high mortality and worst morbidity, which may mask the potential functional benefits of the treatment. Future treatments may need to enroll those mild COVID-19 patients or those who are in the early stages of the disease. (5) The treatment profile of the patients will need to be carefully charted, noting the drugs and ventilator supportive care among others, in order to delineate the true effects of convalescent plasma infusion or the possibility of additive effects of convalescent plasma with antiviral agents and immunomodulatory drugs. (6) The patient’s preexisting health condition is equally an important factor in treatment outcomes and disease progression. In addition to COVID-19, immune-related diseases may worsen the presenting pathology, which will likely require not only eliminating SARS-CoV-2 but also addressing the multifactorial manifestations of disease. (7) The age, gender, ethnicity, genetic factors, and other pertinent patient profiles will need to be factored into the final analysis of the treatment outcomes as this will further guide optimization of the convalescent plasma treatment. Clearly, there remain several factors in order to advance the widespread use of convalescent plasma for treating COVID-19. However, at the minimum, the transparency in reporting the detailed methods and treatment outcomes will ensure rigorous assessment of the true functional effects of convalescent plasma. A glance at the clinicaltrials.gov website reveals 173 ongoing clinical trials on the use of convalescent plasma for COVID-19. Recognition of the factors mentioned earlier will allow direct comparisons of protocols and safety and efficacy readouts across these clinical trials and further evaluate the potential of convalescent plasma for COVID-19.

The Emerging Science and Clinical Trials of Stem Cell Therapy

As noted earlier, plasma therapy involves the use of convalescent plasma, but also the plasma-active components specifically IGs. Under the guise of passive immunity against pathogens in viral epidemics, convalescent plasma is considered the first-line passive immunotherapy since the 1918 Spanish flu and the modern viral epidemics (2003 SARS-CoV-1, 2009–2010 H1N1, and 2012 MERS-CoV), and now Covid-19^27,28. The last several decades have witnessed advancements in molecular technology toward the purification and manufacture of plasma-derived IG as a drug therapy^27,28. Toward this end, human IG formulations have been advanced as the second line of passive immunotherapies against these diseases^27,28. The rationale of human IG for intravenous use (IVIG) is thus based on the similar etiology and inflammatory pathogenesis of SARS-CoV-2 infection to diseases for which the use of IVIG has already been approved by the FDA²⁹. According to clinicaltrials.gov, there are 40 trials using IG for COVID-19. Similar to convalescent plasma treatment, the mechanism of action ascribed to IG therapy is to boost the immune response of the body against SARS-CoV-2.

Along this line of boosting the immune system of COVID-19 patients, mesenchymal stem cells (MSCs) possess secretory functions of robust immunomodulatory biologics^30

–34. Because COVID-19 manifests a massive inflammatory pathology in the lung, characterized by pulmonary edema and an over-reactive immune response, which can lead to hypoxia, respiratory distress, and lung damage, finding a treatment designed to sequester this aberrant inflammation and immune response may prove beneficial against COVID-19³³. Accordingly, cognizant that abrogating COVID-19 may depend on the patients’ properly functioning immune system, the transplantation of MSCs has been proposed to propel the host immune system to effectively eliminate the virus. MSCs display potent anti-inflammatory and immunomodulatory properties. Indeed, our group and many others have shown that MSCs exert anti-inflammatory effects and even repair lung damage³⁴. Although MSCs have been the major cell type for cell therapy in COVID-19, non-MSC stem cells, such as umbilical cord blood monocytes^35,36, that similarly target the inflammatory and immune pathways and promote other regenerative mechanisms (e.g., tissue repair), are also being tested. Interestingly, intravenous administration of MSCs has the natural preponderance to migrate preferentially to the lungs allowing for the first-pass treatment of pulmonary diseases^33,34, such as COVID-19. Moreover, the long track record of safety profile of MSCs for hematologic diseases may expedite their clinical entry for novel indications; indeed, clinicaltrials.gov reveals 31 ongoing studies using stem cell therapy for COVID-19. Preliminary reports in China and the United States suggest solid safety outcomes in patients who have received MSCs and their exosomes^31,32. Together with convalescent plasma and IG treatments, stem cell therapies may offer an innovative approach in fostering immunomodulatory regulation of COVID-19. Moreover, although the lung stands as the main pathological organ in COVID-19, recent studies have implicated extra-lung organs, including the heart and the brain, as well as the gut, suggesting that targeting these organs may prove beneficial in treating the disease. Indeed, combining the envisioned vaccines and immunomodulatory treatments with novel strategies, such as altering the gut microbiome^37

