Prevention and Control of Acute Respiratory Viral Infections in Adult Population: A Systematic Review and Meta-Analysis on Ginseng-Based Clinical Trials

Introduction: Acute respiratory infections are continuously emerging. Discovered in Wuhan city, China in 2019, COV-SARS-2 and most viral respiratory diseases presently do not have a definitive cure. This paper aims to evaluate the therapeutic effectiveness of ginseng for prevention and control of acute respiratory illness including SARS-COV-2 in adult population.

We performed a systematic literature review using databases PubMed, Medline, Scopus, Google Scholar, Web of Science, and Cochrane library from 1st through the 27th of April 2020. All related articles that reported the use of Ginseng in COVID-19 patients were included in this analysis. Screening was done by 2-independent researchers. The meta-analysis was performed using comprehensive meta-analysis package.

596 articles were retrieved for the time frame. After screening, 5 articles with RCTs outcomes relevant to the review were selected. Ginseng was found to be effective in the reduction of risk by 38 % and 3-days shorter duration of acute respiratory illness (ARI) in all trials than placebo.

As the world continues to race to find a cure, it is important to consider the use of ginseng which has been proven over the years to be effective in the treatment of acute respiratory illnesses. Further studies should however be conducted to determine the right dosage to improve efficacy and prevent adverse events.

COVID-19, coronavirus, vaccine, therapy, randomized control clinical trial, systematic review, Novel Acute Respiratory Illness, ginseng, placebo-controlled trials, randomized control trial, meta-analysis. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Highlight /i1 COVID-19 is very infectious ravaging the globe /i1 Millions have been infected and hundreds of thousands lost their lives to COVID- 19 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 3 /i1 Due to absence of vaccines, urgent search for vaccines and drugs is still underway /i1 Ginseng has been useful in similar respiratory viral infections in the past /i1 Current paper throws more light on the need to consider ginseng for COVID-19 control 1.0 Introduction Coronaviruses (CoVs) are a large family of viruses that cause illness ranging from mild illness like the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV). Corona viruses are usually zoonotic diseases transferred from animals to humans. SARS-CoV is believed to have been transmitted from civet cats to humans and MERS-CoV from dromedary camels to humans 1. Novel coronavirus disease (COVID-19) is a new strain of a corona virus first discovered in Wuhan city in China on 12 th December 2019 where it is believed the first animal to human transmission took place. The WHO officially named the corona virus on the 11th, February 2020 as COVID-19 and it was categorized as pandemic on 11 th March by WHO 2. The disease has been reported in over 190 countries, over 2 million deaths and over 100 million confirmed cases according to WHO’s report 2. The impact of COVID-19 pandemic has been greatly felt in all areas of development. Signs including respiratory symptoms, fever, cough, shortness of breath and breathing difficulties have been associated with the disease. In more severe COVID- 19 cases, infection can cause pneumonia, severe acute respiratory syndrome, kidney failure and death 1, 3. To the best of our knowledge, currently there is no approved therapy to treat COVID-19 patients 4, 5. As emerging infectious diseases are on the rise, the search for alternative vaccines and therapies has never been more anticipated than now. It is best to learn from the known to the unknown, lessons and management of previous similar viral diseases can be of great asset towards the fight against the current COVID-19 pandemic and other emerging acute respiratory diseases. In previous corona virus epidemics and acute respiratory diseases, herbal and alternative medicines have played important roles both in the prevention and in the treatment of the diseases. For instance, Chinese . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 4 medicinal approaches were used to prevent and treat severe acute respiratory syndrome (SARS) from the 2003 SARS-coronavirus disease 6. Herbal and Traditional Chinese medicines (TCM) have played critical roles in previous viral diseases including SARS- CoV, influenza A H1N1, influenza A H7N9 and COV-SARS viral diseases 7, 8. Traditional Chinese medicines have also been used to prevent and treat severe acute respiratory syndrome (SARS) and H1N1 coronavirus diseases 8, 9 . Ginseng has been traditionally used in Asia for thousands of years to treat a variety of ailments. Ginsenosides, poly and oligosaccharides found in ginseng have been shown in various studies to enhance immune response against viral diseases 9. In other studies, standardized ginseng extract was shown to have preventive and therapeutic effect on influenza virus patients with lower incidence of influenza and stronger immune responses against the disease 10. Ginseng has been used either alone or combined with other herbs for treating chronic respiratory diseases 11 and upper respiratory tract infections 12, 13. Ginseng has also played critical role in the treatment of respiratory viruses which are a major cause of influenza-like viral illness (ILI) including coronaviruses with symptoms characterized by sudden onset of high fever (> 38°C), headache and cough 14, 15 similar to COVID-19. As the world seek for answers on how soon probable therapies and vaccines could be developed to control the spreading and to treat the infected persons of respiratory infections, the use of ginseng should be much investigated. Especially in resource limited countries to prevent infection with COVID-19 and to treat mild COVID-19 cases. However, to the best of our knowledge its effectiveness in treating symptoms associated with COVID-19 has not be explored. Despite the in vivo, in vitro and clinical trials done on ginseng to show their safety and efficacy in preventing and treating viral respiratory infections and chronic respiratory diseases, it has not been considered as potential therapeutic and preventive agent against COVID-19. We aimed in the present study to explore the efficacy of ginseng in preventing and treating acute respiratory viral diseases and the potential of ginseng to serve as preventive or treatment alternative for COVID- 19. Also, the active compounds of ginseng could serve as agents for COVID-19 drug design and development. 2.0 Background . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 5 Insert figure 1: 2.1 Human Pandemic in Retrospect It's been eleven years since the world experienced its devastating last pandemic, the 2009 H1N1 swine flu. Within a space of a year specifically from spring 2009 through to spring 2010, the virus infected huge number of people totaling 1.4 billion across the world and claimed about 1 million lives 16. Presently, over 190 countries of the world have experienced the COVID-19 pandemic, caused by a novel coronavirus labelled SARS- CoV-2 with sequence homology to SARS-COV 16(p19). The emergence of pandemic throughout history occurs at the human–animal interface, when animal infections (zoonotic infections) breach species barriers to infect human 17. During the past several centuries, pandemics that have been identified range from smallpox, measles, H1N1, influenza, AIDS, H2N2, H3N2, Spanish flu, and multi-drug resistance tuberculosis 18, 19, 20, 21). Table 1 gives more insight. As indicated earlier, the last pandemic the world saw is H1N1 swine flu which has several similar characteristics like the present COVID-19 in terms of rates of infection and mortality. Both past and present pandemics have cost the world trillions and trillions of U.S dollars 22. But there are some significant differences between the 2009 H1N1 swine flu and 2019 novel coronavirus (nCOVID-19) and pathophysiologically. By all serious estimates, COVID-19 is going to be a major killer." Before the world experienced the 2009 H1N1 swine flu pandemic there was the first H1N1 Spanish flu in 1918 which remains the deadliest pandemic in the human history 23. The 2009 swine flu pandemic was caused by a new strain of H1N1 that originated in Mexico in 2009. From spring 2009 to June 2009 WHO declared it a pandemic. Comparatively, from April 2009 to April 2010, the wine flu was associated with 12,500 deaths (mortality rate of about 0.02%), and over 274,000 hospitalizations out of the 60.8 million cases 24. The mortality rate for COVID-19 is presently much higher, around 2.13%. This is because, most strains of flu viruses, including those that cause seasonal flu, cause the highest percentage of deaths in people ages 65 and older. But in the case of the H1N1, older people seemed to have already built up enough immunity and were not much affected compared to COVID-19 25. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 6 Table 1: History of global pandemics, mortality, and epic centres Pandemic Year Epicentre Lives lost Antonine plague: smallpox 165–180 AD Rome 5 million Cyprus Plaque of Cyprian 250-271 AD 5000 per day Plague of Justinian: bubonic 541–750 AD Brazil 10% of the world population Black death: bubonic plague 1346-53 Asia to Europe >1/2 of Europe’s population Cocoliztli 1545-48 Mexico & C. America 90% of Western Hemisphere Great plaque of London 1665-66 London 100,000+ Measles: The Americas 16th–19th centuries Great plaque of Marseille 1720-1723 France 100,000 Smallpox: Australasia 18th–19th centuries Smallpox: Americas 16 th-19th centuries Americas Measles: Pacific Islands 19th century Pacific Islands 3rd Bubonic plague: China 19th century China Russian influenza pandemic 1889–90 Moscow 100,000 H1N1 Spanish influenza pandemic 1918-20 Spain 500 million H2N2 Asian influenza pandemic 1958–59 Asia 1 million H3N2 Hong Kong influenza pandemic 1968–69 Hong Kong 35 million Multidrug-resistant tuberculosis 1980s–present AIDS pandemic 1981-present 35 million . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 7 H1N1 influenza ’A’ pandemic 2009–10 151,700-575,400 COVID-19 2019-Present Wuhan-China Over 94 million 2.2 COVID-19 Pathophysiology in humans A new novel coronavirus-induced pneumonia COVID-19 (SARS-CoV-2) first appeared in Wuhan, China in December 2019 25. From its outbreak till date, it has spread to several countries globally 26. As of 20 th July, 2021, there were over 191 million confirmed cases of COVID-19 reported (in accordance with the applied case definitions and testing strategies in the affected countries), including 4.1 million deaths and this COVID-19 is steadily growing by human-to-human transmission 26. The pathogenesis of Covid-19 is still not clear. Little is known about the pathogenesis of coronavirus disease in humans. Coronavirus disease (COVID-19) is caused by SARS- COV-2 which is a potentially fatal disease that is of great global public health concern. Patients with COVID-19 show similar symptoms of SARS-CoV and MERS-CoV which include fever, fatigue, dry cough, dyspnea, myalgia, normal or decreased leukocytes counts, proinflammatory cytokines and radiographic evidence of pneumonia 27,28. Severe pneumonia characterized by interstitial pneumonia, in which there is alveolar fibrosis, as a consequence of congestion, oedma and remodeling of lung parenchyma 29 and necrotizing alveolitis/bronchiolitis; characterized by foci necrosis of the epithelium, and secretions into the lumina is also seen in COVID-19 patient. The above mechanisms impair gaseous exchange mechanisms, leading to hypoxia/hypoxaemia and consequently, severe respiratory distress syndrome and multiorgan failure 26,30. The virus is mainly spread during close contact and through respiratory droplets. The virus accesses host cells through the enzyme ACE2 (figure 2), which is most abundant in the type II alveolar cells of the lungs. ACE2, found in the lower respiratory tract of humans, is identified as cell receptor sites for SARS-CoV 31 and regulates both the cross- species and human-to-human transmission 32. The lungs are the therefore the most target organ of infection by the COVID-19 virus. The virus uses a special surface glycoprotein called a "spike" (peplomer) (figure 2) to connect to ACE2 and enter the host cell. Isolated from the bronchoalveolar lavage fluid (BALF) of a COVID-19 patient, Zhou et . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 8 al., ( 33) have confirmed that the SARS-CoV-2 uses the same cellular entry receptor, ACE2, as SARS-CoV. The viral peplomer is pathogenic, inducing host immune response 34. The virion S-glycoprotein on the surface of coronavirus (figure 2) can attach to the receptor, ACE2 on the surface of human cells 35. ACE2 protein presents in abundance on lung alveolar epithelial cells and enterocytes of small intestine remarkably which may help understand the routes of infection and disease manifestations. Based on current epidemiological investigation, the incubation period is 1–14 days, mostly 3–7 days. And the COVID-19 is contagious during the latency period 36. It is highly transmissible in humans, especially in the elderly and people with underlying diseases. The first event after internalization into host tissue is viral uncoating followed by translation of the viral genomic RNA to produce a virus-specific RNA-dependent RNA polymerase and various viral proteins shown in figure 2 37. Clinically, patient presents with difficulty in breathing (a direct result of airway congestion and obliterating alveolitis), chest tightness, fever, sore throat (due to activation and proliferation of tonsilar lymph nodes). Other extrapulmonary manifestations are due to severe inflammatory response syndrome. The