key: cord-0728302-c6od3zxm
authors: Martin, Brett R; Richardson, Joshua
title: An exploratory review of Potential Adjunct Therapies for the Treatment of Coronavirus Infections
date: 2021-12-11
journal: J Chiropr Med
DOI: 10.1016/j.jcm.2021.12.005
sha: 7457ed16d3a06bb6607d1172c25a03bd3de541f2
doc_id: 728302
cord_uid: c6od3zxm

Objective The purpose of this exploratory review c, including vitamin D, zinc, vitamin A, elderberry (S nigra), garlic (A sativum), licorice (G glabra), stinging nettle (U dioica), N-acetylcysteine, quercetin and selenium as potential adjunct therapies for the treatment of coronavirus infections. Methods A search of PubMed was performed for articles published from 2005 to 2021. Key words searched were zinc, vitamin A, vitamin D, Sambucus nigra, Allium sativum, Glycyrrhiza glabra, Urtica dioica, N-Acetylcysteine, quercetin, selenium and coronavirus. Results There were 47 articles selected for this review. Findings included that vitamin D, zinc, vitamin A, S nigra, A sativum, G glabra, U dioica, N-acetylcysteine, quercetin and selenium have been shown to produce anti-inflammatory, immunostimulatory or antiviral effects that may enhance the actions of standard therapeutics for the treatment of CoV infections. We found only research articles related to the effects of vitamin D, zinc, G glabra, quercetin and selenium against COVID-19. Conclusion We identified non-pharmaceutical supplements (Vitamin D, zinc, vitamin A, S nigra, A sativum, G glabra and U dioica) which may have potential to provide support for those with coronavirus infections. However, rigorous clinical studies need to be performed before any clinical recommendations can be made at this time.

