The World Health Organisation (WHO) is currently testing the antiviral activity of herbal medicines against Coronavirus (COVID-19). Many herbal targets exist that warrant further research.
Coronaviruses are one cause of the common cold (1). Severe acute respiratory syndrome (SARS-CoV) and the Middle East respiratory syndrome (MERS-CoV) are both coronaviruses (2). Whilst research is being conducted to find pharmaceutical therapeutics for coronavirus, the elusive search for the cure to the common cold is a well known. Herbal medicines have demonstrated anti-influenza and anti-coronavirus activity in past in-vitro and in-vivo studies and this information may guide future research in herbal medicine on influenza and coronaviruses.
Warning
At present Western medicine has no therapeutic treatment available to treat coronavirus. Measures are supportive only and no vaccine is available. The information presented in this article is not aimed to deter anyone from seeking professional medical advice. The herbal medicines mentioned in this article have not been shown in any instance to mitigate, prevent, treat, diagnose, or cure COVID-19 in people.
Herd immunity
Herd immunity describes natural immunity. The term has been adopted by the pharmaceutical industry to describe the effects of artificial immunity through vaccination. An individual's immunity can be acquired through artificial immunity via vaccination or through natural infection (3). Individuals, who are immune to a disease act as a barrier in the spread of disease, slowing or preventing the transmission of disease to others, hence protect the vulnerable. No one supporting herd immunity supports a rapid spread of COVID-19 in vulnerable populations. Herd immunity is a controlled distribution of COVID-19 among groups that are least at risk; restrictions are introduced as and when needed. In an ideal world we would isolate the sick and old on an island while the coronavirus was allowed to run its course in the healthy population. When the herd immunity level of 60% is achieved the virus would be unable to infect further hosts, allowing the vulnerable to safely return. The herd immunity level (HIL), is the percentage at which the disease may no longer persist in the population, putting an end to the pandemic. The herd immunity level for SARs was 50%-80% (4). Regardless of fast tracking vaccine research, most vaccinologists agree a vaccine time-frame of 18 months, presently meaning natural herd immunity is the only option. The other option is an 18 month lock-down and stalling of the global economy until a viable vaccine is produced.
Read about past difficulties with coronavirus vaccine research in Coronavirus (COVID-19) Lockdown; How Long will it Last?
This concept of promoting natural herd immunity was expressed by Sir Patrick Vallance FRS FMedSci FRCP and Government Chief Scientific Adviser (GCSA), who says coronavirus may become an annual event and that Britain needs herd immunity to combat the spread of Covid-19 (3). Professor of Infectious Disease Modelling Graham Medley at the London School of Hygiene and Tropical Medicine also agreed and explained why the Government is trying to actively promote herd immunity by allowing schools to stay open (4). It must be stressed that both experts said at the same time we have to shield the vulnerable and we can do this by taking common sense measures, such as limiting visits and acting like we have the virus when we do.
The UK approach is unique and has received much criticism. The outcomes of the current UK strategy to leave schools open for that short time only will eventually be known by comparing the deaths rates of countries who took different approaches. If this is indeed "the big one", history has shown us that coronavirus will likely come in waves and the UK government's strategy also serves to better prepare the UK for the next wave. A vaccine is of no use when herd immunity is achieved.
To learn which countries are more accepting of the inevitably of COVID-19 to overwhelm health systems and the concurrent need to protect the economy read also Coronavirus (COVID-19) Countries Adopting Herd Immunity
Infection rates
It is that 80% expected to be infected with corona virus (5). To put this into perspective, 80% of global population is 6,240,000,000. In words that is six billion two hundred and forty million people. “Globally, about 3.4% of reported COVID-19 cases have died,” WHO Director-General Tedros Adhanom Ghebreyesus said during a press briefing at the agency’s headquarters in Geneva (6). 3.4% of 212,160,000 in words are two hundred and twelve million, one hundred and sixty thousand deaths globally. We do not know the figures of people with COVID-19 as not everyone is receiving tests, so this is figure is likely inaccurate. At this stage deaths appear to be in the elderly with associated age related diseases (7).