virus spike protein (peplomer) acts as an exogenous pyrogen which upset the hypothalamic temperature regulatory set point (increases the set point) via cyclooxygenase dependent prostalglandins E2 production. Inflammatory cells such as lymphocytes and polymorphs have also been reported to be involved in the pneumonia caused by coronavirus. Insert figure 2: The corona viral particle (COVID-19) attaches to the cellular receptor angiotensin- converting enzyme 2 (ACE2), releases its viral genomic RNA into the host cell and it is translated into proteins necessary for the assembly of new virions within the host cell. Key; S: spike, E: envelope, M: membrane, N: nucleocapsid. PP: polyproteins, ORF: Open reading frame, CoV: coronavirus. Adapted from 38. 2.3 Safety and efficacy of ginseng as an alternative medicine for disease control . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 9 Ginseng has been attributed with a large number of therapeutic effects including antioxidative, anti-inflammatory, vasorelaxant, antiallergic, antidiabetic, and anticancer effects 39. Ginseng extract alone or in combination with other herbs have been employed by herbal therapeutic and preventive medicine in the treatment of a number of medical illnesses 11. Ginseng is well known for its immune modulating effect and has been utilized in immune homeostasis and promoting resistance to illness or microbial infection through the immune system effects 39. Of particular importance is its use in respiratory infections such as chronic obstructive pulmonary disease, influenzas like illnesses and other respiratory tract infections 12, 13, 14, 40. The main active component of Ginseng that is responsible for its pharmaceutical activities and drug interactions are the Ginsenosides 41. There are many types of Ginsenoside with type Rg3 being one of the most important functions on lung diseases. It possesses anti-inflammatory, anti-tumour and anti- fatiguing properties. 42. Ginseng has been generally believed to be protective against pulmonary diseases 43. However, the studies on the efficacy of ginseng in the treatment of pulmonary diseases have been inconclusive due to contradicting evidences from different clinical trials with some studies establishing no clinical significance in alleviation of respiratory symptoms in clinical trials involving ginseng and placebos 40,42. Moreover, other studies have suggested promising pulmonary function and quality of life in patient with chronic obstructive pulmonary disease with the use of ginseng 44,45. Ginseng has been shown to be relatively safe and well tolerated with no significant adverse reaction noted when compared with placebo during clinical trials 39. In addition, drug interaction with Ginseng appears to be rare as drug interaction studied have been inconclusive and have largely yielded negative results or results that suggest only a weak interaction 46. 2.4 Clinical characteristics Table 2: Clinical characteristics of SARS, MERS, H1N1 and COVID-19 Outbreak Pulmonary signs and symptoms Imaging features Complications Approved vaccine(s) Approved drug(s) Reported use of ginseng/ alternative medicine Novel influenza A (H1N1) Fever, cough, fatigue, headache, chills, sore GGO in lung, atelectasis, lung opacities, perihilar reticular, Common cause of death by ARDS, viral pneumonia, YES Yes Yes; Ginseng administration . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 10 throat, coryza alveolar infiltration, otitis media SARS- CoV Hyperpyrexia (more than 38 /i1) Interstitial GGO in lung, parenchymal lesions Common cause of death by ARDS NO Combinati on therapy including TCM Sometimes, Glycyrrhizin from liquorice roots MERS- CoV Fever, cough, polypnea GGO in lung, parenchymal lung lesions, ARDS, renal failure, pericarditis NO NO, supportive care No data COVID- 19 Fever, cough, fatigue, Hyperpyrexia (more than 38 /i1), diarrhoea, dyspnea GGO in lung, pneumonia, ARDS Common cause of death by Pneumonia, ARDS, shock YES NO, supportive care Yes