The coronavirus (CoV) is a single stranded RNA virus (ssRNA). 1 As a positive sense virus, the RNA in its genome encodes for the sense strand allowing it to quickly translate proteins. 1 The CoV is a sizeable, enveloped virus within the order of Nidovirales, family of Coronaviridae, sub-family Coronavirinae. 1 The CoV is categorized in the genera of Coronavirinae as follows, alpha-coronavirus (α-CoV), beta-coronavirus (β-CoV), delta-CoV and gamma-CoV. 2 α and β-CoV are the primary viruses that infect the human population. 2, 3 However, researchers have hypothesized that studying treatments for other strains of CoV such as delta or gamma may be applicable for the development of therapeutic strategies for human infections. 4 The viruses from the sub-family, Coronavirinae, are capable of infecting birds and mammals, which allows for the potential of zoonotic infections. 2, 5, 6 The coronavirus disease (COVID)-19 that caused the pandemic that began in 2019 is an example of a zoonotic infection that majorly impacted the human population. 7 COVID-19 is caused by a severe acute respiratory syndrome (SARS)-CoV-Pathogenic viruses have the ability to infect and reproduce in a host by overwhelming the defenses of the body resulting in disease. 14 Once cells are invaded and replication begins, the possibility of both chronic and acute illnesses of the hepatic, gastrointestinal, respiratory and neurological system ensues. 11 The pathophysiological process is characterized by an increased expression of nuclear factor-κB (NF-κB). 15 NF-κB is an inflammatory transcription factor that upregulates the arachidonic cascade and eicosanoid production and release. 16 The activation of NF-κB potentiates the release of the inflammatory mediators interleukin (IL)-1, IL-6 and IL-8, monocyte chemotactic protein (MCP)-1 and tumor necrosis factor (TNF). 15, 17 The IL-1 family stimulates the release of other inflammatory cytokines. 18 IL-6 was the primary mediator amplifying systemic inflammatory state. 17 IL-8 is involved with the nonspecific inflammatory response by activating neutrophils and recruiting T cells to the site of inflammation. 19 MCP-1 promotes the generation of various chemicals that intensify the inflammatory process. 19 TNF activates NF-κB potentiating the synthesis of proinflammatory eicosanoids. 20 The synthesis and release of plasminogen activator inhibitor-1 (PAI-1), which is a procoagulant, is correlated with a severe case of the infection. 17 PAI-1 is involved with the formation of a thrombus, which has been shown to be a complication of CoV infections including COVID-19. 21, 22 The primary host of the SARS-CoV-2 that caused COVID-19 was suspected to be animal in origin. 3 The source of the infection has not been established. 10, 23 However, the preliminary cases were traced back to Wuhan, China. 10, 23 The typical host of the SARS-CoV-2 and COVID- 19 is the chiroptera, more commonly known as the bat. 10, 23 Bats are capable of acting as the primary reservoir for several species of CoV. 10, 23 There are several characteristics of bats that could allow them to be the ideal agent to increase the rate of transmission of the virus. 14 Bats live in close proximity to one another, have a long life span and are able to migrate over great distances. 14 Once the virus is spread from an animal reservoir to a human, it can be transmitted to other people via respiratory droplets. 10, 23 The respiratory droplets come in direct or indirect contact to mucous membranes of the oral or nasal cavity. 10, 23 CoV can be aerosolized indoors, which potentiates the spread of the virus. 10, 23 The SARS-CoV-2 targets the ACE-2 receptor that is expressed in the epithelial lining of the respiratory tract and the mucosa of the small intestine. 23 As the respiratory tract and gastrointestinal lining contain ACE-2 receptors, the signs and symptoms that manifest are associated with these systems. 10 Consequently, the onset of symptoms related to COVID-19 is characterized by a cough, dyspnea, fever, fatigue, headache, chills, pharyngitis, myalgias, malaise, anosmia and ageusia. 24 However, diarrhea and nausea may be present. 23 For a majority of cases, the infection is mild and transient. 23 Complications of COVID-19 can occur due to damage to the alveoli of the lungs increasing the susceptibility of the individual to develop pneumonia, acute respiratory distress syndrome or respiratory arrest. 23 The populations that are most at risk for developing a severe infection resulting in complications are the elderly, immunocompromised and individuals with preexisting conditions. 23 There is the potential for excessive inflammation that can overwhelm the body causing multiorgan failure or death. 23 There are several medications utilized for the treatment of CoVs including SARS-CoV-2, which causes COVID-19. Tocilizumab is an antirheumatic and immunosuppressant medication that has been shown to reduce the severity of CoV infections by down-regulating IL-6 and PAI-1. 25, 26, 27 Chloroquine and hydroxychloroquine have impeded the ability of the virus to enter the cells of the host in in vitro studies. 28 However, its clinical efficacy has been highly debated. The combination of Lopinavir and Ritonavir demonstrated some benefits in in vitro studies and a systemic review revealed that there was a reduction in overall mortality and intubation rates. 28 Unfortunately, these antivirals must be utilized within the initial replication phase to have a positive clinical outcome. 28 Ribavirin was required at a very high dose to diminish viral replication. 28 The high dosage may increase the risk of adverse effects experienced by the patient. 28 To enhance its efficacy, it is recommended to use in conjunction with other therapies. 28 Currently, Remdesivir appears to be the most effective agent for impairing the replication of the CoV. 28 It has demonstrated potent antiviral activity in in vitro trials. 28 To date, there have been no clinical trials with Remdesivir and there are concerns related to the safety and efficacy for the treatment of human diseases. 29 Various vaccines are currently available to combat the virus that causes COVID-19. The overall efficacy of the BioNTech/Pfizer, Moderna, AstraZeneca/Oxford and Janssen vaccines are 95%, 94.1%, 66.7% and 66.9% respectively. 30 However, the number of cases is currently on the rise due to variations of the original virus. One study found that the Delta variant is 60% more infectious and that it is moderately resistant to vaccines especially in people that were only administered a single dose. 31 In addition, US citizens are hesitant to vaccinate due to a fear of the potential side effects, a lack of trust in the government and their policies and negative attitudes circulating on social media. 32 Due to the absence of a highly effective antiviral medication, the formation of new viral variants, the potential resistance to vaccine and the unwillingness of some individuals to vaccinate, the utilization of non-pharmaceutical therapeutics as adjuncts may have the potential improve the clinical outcome of infections. Certain natural extracts have the ability to enhance the immune function. For example, vitamin A has been shown to regulate T cell activation. 33 Other nutraceuticals can reduce prooxidant production and inflammation, which may improve the symptomatology associated with an infection.

However, at this time, it is unknown what non-pharmaceutical products may have an effect on those infected with coronavirus. Therefore, the purpose of this exploratory review is to identify and discuss non-pharmaceutical products for the treatment of coronavirus.

We selected the following supplements: vitamin D, zinc, vitamin A, elderberry (Sambucus nigra), garlic (Allium sativum), licorice (Glycyrrhiza glabra),stinging nettle (Urtica dioica), N-Acetylcysteine (NAC), quercetin and selenium. A narrative review of the literature was performed in October of 2020 utilizing the computerized database Pubmed. We searched for studies published in English between 2005-2021. The relevant key words that were zinc, vitamin A, vitamin D, Sambucus nigra, Allium sativum, Glycyrrhiza glabra, Urtica dioica, N-Acetylcysteine, quercetin, selenium and coronavirus. The search parameters have been provided in Table 1 . The only academic resource utilized was Pubmed. The studies selected for this review evaluated the potential inhibitory activity of the therapeutics against the CoV infections and were available as free full text articles. Literature reviews, hypothetical reviews, narrative reviews, commentary articles and studies evaluating herbal formulas or in vivo intravenously administered nutraceuticals were excluded.