Previous estimated pandemic global death rates
The WHO estimated in a very roundabout way that the Ebola virus resulted in 11 300 deaths and that the expected death toll from a severe influenza pandemic might be 2500 times higher. This is a figure of 28,750,000. The WHO clearly stated that another global pandemic was likely and the world remained woefully unprepared (8). The WHO Global Influenza Surveillance and Response System (GISRS) comprises of 153 institutions in 114 countries (9). The WHO and partners are developing a “Global Influenza Strategy” launched in 2018 (10).
Likelihood of pandemic
Pandemics ignore borders, social class, economic status and age. Globalisation, urbanisation, mass migration and overcrowding accelerate spread. Since 1918 Pandemic Influenza outbreaks have been predictably unpredictable; but always global and needing a global response (11). The Spanish Flu infected one-third of the Earth’s population (500 million people) and is estimated to have killed between 50-100 million (12).
Recent influenza pandemic threats
Avian Flu: 2003 Severe acute respiratory syndrome-related coronavirus (SARSr-CoV), started in China (13).
Swine Flu: 2009 The A (H1N1) Swine Flu started in Mexico, pandemic spread to 214 countries. “The world was lucky” WHO.
Camel Flu: New Global Threat coronavirus Middle East Respiratory Syndrome (MERS) is reported from Saudi Arabia and the Republic of Korea (14).
Coronavirus: 2020 is the latest threat for a global pandemic. This coronavirus is a also known as SARS-CoV-2.
Medical Treatment Options for infleunza
Neuraminidase inhibitors (NA inhibition)
The influenza A virus possesses two surface glycoproteins known as haemagglutinin (HA) and neuraminidase (NA). Balanced HA-NA functions are necessary for efficient influenza virus replication. Inhibiting HA and NA slows down viral replication (15). Three classes of antiviral drugs are available for the prevention and/or treatment of influenza. These drugs are known as neuraminidase inhibitors. Resistance to neuraminidase inhibitors exists and is growing (16).
Medical options for seasonal influenza
There is no vaccine for this current coronavirus. Regarding seasonal influenza, the WHO recommends that annual influenza vaccination as the most effective way to prevent influenza. The following discussion aims to demonstrate the difficulties faced by vaccine manufacturers. An influenza vaccine encourages the body to produce antibodies against virus's haemagglutinin (HA) surface protein. HA is highly mutable, which is why vaccine producers must devise a new formula every year. Influenza vaccine failure can occur when companies incorrectly guess which strains will be in circulation and when circulating strains continue to mutate after the vaccine is made, resulting in vaccine escape mutants.
Influenza vaccine effectiveness however is a hotly debated with a broad range of estimates. According to Public Health England (PHE) and Eurosurveillance regarding the 2017/18 flu season, the influenza Type B Yamagata lineage was circulating which was contained in the quadrivalent but not in last season’s trivalent 2017/18 vaccine (17, 18). It is known that older people have weaker immune system, meaning their protective immune response is low after vaccination and they are less likely to produce antibodies against the disease as desired (19).
CDC Eurosurveillance estimates
CDC state flu vaccine effectiveness in reducing risk of flu between 2005 and 2018 ranges from between 10-60% among the overall population (20). Eurosurveillance indicated 2017/18 flu vaccine effectiveness ranged between 25 and 52% (18).
Netherlands prospective observational cohort study
A study in older adults found influenza vaccination effective at reducing laboratory confirmed influenza virus infections but not influenza-like illness (ILI). ILI, also known as acute respiratory infection (ARI) is the reason for hospitalisations. The incidence of ILI was similar between vaccinated and non-vaccinated (21).
Cochrane review
A 2014 Cochrane flu vaccine review in 88,000 participants had much lower estimates concluding influenza vaccines “probably have a small protective effect against influenza and ILI”, concluding 71 people needing to be vaccinated to avoid one influenza case (1.4% effective) (22).