s 47, 48 49, 50, 48 2 51, 52, 53 30, 54 9, 55, 56,37,57 GGO = Ground-glass opacity, ARDS = acute respiratory distress syndrome. SARS= severe acute respiratory syndrome, MERS=Middle East respiratory syndrome, COVID- 19=corona virus disease 2019 58. 3. Methods 3.1. Data sources and selection We conducted a comprehensive systematic literature search by employing the 6 electronic literature databases MEDLINE [15], PUBMED [17], SCOPUS [65], GOOGLE SCHOLAR [439], WEB OF SCIENCE [42] and the COCHRANE LIBRARY [33] from 1 st April, 2020 to 27 th April, 2020. Furthermore, Medical Subject Heading (MeSH) search was done at National Library of Medicine to create the MeSH terms. Secondary, additional manual search were done by following the relevant reference list of the selected papers. In addition, leading companies with trials on ginseng for respiratory diseases were contacted via email. Studies in each language were screened using the following inclusion criteria: (1) human subjects, (2) use of a control procedure, (3) subjects randomized among treatment conditions, and (4) mono-preparation tests of Panax ginseng or P. quinquefolium. Search strategy . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 11 The database search was conducted in the month of April 2020 from the databases using the MESH terms linked by a Boolean search operators like ‘OR’ for the key MESH terms ‘Ginseng’‘Panax Eleutherococcus’, ‘Eleuthero’, ‘Acanthopanax’, ‘Oplopanax’, ‘Echinopanax’ ‘AND’ ‘Covid-19’, ‘Coronavirus’, ‘Corona virus’, ‘Virus infection’, ‘Viral infection’, ‘Acute respiratory’, ‘Respiratory disease’, ‘Respiratory illness’, and other key words like ‘Trial’, ‘clinical trial’, ‘Randomi’, ‘Controlled study’, ‘Double blind’ and ‘Placebo’ and ‘AND ‘aged’. An initial assessment using the inclusion criteria was made by reading abstracts. Articles that appeared to meet the criteria were then read in full by two authors, who then discussed the articles and made the decision to include or exclude them. 3.2. Data extraction and methodological quality assessment Two authors extracted data from the articles using a standardized, predefined method that considered trial methods, study design, patient characteristics, type of ginseng, outcomes, and side effects. We used the Jadad scale to evaluate the quality of clinical trials 59. Points were awarded depending on the description of randomization, double- blinding, and appropriate/inappropriate methods, including withdrawals and dropouts. On a five-point scale, trials with three or more points were considered high quality. Discrepancies were settled through discussions involving two authors. 3.3. Review process The RCTs were heterogeneous with respect to ginseng species or variety, indications, dose, participant characteristics, and outcome measures. The outcomes of some studies, however, were poorly presented. Therefore, we decided not to pool the data statistically, but performed a qualitative review instead. We reviewed RCTs to formulate conclusions on the effectiveness of ginseng for the following indications: glucose metabolism, physical performance, sexual function, psychomotor function, cardiac function, pulmonary disease, and cerebrovascular function. This method consisted of four levels of evidence on the methodological quality and outcome of the studies as follows: level 1, strong evidence, from generally consistent findings of multiple relevant, high-quality RCTs; level 2, moderate evidence, from generally consistent findings of one relevant, high-quality RCT and one or more relevant, low-quality RCTs; level 3, limited evidence, from generally consistent findings of multiple relevant, low-quality RCTs; and level 4, inconclusive evidence, from only one relevant, low-quality RCT, no relevant RCTs, or . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 12 RCTs with conflicting results. “Generally consistent” was defined as two-thirds or more of the studies having the same result (positive or negative), and “multiple” was defined as more than one. 4. Results Final data analyzed Our searches identified 596 potentially relevant studies, of which 5 trials met our inclusion criteria (Figure 3). Insert figure 3 The key data from all the included RCTs are summarized in Tables 4−6. 3.2. Description of studies and clinical questions Of the 5 trials, 3 originated in Canada, 1 were in the United States, 1 were in South Korea. The clinical variables investigated were as follows: assessment of the effect of ginseng on acute respiratory diseases, prevention respiratory diseases. Table 4: Summary of selected references. Number Trial type Research topic Participants (n) Reference 1 P-CT ARI 2109, 20 weeks in total 60 2 RCT ARI 43, 4 weeks 61 3 Randomized, D- B, P-CT Respiratory Infections 783 for 6 months 62 4 RCT Upper respiratory tract infections 323 for 4 months 63 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 13 5 D-B RCT ARI 100 for 12 weeks 14 RCT = Randomized Clinical Trial. CT = Controlled Trial, D-B = Double-Blind, P-CT = Placebo-Controlled Trial, ARI = Acute respiratory illness Table 5: Methodological quality of included studies according to Jadad et al. (Jadad et al., 1996) and Schultz et al. (Schulz et al., 1995).