–41, will likely enhance the overall prognosis of COVID-19.

Conclusions

Science and medicine may take time to advance a vaccine, antiviral drug, convalescent plasma treatment, and IG and stem cell therapies to the clinic. Mortality rate ranges from 0.1% to as high as 10%, with the elderly (>65 years of age) and those with preexisting immune-related and inflammatory diseases (hypertension, diabetes, heart diseases), showing higher incidence of mortality^42
–44. Given the morbidity not only in the acute stage, but the realization of equally devastating long-term effects, including cardiovascular and cerebrovascular consequences^45

–49, warrants immediate action to at least lessen the spread of the virus. Without access to the vaccine and other proven therapies, just like in 1918 Spanish flu era, the best course of action for the meantime is practicing social distancing and good hygiene, which represents a logical strategy to curve the course and to address the disillusioned comfort of COVID-19.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Mia C. Borlongan

References

Reddy

Kong

Hyle

Baggett

Huang

Parker

Paltiel

Losina

Weinstein

Freedberg

Walensky

. Lung cancer mortality associated with smoking and smoking cessation among people living with HIV in the United States. Version 2. JAMA Intern Med. 2017;177(11):1613–1621.

Potenza

Steinberg

McLaughlin

Rounsaville

O’Malley

. Gender-related differences in the characteristics of problem gamblers using a gambling helpline. Am J Psychiatry. 2001;158(9):1500–1505.

Hayakawa

Fischbeck

Fischhoff

. Traffic accident statistics and risk perceptions in Japan and the United States. Accid Anal Prev. 2000;32(6):827–835.

Johns Hopkins University & Medicine CORONAVIRUS RESOURCE CENTER. Maps & trends—Tracking global cases and tracking critical data; 2020 [cited 2020 Jun 5]. Available from https://coronavirus.jhu.edu/data.

Fauci

Lane

Redfield

. Covid-19 - navigating the uncharted. N Engl J Med. 2020;382(13):1268–1269.

Wilson

Norton

Young

Collins

. Airborne transmission of severe acute respiratory syndrome coronavirus-2 to healthcare workers: a narrative review. Anaesthesia. 2020;75(8):1086–1095.

West

Michie

Rubin

Amlôt

. Applying principles of behaviour change to reduce SARS-CoV-2 transmission. Nat Hum Behav. 2020;4(5):451–459.

Leung

NHL

Chu

DKW

Shiu

EYC

Chan

McDevitt

Hau

BJP

Yen

DKM

Peiris

JSM

Seto

, et al. Respiratory virus shedding in exhaled breath and efficacy of face masks. Nat Med. 2020;26(5):676–680.

Yang

Peng

Wang

Guan

Jiang

Sun

Chang

. The deadly coronaviruses: the 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China. J Autoimmun. 2020;109:102434.

10.

Spiteri

Fielding

Diercke

Campese

Enouf

Gaymard

Bella

Sognamiglio

Sierra Moros

Riutort

Demina

, et al. First cases of coronavirus disease 2019 (COVID-19) in the WHO European Region, 24 January to 21 February 2020. Euro Surveill. 2020;25(9):2000178.

11.

Ietto

. SARS - CoV-2: reasons of epidemiology of severe ill disease cases and therapeutic approach using trivalent vaccine (tetanus, diphtheria and Bordetella pertussis). Med Hypotheses. 2020;141:109779.