Rice university study
According to Clinical Infectious Disease Journal, the Rice University study predicted the 2018/2019 influenza vaccine to be 20% effective. The study concludes this is due to viral mutations related to vaccine production in eggs (23).
Natural anti-viral medicine
Covid -19 is a corona virus like Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the recently identified Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV) (24). Haemagglutinin exists in the structure of the coronavirus and is a target for herbal treatment (25). Neuraminidase inhibitors are the cornerstones of the management of patients hospitalised for suspected MERS-CoV infection and SARS corona virus hence neuraminidase is a potential target for herbal treatment (26).
Pharmacognocy
Constituents in herbs exhibit a diverse array of anti-viral, virostatic, antimicrobial, immune enhancing and anti-influenza activities (27).
COVID 19 and Traditional Herbal Medicines (THMs)
A recent report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) acknowledges the of Chinese government has initiated a series of major emergency research programmes many things but also including traditional Chinese medicines and the WHO are currently looking to determine the effectiveness of Traditional Chinese Medicines (TCM) against COVID-19 (28). Many herbal medicines have demonstrated both in-vitro and in-vivo anti-viral activity and warrant future research.
Anti-viral herbal actions required
Haemagglutinin inhibition (prevent viral replication)
Neuraminidase inhibition (prevent viral replication)
Surface spike protein inhibition (prevent viral entry)
Increasing interferon (boost natural immunity)
Inhibit the cytokine storm (prevent the inflammatory cascade)
Herbal Medicines have demonstrated the following actions in in-vitro and in-vivo studies.
Haemagglutinin (HA) inhibition
Influenza haemagglutinin (HA) is a glycoprotein found on the influenza virus surface, along with neuraminidase assists viral replication. (29) The following herbs have been shown to display HA inhibitory effects;
• Catechins isolated from green tea, like EGCG, were found to exhibit mild anti-influenza effect (61) .
• Elderberry (Sambucus nigra) has been traditionally used for treating influenza and colds in western countries. The highly active flavonoids extracted from elderberry inhibit H1N1 infection, comparable to the anti-influenza drug of Oseltamivir. (62) Flavonoids from elderberry extract block viral entry by binding to H1N1 virions. Elderberry inhibits several strains of influenza virus in vitro (30).
• The constituent curcumin in Turmeric (Curcumin longa) targets HA to inhibit virus entry.
• The constituent andrographolide from Andrographis (Andrographis paniculata) displayed inhibitory activity against avian influenza A (H9N2 and H5N1) and human H1N1 influenza A viruses in vitro and in vivo. (64) Andrographolide interferes with HA to prevent the virus from binding to cellular receptors (65).
• The constituent rosmaranic acid from Rosemary (Rosmarinus officinalis) inhibits HA (31).
Neuraminidase (NA) inhibition
Viral neuraminidase is found on influenza virus surfaces and enables viral release from host cells (32).The following herbs have been shown to display NA inhibitory effects;
• The principle active ingredient of the first oral NA inhibitor Oseltamivir is derived from Star anise (Illicium verum) (33).
• Berberine containing herbs such as Barberry (Berberis vulgaris) are antibacterial, antimicrobial, antifungal and antiviral (34). NA inhibition activity of berberines is comparative with Oseltamivir. (35)
• Ganoderma triterpenoids from Reishi (Ganoderma lucidum) display NA inhibition against H5N1 and H1N1 (51).
• Elderberry is also a natural NA inhibitor (36). The compound cyanidin-3sambubiocide, an anthocyanin flavonoid displays potent NA inhibition. (37) The extract displays inhibitory potential on H5N1-type influenza A virus (avian influenza) (36).
Surface spike protein inhibitors
Surface spike proteins are located on the coronavirus surface are involved in mediating the entry of coronavirus into human host cells. Two small molecules, tetra-O-galloyl-beta-D-glucose (TGG) and luteolin have been identified as displaying anti-SARS-CoV activities in wild-type SARS-CoV infection system. TGG is isolated from the traditional Chinese medicine Indian gooseberry (Phyllanthus emblica) (38). More than 200 Chinese medicinal herb extracts were screened for antiviral activities against Severe Acute Respiratory Syndrome-associated coronavirus (SARS-CoV). Four of herbal extracts showed moderate anti-SARS-CoV activity.