We selected 47 journal articles from 325 found during our search. The results of the literature review revealed a variety of articles related to the antiviral nature of non-pharmaceuticals against CoV infections.

The research on the effects of natural agents for the treatment of CoV infections was limited for all nutraceuticals with the exception of vitamin D. However, there were a few studies discussing the antiviral activity of the nutraceuticals against CoV infections. Although these vitamins, minerals and herbs do not have an abundant amount of research supporting their use, this information may assist with further study of their effect on the pathophysiology of the infection initiated by the CoV. It is possible that use of non-pharmaceuticals may support other mainstream therapies which may ultimately improve the clinical course of the disease.

We considered if Vitamin D may attenuate the symptoms associated with infections due to the CoV. Since NF-κB is activated during a CoV infection, vitamin D may down-regulate the inflammatory process by inactivating the transcription factor. 34 IL-6 is the primary IL associated with the inflammatory process induced by CoV infections. 17 This has been proposed as a target for therapeutic treatment. 25, 26, 27 Vitamin D can mitigate the levels of IL-6 and attenuate the concentration of other inflammatory mediators that may contribute to the severity of CoV such as IL-1, IL-8 and TNF-α as well as increase the production of the anti-inflammatory agent IL-10. 35, 36, 37 The direct inhibition of MCP-1, which is elevated with a CoV infection, by vitamin D has not been shown. However, evidence shows that vitamin D can assuage the sequela of MCP-1 activity by decreasing macrocyte migration and the expression of receptors associated with MCP-1 and chemokines overall decreasing the inflammatory response. 38 Vitamin D can reduce the activity of procoagulants, but there is no evidence that it has a direct effect on the physiologic function of PAI-1, which is secreted in greater concentrations during an infection. 17, 39 As hemostatic and thrombotic complications have been observed in cases of COVID-19 and anticoagulants are administered as part of the standard therapy, the additional anticoagulant activity of vitamin D may have a positive impact on the treatment outcome. 40 In addition, vitamin D may enhance the immune function increasing resistance to certain pathogens. A correlation between a vitamin D deficiency and an increased risk of developing an infection especially those of the upper respiratory tract has been established. 41 In addition, patients that are suffering from severe infections have significantly lower levels of vitamin D. 41 Supplementing with vitamin D may reduce the susceptibility to infection by enhancing the conversion of monocytes to macrophages via regulation of gene expression. 41, 42 This potentiates the phagocytosis of antigens and may aid in eliminating the pathogen. 41 In addition, vitamin D is capable of regulating the release of inflammatory mediators by lymphocytes, which may decrease the severity of an infection. 41 There were 10 studies that determined vitamin D status and the susceptibility of the individual to develop an infection, 7 found an associated between a deficiency of vitamin D in the form of 25hydroxycholecalciferol and the potential to be infected with COVID-19. 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 In the 3 articles that did not find a correlation between vitamin D status and the risk of infection, 1 article recorded a significantly lower level of vitamin D when age and body mass index (BMI) were adjusted for, which indicates that additional factors may influence the development of an infection. 50 The other 2 studies observed vitamin D users compared to nonusers. In both of these articles, habitual use of vitamin D was recognized to reduce the incidence of developing COVID-19. 51, 52 This seems plausible as the data collected by Cereda et al found that only 11.7% of those afflicted with COVID-19 had supplemented with vitamin D in the in the past 3 months. 49 Consequently, individuals chosen for these studies may have supplemented with vitamin D in the past year, but were not necessarily ingesting vitamin D on a consistent basis.

Another distinguishing factor between the studies was the measurement of vitamin D levels as 25-hydroxycholecalciferol. All 10 of the studies evaluated vitamin D levels of the patients with COVID-19. Of the 3 studies that did not find an association between vitamin D status and the risk of infection, 2 of studies considered 20 ng/mL as deficient and 1 used 10 ng/mL as its deficiency value. 50, 51, 52 One of the studies that documented an association used 10 ng/mL as an indication of deficiency while the other 3 measured a deficiency under 20 ng/mL and 2 gauged a severe deficiency under 5 or 10 ng/mL. 43, 44, 46, 47, 48, 49 Individuals with a severe deficiency had a greater potential of infection. 46, 47 The discrepancy between the studies may be alleviated by the statistics obtained by D'Avolio et al. D'Avolio et al noted that patients with COVID-19 had a median vitamin D level of 22 ng/mL signifying that those that are infected may be borderline clinically deficiency. 45 Consequently, the analysis of infected patients with a severe deficiency may be the critical difference in the results of the studies that did not find an association between vitamin D levels and infection risk.