12.

D’Adamo

Yoshikawa

Ouslander

. Coronavirus disease 2019 in geriatrics and long-term care: the abcds of COVID-19. J Am Geriatr Soc. 2020;68(5):912–917.

13.

Barry

. Pandemics: avoiding the mistakes of 1918. Nature. 2009;459(7245):324–325.

14.

Nickol

Kindrachuk

. A year of terror and a century of reflection: perspectives on the great influenza pandemic of 1918-1919. BMC Infect Dis. 2019;19(1):117.

15.

Bloch

Shoham

Casadevall

Sachais

Shaz

Winters

van Buskirk

Grossman

Joyner

Henderson

Pekosz

, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020;130(6):2757–2765.

16.

Vilensky

Foley

Gilman

. Children and encephalitis lethargica: a historical review. Pediatr Neurol. 2007;37(2):79–84.

17.

Hayase

Tobita

. Influenza virus and neurological diseases. Psychiatry Clin Neurosci. 1997;51(4):181–184.

18.

McCall

Vilensky

Gilman

Taubenberger

. The relationship between encephalitis lethargica and influenza: a critical analysis. J Neurovirol. 2008;14(3):177–185.

19.

Garraud

Heshmati

Pozzetto

Lefrere

Girot

Saillol

Laperche

. Plasma therapy against infectious pathogens, as of yesterday, today and tomorrow. Transfus Clin Biol. 2016;23(1):39–44.

20.

Luke

Kilbane

Jackson

Hoffman

. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?. Ann Intern Med. 2006;145(8):599–609.

21.

Mair-Jenkins

Saavedra-Campos

Baillie

Cleary

Khaw

Lim

Makki

Rooney

Nguyen-Van-Tam

Beck

; Convalescent plasma study group. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis Version 2. J Infect Dis. 2015;211(1):80–90.

22.

Ren

Wang

Zhang

Xia

. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020;15:10.1002/jmv.25882.

23.

Duan

Liu

Zhang

Zhou

Chen

Meng

Peng

, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490–9496.

24.

Shen

Wang

Zhao

Yang

Yuan

Wang

Yang

Xing

Wei

, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020;323(16):1582–1589.

25.

Zeng

Gou

Zhang

Lin

Cui

Zhang

, et al. Effect of convalescent plasma therapy on viral shedding and survival in covid-19 patients. J Infect Dis. 2020;29. jiaa228.

26.

Ahn

Sohn

Lee

Cho

Hyun

Baek

Jeong

Kim

Yeom

Roh

, et al. Use of Convalescent plasma therapy in two covid-19 patients with acute respiratory distress syndrome in Korea. J Korean Med Sci. 2020;35(14):e149.

27.

Morabito

Gangadharan

. Active therapy with passive immunotherapy may be effective in the fight against Covid-19. Clin Transl Sci. 2020;18.

28.

Valk

Piechotta

Chai

Doree

Monsef

Wood

Lamikanra

Kimber

McQuilten

So-Osman

Estcourt

, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. Cochrane Database Syst Rev. 2020;5(5):CD013600.

29.

Prete

Favoino

Catacchio

Racanelli

Perosa

. SARS-CoV-2 inflammatory syndrome. Clinical features and rationale for immunological treatment. Int J Mol Sci. 2020;21(9):3377.

30.

Atluri

Manchikanti

Hirsch

. 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. 2020;23(2):E71–E83.

31.

Leng

Zhu

Hou

Feng

Yang

Han

Shan

Meng

Wang

Fan

, et al. Transplantation of ACE2⁻ mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia. Aging Dis. 2020;11(2):216–228.

32.

Sengupta

Lazo

Woods

Nolan

Bremer

. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells Dev. 2020;29(12): 747–754..

33.

Rogers

Harman

Bunnell

Schreiber

Xiang

Wang

Santidrian

Minev

. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. Version 2. J Transl Med. 2020;18(1):203.

34.