The herbal medicines tested were;
• Red spider lily (Lycoris radiate)
• Sweet wormwood (Artemisia annua)
• Large-lipped rustyhood (Pterostylis lingua)
• Japanese evergreen spicebush/ wūyào (Lindera aggregate) (39).
Interferons
Interferons (IFN) are proteins called cytokines produced by white blood cells. IFN “interferes" with viral replication to protect cells from virus infections by triggering an increase in natural killer cells, macrophages, phagocytes and other immune cells to eradicate pathogens, not only viruses, but also bacteria, fungus, parasites and tumours (40). IFN up-regulates antigen presentation by increasing the expression of major histocompatibility complex (MHC) antigens which allow T cells to differentiate foreign antigens from self peptides so as to avoid auto-immunity. (40) Fever is mediated by the release of endogenous pyrogens, cytokines such as tumour necrosis factor (TNF), interleukin (IL)-1, IL-6, and IFN into the bloodstream (41).
The following herbs have been shown to increase IFN;
• Elderberry (Sambuccus nigra) fruit extracts enhance IFN-β response (42).
• Astragalus (Astragalus membranaceus) root extract enhances IFN-β response (42). Astragalus polysaccharide enhances immunity and inhibits H9N2 avian influenza virus in vitro and in vivo. (43)
• Echinacea’s (Echinacea angustifolia/Echinacea angustifolia) anti-viral properties are contributed to its action to increase IFN. (44-46) These anti-viral properties are comparable with Oseltamivir (47).
• Curcuma in Turmeric’s (Curcuma longa) immune-stimulatory and anti-inflammatory activities are in part contributed to its ability to increase IFN (63).
Preventing inflammatory cascade (cytokine storm)
The cytokine storm is when immune cells and their activating compounds (cytokines)are overproduced. During influenza infection it is this surge of activated immune cells into the lungs that leads to high mortality rates (48). Suppression of the cytokine release correlates with reduced death rates in clinical diseases such as pandemic influenza where a cytokine storm plays a significant role in high mortality rates (61, 62). The following herbs have been shown to inhibit the inflammatory cascade;
• The immune-modulatory activities of Echinacea (Echinacea purpurea) comprise of stimulation of macrophages phagocytic activity and suppression of the proinflammatory cytokines and chemokine responses of epithelial cells to viruses and bacteria. (49)
• The active constituent andrographolide in Andrographis (Andrographis paniculata) inhibits influenza A virus and reduces inflammatory cytokine expression induced by infection. (50)
• Curcumin (Curcuma longa) a polyphenol in turmeric, inhibits key pro-inflammatory cytokines, interleukin (IL) IL-1, IL-6 and tumour necrosis factor (TNF) TNF-α. (51)
Vitamins
Vitamin D
Vitamin D deficiency is described as a European pandemic and deficiency in the Irish well established (52, 53). Vitamin D is known to treat colds. Results in treating flu like symptoms have been described a dramatic (54). Influenza-like illness (ILI) is the reason for hospitalisations in influenza. Decreasing ILI will lower the curve and is the primary objective to reduce the strain on the healthcare system. A 2017 meta-analysis of over 11,000 participants found Vitamin D protected against ILI among all participants and that supplementation was safe. Results were greater in vitamin D deficient participants (55). Investigators found in vitamin D deficient individuals, daily or weekly supplementation cut risk of ILI in half (56). In addition, a meta-analysis concluded that long-term vitamin D supplementation prevents overall mortality (57). The NHS acknowledges that Vitamin D can reduce healthcare associated influenza costs (58).
Vitamin C
A Cochrane review looking at Vitamin C for preventing and treating the common cold reported that whilst more research is needed, acknowledged that vitamin C reduced the duration and severity of colds when supplemented regularly (59).