Des. as randomiz ed Randomiz ation well des. and appropriat e Outcom e assessm ent blinded Blinding well Des. and appropriat e Descripti on of Withdra wals/dro p-outs Total Jadad score Allocation concealment McElhaney JE et al. (2004) 60 Yes No Yes No Yes 3/5 Unclear McElhaney JE et al. (2006) 61 Yes Yes Yes Yes No 4/5 Clear McElhaney et al., (2011) 62 Yes Yes Yes Yes Yes 5/5 Clear Predy et al, (2005)63 Canada Yes Yes Yes Yes Yes 5/5 Clear Lee et al., 2012 56 Yes No Yes No Yes 3/5 Unclear Key: Des = Described, Table 6: Focus of the selected studies Authors & Location Quality of Paper Jadad GRADE Type G Dose (d) Patient-X Description McElhaney et al, 2006 61, Canada 4/5 P. quinquefolium ex. (COLD-fX) 0.4 g (16 wk) 43 older people To consider the effects of ginseng on prevention of ARI and their result suggest that it significantly reduced the risk and duration of ARI with nonspecific adverse effects . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 14 Predy et al, 2005 63 Canada 5/5 P. quinquefolium ex 0.4 g (16 wk) 323 adults with history of cold To consider the effects of ginseng on prevention of common colds and their result suggest that it significantly reduced the risk of colds with two cases of type-2 diabetes mellitus side effects McElhaney et al, 2004 (60) USA 2/5 P. quinquefolium ex 0.4 g (8−12 wk) (CVT-E002) 198 elderly subjects To consider the effects of ginseng on prevention of ARI and their result suggest that it is effective at preventing ARI with no side effect McElhaney et al., 2011 ( 62) Canada 5/5 P. quinquefolium ex 0.4 g or 0.8g (6 months) (CVT- E002) To assess the effect of ginseng on prevention and treatment of influenza A and B URIs (LCCUs) and their result suggests effective in the prevention of upper respiratory infections (URIs) in healthy adults with no side effect Lee et al., 2012 ( 56) South Korea 3/5 Panax ginseng ex 3g/day (12 wk) 100 adult subjects To assess the effect of ginseng on prevention of ARI and the result suggests that KRG may be effective in protecting subjects from contracting ARI with no side effects URTI = upper respiratory tract infection; ex = extract; ARI = acute respiratory illness; Pt = patient. Meta-Analysis The fixed effect and the random effect models gave similar values, and in these results, we present the random effect model results. Insert figure 4; The meta-analysis study was carried out using the comprehensive meta-analysis package version 3. The pooled effect size for the Random Effect Model (REM) was 0.625 with lower-upper limit of (0.473-0.825) and p = 0.001) which means that ginseng significantly decreased the incidence of acute and upper respiratory infection by 38 %. This indicate that the participants who received the ginseng product, 38 % were protected from getting the infection and were at less risk compared to the placebo group. The p-value was less than 0.05 and indicates that the observed pooled effect was not due to chance. Again, the . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 15 infections in the dosed group were less severe and it was observed that participant receiving the ginseng products recover about 3-days shorter (8.7 days) than the placebo (11.1 days) 63, 56, 62. Quality control check of the meta-analysis Publication bias was evaluated with the funnel plot. The observation sows that there was less bias in the publication figure 5. The funnel plot was symmetrical, indicating free publication bias. Insert figure 5; The heterogeneity of the meta-analysis Tau square (I 2) of 0.00 % indicating no perceived between study variances as confirmed by the p-value for heterogeneity of greater than 0.05 (0.656); similar population sets. It can therefore be considered that the data was homogenous. In addition, the classical measure of heterogeneity which is Cochran’s Q-value for heterogeneity test which was 2.436 (df =4) indicating sufficiently homogeneous and a reliable result. 4.0 Discussion Ginseng is a medicinal plant that has been used in medical practices for more than 2,000 years. In modern medical practice, ginseng has been used as an active substance in the treatment of disease and infections. For example, German Commission approved the use of ginseng as a tonic for reducing stress related to fatigue and declining sexual capacity 64. In addition, ginseng was approved by WHO in 1999 to enhance recovery. Ginseng is believed to have a broad range of biological activities including anti- inflammatory, antioxidant and anti-tumor actions 65. Ginseng extracts has been shown to reduce to reduce the impacts of H1N1 infections 42. In a cell-based plaque assay study conducted by Kim et al. 42, oral administration of ginseng extract reduces the impact of H1N1 infection in mice. Plaque based assay can be used to determine the number of plaque forming units in a virus sample. This assay is effective in determining virus concentration in terms of infectious dose. Kim et al. 42 suggested that ginseng extract can . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 16 be used in combination with conventional medicine in the treatment of H1N1 infections and coronaviruses. Predy et al. 63 conducted an efficacy study using ginseng extracts in preventing upper respiratory tract infections in a randomized controlled trial. From their study, ingestion of a poly-furanosyl-pyranosyl-saccharide–rich extract of the roots of North American ginseng in a moderate dose over 4 months reduced the mean number of colds per person, the proportion of subjects who experienced 2 or more colds, the severity of symptoms and the number of days of cold symptoms among dosed group were less than the control group. Ginseng extracts has been used in few clinical trials. Published clinical trial results showed that ginseng is safe at various dosages and can be effective in relieving the symptoms and reducing the risk and duration of colds and flu. Taken together with conventional medicine, these findings support the efficacy of ginseng as a therapeutic and prophylactic agent for respiratory infections. In this review we summarized the systematic assessment of 5 double-blind RCTs on the effectiveness of Ginseng in the treatment of acute respiratory illness and upper respiratory tract infection. Importantly, only 5 of all identified publication met our inclusion criteria (Fig. 3). A total of 5 out of 596 identified publications were selected and only 3 out of the 5 selected studies were considered to have good methodological quality because these 3 studies have score value of greater that 3 points on Jadad scoring system (Table 3 - 5). A total of 3 out of the 5 selected studies investigated the effectiveness of ginseng on ARI treatment while 2 studies investigated the effectiveness of ginseng on URI treatment. It is noteworthy that there have been various publications that have claimed that Ginseng is efficient in improving immune responses, effective in treating diseases such as cancer, cardiovascular disease and treating acute respiratory diseases. However, most of these claims are based on uncontrol and nonrandomized clinical studies 66. In order to streamline our identified publications to good quality studies, with good methodology and proper controls, we screened the identified articles using inclusion criteria (Fig. 3). In combination with other herbs, Ginseng has previously been used to treat chronic respiratory diseases and upper respiratory tract infections 62. In addition, Ginseng has also been useful in the treatment of influenza like illness and respiratory tract infection . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 17 14. However, to the best of our knowledge its effectiveness in treating symptoms associated with COVID-19 has not be explored. In this systematic review we evaluated the research evidence currently available to access the effectiveness of ginseng in the treatment and prevention of ARI and URI. Three out of the five reviewed RTCs showed that Ginseng reduces the risk and duration of acute respiratory illness with no accompanying significant adverse event. In RTC conducted by McElhaney et al 60, where they compared the effectiveness of American ginseng, CVT-E002, with placebo in institutionalized elderly people between 2000 and 2001. Their result showed that CVT-E002 has potential to prevent ARI 60. Also, in a similar RTC study conducted by McElhaney et al. 61, where they tested the effectiveness of ginseng in preventing ARI COLD-fX (CVT-E002) on elderly people, their result showed that COLD-fX reduce the risk and duration of ARI symptoms 60. Also, Lee et al 56, investigated the effectiveness of Korean Red Ginseng (KRG) on ARI treatment using 100 volunteers. They concluded that Korean Red Ginseng (KRG) has tendency to prevent subject from contracting ARI and can also reduce the duration of ARI symptoms 56. In addition, in a separate RTCs studies by McElhaney et al and Predy et al 62,63, where they investigated the efficacy of ginseng in treatment of URI in healthy adults. They both concluded that ginseng reduced the severity and duration of URI symptoms 62,63. While there is an ongoing race to develop an effective drug and/ vaccine to cure and prevent the spread of Covid-19. It is worth noting that, in the absence of an effective vaccine or antiviral drug for treatment of COVID-19 patients, health care professionals have adopted a supportive care strategy which involves effort to alleviate the symptoms of COVID-19 patients are mainly respiratory symptoms such as fever, dry cough, sore throat and sputum production. As a result, the findings from these RCTs strengthened the claim that Ginseng is effective in treating ARI and URI. In addition, all the five papers reviewed did not report a significant adverse event that is related to Ginseng usage during the period of these studies (Table 6). While previous studies have emphasized the beneficial effect of Ginseng for various therapeutic purposes. The five RCTs reviewed in this paper have provided a platform for . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 18 consideration of Ginseng for use in supportive care of COVID-19 patients. We hope this review serves as a wake-up call for consideration of Ginseng in treatment of COVID-19. The result from the meta-analysis confirms the applicability of ginseng to significantly prevent acute respiratory viral infections including coronavirus disease in humans with a reduction rate of over 60%. The finding is reliable as the studies reviewed had low degree of bias and very homogeneous with I2 of 0.00 and Cochrane’s q-value of 2.4. 