Garbuzova-Davis

Shell

Mustafa

Hailu

Willing

Sanberg

Borlongan

. Advancing stem cell therapy for repair of damaged lung microvasculature in amyotrophic lateral sclerosis. Cell Transplant. 2020;29:963689720913494.

35.

Darlington

Hou

Habib

Tian

Gao

Ehrhart

Sanberg

Sawmiller

Giunta

Mori

, et al. Human umbilical cord blood-derived monocytes improve cognitive deficits and reduce amyloid-β pathology in PSAPP mice. Cell Transplant. 2015;24(11):2237–2250.

36.

Womble

Green

Shahaduzzaman

Grieco

Sanberg

Pennypacker

Willing

. Monocytes are essential for the neuroprotective effect of human cord blood cells following middle cerebral artery occlusion in rat. Mol Cell Neurosci. 2014;59:76–84.

37.

Bonsack

Jiang

Borlongan

. A gut feeling about stroke reveals gut-brain axis’ active role in homeostasis and dysbiosis. J Cereb Blood Flow Metab. 2020;40(5):1132–1134.

38.

Corey

Kvederis

Kingsbury

Bonsack

Sanberg

Castelli

Lee

Borlongan

. Gut microbiome: lactation, childbirth, lung dysbiosis, animal modeling, stem cell treatment, and CNS disorders . CNS Neurol Disord Drug Targets. 2019;18(9):687–694.

39.

Lee

Tuazon

Corey

Bonsack

Acosta

Ehrhart

Sanberg

Borlongan

. A gutsy move for cell-based regenerative medicine in Parkinson’s disease: targeting the gut microbiome to sequester inflammation and neurotoxicity. Stem Cell Rev Rep. 2019;15(5):690–702.

40.

Lee

Tuazon

Ehrhart

Sanberg

Borlongan

. Gutting the brain of inflammation: a key role of gut microbiome in human umbilical cord blood plasma therapy in Parkinson’s disease model. J Cell Mol Med. 2019;23(8):5466–5474.

41.

Romo-Araiza

Gutiérrez-Salmeán

Galván

Hernández-Frausto

Herrera-López

Romo-Parra

García-Contreras

Fernández-Presas

Jasso-Chávez

Borlongan

Ibarra

. Probiotics and prebiotics as a therapeutic strategy to improve memory in a model of middle-aged rats. Front Aging Neurosci. 2018;10:416.

42.

Ferguson

Rosser

Quintero

Scott

Subramanian

Gumma

Rogers

Kappagoda

. Characteristics and outcomes of coronavirus disease patients under nonsurge conditions, Northern California, USA, March-April 2020. Emerg Infect Dis. 2020;26(8):1679-1685.

43.

Verma

Vishwakarma

Verma

Nath

Khan

HTA

. Time-to-death approach in revealing chronicity and severity of covid-19 across the world. PLoS One. 2020;15(5):e0233074.

44.

Promislow

DEL

. A geroscience perspective on COVID-19 mortality. J Gerontol A Biol Sci Med Sci. 2020;17:glaa094.

45.

Bridwell

Long

Gottlieb

. Neurologic complications of COVID-19. Am J Emerg Med. 2020;38(7):1549.e3–1549.e7.

46.

Larson

Savastano

Kadirvel

Kallmes

Hassan

Brinjikji

. COVID-19 and the cerebro-cardiovascular systems: what do we know so far? J Am Heart Assoc. 2020;12:e016793.

47.

Madjid

Safavi-Naeini

Solomon

Vardeny

. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol. 2020.

48.

de Havenon

Ney

Callaghan

Yaghi

Majersik

. Excess neurological death in New York City after the emergence of COVID-19. [published online ahead of print, 2020 July 20]. J Neurol 2020. DOI: 10.1007/s00415-020-10084-2.

49.

Chen

Laurent

Onur

, et al. A systematic review of neurological symptoms and complications of COVID-19. [published online ahead of print, 2020 July 20]. J Neurol 2020. DOI: 10.1007/s00415-020-10067-3.