Zinc
A systematic review and meta-analysis of randomised controlled trials of zinc for the treatment of the common cold found that zinc may shorten the duration of symptoms of the common cold by between two and three days (60). The NHS promote zinc as an immune stimulant and say it can cut length of common cold (61) . A Cochrane study found that zinc inhibits rhinoviral replication and can treat the common cold. The review found that when taken within 24 hours of onset of symptoms, zinc is beneficial in reducing the duration and severity of the common cold in healthy people. People taking zinc are less likely for their cold to persist beyond seven days of treatment. Zinc supplementation for at least five months reduces incidence, school absenteeism and prescription of antibiotics for children with the common cold (62).
Abbreviations
Acute respiratory infection (ARI)
Haemagglutinin (HA)
Interleukin (IL)
Influenza-like illness (ILI)
Interferon (IFN)
Major histocompatibility complex (MHC)
Neuraminidase (NA)
Tumour necrosis factor (TNF)
World Health Organisation WHO
1. Paules CI, Marston HD, Fauci AS. Coronavirus Infections-More Than Just the Common Cold. Jama. 2020.
2. Gong SR, Bao LL. The battle against SARS and MERS coronaviruses: Reservoirs and Animal Models. Animal models and experimental medicine. 2018;1(2):125-33.
3. Merrill RM. Introduction to Epidemiology2013.
4. Wallinga J, Teunis P. Different Epidemic Curves for Severe Acute Respiratory Syndrome Reveal Similar Impacts of Control Measures. American Journal of Epidemiology. 2004;160(6):509-16.
5. Hutchison LWaC. 80% of population could become infected by coronavirus: BBC News; 2020
6. Higgins-Dunn BLJaN. WHO says coronavirus death rate is 3.4% globally, higher than previously thought: CNBC News; 2020
7. Leung H. A 36-Year-Old Man Is the Youngest Fatality of the Wuhan Coronavirus Outbreak So Far. Time. 2020.
8. Pandemic risk: how large are the expected losses? [press release]. Geneva Switzerland2020.
9. WHO. Pandemic influenza: an evolving challenge 2018 [Available from:
10. WHO. WHO launches new global influenza strategy 2019 Mar 11 [Available from: https://www.who.int/news-room/detail/11-03-2019-who-launches-new-global-influenza-strategy.
11. WHO. Pandemic influenza: an evolving challenge [Internet]. 2018 [updated 2018 May 22. Available from: http://www.who.int/influenza/pandemic-influenza-an-evolving-challenge/en/.
12. Taubenberger JK. The origin and virulence of the 1918 "Spanish" influenza virus. Proc Am Philos Soc. 2006;150(1):86-112.
13. Xu R-H, He J-F, Evans MR, Peng G-W, Field HE, Yu D-W, et al. Epidemiologic clues to SARS origin in China. Emerging infectious diseases. 2004;10(6):1030-7.
14. Bhatia PK, Sethi P, Gupta N, Biyani G. Middle East respiratory syndrome: A new global threat. Indian journal of anaesthesia. 2016;60(2):85-8.
15. Mitnaul LJ, Matrosovich MN, Castrucci MR, Tuzikov AB, Bovin NV, Kobasa D, et al. Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. Journal of virology. 2000;74(13):6015-20.
16. Nitsch-Osuch A, Brydak LB. Influenza viruses resistant to neuraminidase inhibitors. Acta biochimica Polonica. 2014;61(3):505-8.
17. Cosford P. Flu and flu vaccines: Expert interview: Public Heath UK 2018 [Available from: https://publichealthmatters.blog.gov.uk/2018/01/11/flu-and-flu-vaccines-expert-interview/.
18. Marc Rondy EK, Hanne-Dorthe Emborg, Alin Gherasim, Richard Pebody, Ramona Trebbien, Francisco Pozo et al. Interim 2017/18 influenza seasonal vaccine effectiveness: combined results from five European studies. Eurosurveillance. 2018 Mar 01;Volume 23(9).
19. CDC. Vaccine Effectiveness - How Well Does the Flu Vaccine Work? [Internet]. 2018 [updated 2018 Sept 06.
20. CDC. Seasonal Influenza Vaccine Effectiveness, 2005-2018 [Internet]. 2018 [updated 2018 Feb 15. Available from: https://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm.