5.0 Conclusion The swift emergence of new infectious virus and drug-resistant variants has limited the availability of effective antiviral agents and vaccines. Thus, the development of broad- spectrum antivirals and immunomodulating agents that stimulate host immunity and improve host resilience is essential. Acute Respiratory illnesses (especially among adult population) require significant medical intervention in the primary health-care setting and it should be taken as a matter of urgency, irrespective of gender and age. In spite of the worldwide expansion of the use of ginseng at various dosages over the years, some clinical trials have shown that ginseng has the potential to prevent acute and upper respiratory illnesses, by relieving the symptoms and reducing the risk and duration of the manifestation of different respiratory viruses causing illness (SARS etc.). As the race to develop an efficient drug / vaccine to prevent and treat the spread of COVID-19 continues, this study has been able to reveal the effectiveness of the use of ginseng over the years in treating and alleviating the symptoms of upper and acute respiratory illnesses and further studies into the applicability of ginseng in coronavirus disease prevent and severity reduction is warranted. Ginseng was also observed that the dosed but infected group had less severe infection, shorter sickness duration with faster recovery times than the placebo 63, 56, 62 . Although it is generally believed that ginseng is protective against pulmonary diseases, more research work and clinical trials which can further reveal its benefits for therapeutic purposes, including the treatment of both young and old COVID-19 patients are needed. Also, it will be prudent to further examine factors that may precipitate adverse events as a result of frequent or prolonged ingestion of regulated ginseng extracts. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 19 6.0 References 1. WHO . Coro naviru s. W orld He alth O rgani sa tion. P ubli she d 2020 . Acc e ssed Ap ril 2 7, 2020 . http s: //ww w.wh o.int / w e s t ernpa ci fic / h e a lth -t opi c s / c or o n aviru s 2. 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CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint 24 Appendix A: Search strategies with the Boolean operators and MeSH Terms as used in Web of Science (TITLE-ABS-KEY(ginseng OR "jen shen" OR ninjin OR renshen OR "ren shen" OR schinseng OR shinseng OR panax OR eleutherococcus OR eleuthero OR acanthopanax OR ciwujia OR oplopanax OR echinopanax)) AND (TITLE-ABS-KEY("covid 19" OR coronavirus* OR "corona virus*" OR "virus infection*" OR "viral infection*" OR "acute respiratory" OR "respiratory disease*" OR "respiratory illness*" OR "respiratory infection*" OR "respiratory syndrome*" OR "respiratory tract disease*" OR "respiratory tract illness*" OR "respiratory tract infection*" OR "respiratory tract syndrome*" OR sars OR mers OR "pulmonary disease*" OR "pulmonary illness*" OR "pulmonary infection*" OR "pulmonary syndrome*" OR "lung disease*" OR "lung illness*" OR "lung infection*" OR "lung syndrome*")) AND (TITLE-ABS-KEY(trial* OR randomi* OR "controlled stud*" OR "double blind" OR placebo*)) AND (TITLE-ABS-KEY(aged OR aging OR elder* OR older OR senior* OR "old person*" OR "old people" OR "old population*")) . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint Figures Figure 1: Pictorial view of COVID-19. (Created with BioRender) . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint Figure 2: The life cycle of CoV in host cells. (Created with biorender.com) . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint Figure 3: Updated 2020 PRISMA flow diagram for systematic review and meta-analysis; http://www.prisma-statement.org/. Reports assessed for eligibility (n = 16) Records identified from*: Total Databases (n =596) Medline (n=17) Scoupus (n= 65) Google Scholar (n=439) Web of Science (n=42) Cochrane library (n=33) Records removed before screening: Duplicate records removed (n = 65) Records removed for other reasons (n = 313) Records screened (n = 218) Records excluded** (n = 156) Reports sought for retrieval (n = 62) Reports not retrieved (n = 46) Reports excluded: Outcome didn’t meet our study objective (n = 3) Use of ginseng in combination with other studies (n = 8) Studies included in review (n = 5) Reports of included studies (n = 5) Identification of studies via databases Id en tifi ca tio n Sc re en in g In cl ud ed . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint Figure 4: Meta-analysis results . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint Figure 5: Funnel plot -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 0.0 0.2 0.4 0.6 0.8 Standard Error Log odds ratio Funnel Plot of Standard Error by Log odds ratio . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 25, 2021. ; https://doi.org/10.1101/2021.07.23.21260970doi: medRxiv preprint