21. van Beek J, Veenhoven RH, Bruin JP, van Boxtel RAJ, de Lange MMA, Meijer A, et al. Influenza-like Illness Incidence Is Not Reduced by Influenza Vaccination in a Cohort of Older Adults, Despite Effectively Reducing Laboratory-Confirmed Influenza Virus Infections. The Journal of infectious diseases. 2017;216(4):415-24.
22. Demicheli V, Jefferson T, Ferroni E, Rivetti A, Di Pietrantonj C. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2018;2:CD001269.
23. Bonomo ME, Deem MW. Predicting Influenza H3N2 Vaccine Efficacy From Evolution of the Dominant Epitope. Clinical Infectious Diseases. 2018;67(7):1129-31.
24. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;1282:1-23.
25. Zeng Q, Langereis MA, van Vliet ALW, Huizinga EG, de Groot RJ. Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(26):9065-9.
26. Bleibtreu A, Jaureguiberry S, Houhou N, Boutolleau D, Guillot H, Vallois D, et al. Clinical management of respiratory syndrome in patients hospitalized for suspected Middle East respiratory syndrome coronavirus infection in the Paris area from 2013 to 2016. BMC Infect Dis. 2018;18(1):331.
27. Arora R, Chawla R, Marwah R, Arora P, Sharma RK, Kaushik V, et al. Potential of Complementary and Alternative Medicine in Preventive Management of Novel H1N1 Flu (Swine Flu) Pandemic: Thwarting Potential Disasters in the Bud. Evidence-based complementary and alternative medicine : eCAM. 2011;2011:586506.
28. WHO. Determination of the effectiveness of Traditional Chinese Medicines (TCM). Geneva 2020 Feb 24.
29. Wilks S, de Graaf M, Smith DJ, Burke DF. A review of influenza haemagglutinin receptor binding as it relates to pandemic properties. Vaccine. 2012;30(29):4369-76.
30. Zakay-Rones Z, Varsano N, Zlotnik M, Manor O, Regev L, Schlesinger M, et al. Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama. J Altern Complement Med. 1995;1(4):361-9.
31. Shen X, Zhang X, Liu S. Novel hemagglutinin-based influenza virus inhibitors. Journal of thoracic disease. 2013;5 Suppl 2(Suppl 2):S149-S59.
32. Contributors W. Viral neuraminidase. Wikipedia2-19.
33. Oseltamivir. 2018.
34. Wu Y, Li JQ, Kim YJ, Wu J, Wang Q, Hao Y. In vivo and in vitro antiviral effects of berberine on influenza virus. Chinese journal of integrative medicine. 2011;17(6):444-52.
35. Enkhtaivan G, Muthuraman P, Kim DH, Mistry B. Discovery of berberine based derivatives as anti-influenza agent through blocking of neuraminidase. Bioorganic & medicinal chemistry. 2017;25(20):5185-93.
36. Krawitz C, Mraheil MA, Stein M, Imirzalioglu C, Domann E, Pleschka S, et al. Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human respiratory bacterial pathogens and influenza A and B viruses. BMC Complement Altern Med. 2011;11:16.
37. Swaminathan K, Dyason J, Maggioni A, von Itzstein M, M Downard K. Binding of a natural anthocyanin inhibitor to influenza neuraminidase by mass spectrometry2013.
38. Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. 2004;78(20):11334-9.
39. Li S-y, Chen C, Zhang H-q, Guo H-y, Wang H, Wang L, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Research. 2005;67(1):18-23.
40. Wikipedia. Interferon. Wikipedia2018.
41. Netea MG, Kullberg BJ, Van der Meer JWM. Circulating Cytokines as Mediators of Fever. Clinical Infectious Diseases. 2000;31(Supplement_5):S178-S84.
42. Frokiaer H, Henningsen L, Metzdorff SB, Weiss G, Roller M, Flanagan J, et al. Astragalus root and elderberry fruit extracts enhance the IFN-beta stimulatory effects of Lactobacillus acidophilus in murine-derived dendritic cells. PLoS One. 2012;7(10):e47878.
43. Kallon S, Li X, Ji J, Chen C, Xi Q, Chang S, et al. Astragalus polysaccharide enhances immunity and inhibits H9N2 avian influenza virus in vitro and in vivo. Journal of animal science and biotechnology. 2013;4(1):22-.
44. McCann DA, Solco A, Liu Y, Macaluso F, Murphy PA, Kohut ML, et al. Cytokine- and interferon-modulating properties of Echinacea spp. root tinctures stored at -20 degrees C for 2 years. J Interferon Cytokine Res. 2007;27(5):425-36.
45. Wu H, Nardone A, Lacetera N. Effects of a standardized purified dry extract from Echinacea angustifolia on proliferation and interferon gamma secretion of peripheral blood mononuclear cells in dairy heifers. Res Vet Sci. 2009;87(3):396-8.
46. Zhai Z, Liu Y, Wu L, Senchina DS, Wurtele ES, Murphy PA, et al. Enhancement of innate and adaptive immune functions by multiple Echinacea species. J Med Food. 2007;10(3):423-34.
47. Karel Rauš SP, Peter Klein, Roland Schoop and Peter Fisher. Effect of an Echinacea-Based Hot Drink Versus Oseltamivir in Influenza Treatment: A Randomized, Double-Blind, Double-Dummy, Multicenter, Noninferiority Clinical Trial
Curr Ther Res Clin Exp. 2015;77:66–72.
48. Aida Sivro DRS, Lyle R. McKinnon. The Role of Cytokine Storm in Influenza Pathogenesis. Purple Paper. 2011(23).
49. Hudson JB. Applications of the phytomedicine Echinacea purpurea (Purple Coneflower) in infectious diseases. Journal of biomedicine & biotechnology. 2012;2012:769896-.
50. Ding Y, Chen L, Wu W, Yang J, Yang Z, Liu S. Andrographolide inhibits influenza A virus-induced inflammation in a murine model through NF-kappaB and JAK-STAT signaling pathway. Microbes and infection. 2017;19(12):605-15.
51. Sordillo PP, Helson L. Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. In vivo (Athens, Greece). 2015;29(1):1-4.
52. Cashman KD DK, Skrabakova Z, Gonzalez-Gross M, Valtuena J, De Henauw S, , et al. Vitamin D deficiency in Europe: pandemic? . Am J Clin Nutr. 2016;103:1033–44.
53. Fiona O'sullivan EL, Dervla Kelly, Jos van Geffen, Michiel van Weele, Helene McNulty et al. Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. The Journal of Nutrition. 2017 May;147(5):858–68,.
54. Schwalfenberg G. Vitamin D for influenza. Can Fam Physician. 2015 61(6):507.
55. Adrian R Martineau DAJ, Richard L Hooper, Lauren Greenberg, John F Aloia, Peter Bergman et al., . Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356(16).
56. Morrison SMaM. Study confirms vitamin D protects against colds and flu [Internet ]. Harvard Gazette; 2017
57. Yayuan Zheng JZ, Manru Zhou, Liao Cui, Weimin Yao , Yuyu Liu Meta-Analysis of Long-Term Vitamin D Supplementation on Overall Mortality PLOS ONE. 2013;8(12):1-13.
58. NHS. 'Add vitamin D to food to prevent colds and flu', say researchers 2017 [Available from: https://www.nhs.uk/news/food-and-diet/add-vitamin-d-to-food-to-prevent-colds-and-flu-say-researchers/.
59. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews. 2013(1).
60. Science M, Johnstone J, Roth DE, Guyatt G, Loeb M. Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. Canadian Medical Association Journal. 2012;184(10):E551.
61. NHS. Zinc 'can cut length of common cold': Crown 2020 [Available from: https://www.nhs.uk/news/medication/zinc-can-cut-length-of-common-cold/.
62. Singh M, Das RR. Zinc for the common cold. Cochrane Database of Systematic Reviews. 2011(2).