Meltzer et al was the only study that did not determine vitamin D status based on serum received from active participants. In their study, the investigators indicated that a vitamin D deficiency was correlated with an increased incidence of infection. 43 However, this was a retrospective study based on medical records from the past year. Individuals with deficiency as determined by less than 20 ng/ml of vitamin D according to previous test results had a higher potential to test positive than patients with serum vitamin D over 20 ng/ml. 43 Due to the absence of a consensus on the association between the risk of being infected and vitamin D status, a meta-analysis review was conducted. There were 8 meta-analysis studies conducted reviewing the incidence of infection and serum vitamin D. All 8 of the meta-analysis studies determined that individuals with lower levels of vitamin D had a greater susceptibility to the infection. 53, 54, 55, 56, 57, 58, 59, 60 However, Liu et al found that only 4 of the 10 studies analyzed reported a correlation of infection with low vitamin D, yet overall, the authors concluded that the data reflected a relationship between a vitamin D deficiency or insufficiency and the potential to be infected. 54 The data collected by Pereira et al indicated that 3 studies recorded patients with serum 25-hydroxycholecalciferol less than 20 ng/mL had a higher potential to be infected and in 17 studies 39% of patients with COVID-19 were vitamin D deficient while 38% of patients in 13 studies had insufficient levels of vitamin D. 53 The meta-analysis by Petrelli et al documented that patients with a vitamin D deficiency were at a 50% higher risk of being infected than individuals with normal levels. 57 From the quantity of evidence available, there appears to be a strong association between low serum vitamin D and the susceptibility to developing an infection.

There were 6 studies analyzing vitamin D levels and the severity of infection. Six of the studies signified that a vitamin D deficiency was associated with a severe infection. 45, 46, 47, 48, 61, 62 Avolio et al found that cases with a severe infection from SARS were vitamin D deficient with a mean serum vitamin D value at 11.1 ng/mL, which seems consistent with the data from other trials. 45 According to Cereda et al, 54 .3% of the population with a severe vitamin D deficiency had a higher probability of being admitted to the intensive care unit (ICU). 48 The data from De Smet et al was congruent with that from Cereda et al concluding that 59% of individuals hospitalized were vitamin D deficient, 30% were experiencing inflammation of the cells in the interstitial space of the lungs and 46% experienced damage to the alveoli with consolidation and fibrosis of the lung tissue. 61 A potential reason that individuals with a vitamin D deficiency may have a greater incidence of a severe infection is a marked reduction in lymphocytes and CD8 T cells, which has been found in patients with COVID-19. 63 CD8 T cells are converted into cytotoxic T cells, which minimize the spread of microbial infections. 64 Therefore, it is plausible that a vitamin D deficiency may be correlated with a severe COVID infection.

There were 8 out of the 10 meta-analysis articles that discussed vitamin D deficiencies and the potential for succumbing to a serious infection. All 8 of the reviews found that low levels of vitamin D were correlated with a severe infection. 53, 55, 56, 57, 58, 59, 60, 65 Pereira et al evaluated twenty-five articles and determined that 65% of patients with a severe COVID-19 infection had a vitamin D deficiency. 53 The analysis by Munshi et al observed that individuals with insufficient levels of vitamin D were at risk of a serious infection with a poor prognosis. 65 Although all of the meta-analysis articles agreed that patients that are vitamin D deficient have a greater potential for a severe CoV infection, there was a general lack of information and a few discrepancies in relation to vitamin D status and the requirement for hospitalization, a ventilator or admission to the ICU. There were 3 studies included in the article by Wang et al that indicated that there was a higher rate of hospitalizations and 2 studies that showed that the duration of hospital stays was longer in individuals that were vitamin D deficient. 56 One study in the analysis performed by Kazemi et al paralleled the conclusion by Wang et al. 58 The results of 4 studies from the data collected by Kazemi et al demonstrated that there was a correlation between vitamin D deficiency and severe pulmonary involvement, the development of acute respiratory distress and the requirement for ventilation. 58 However, in 4 articles, Kazemi et al did not find an association between a vitamin D deficiency and the rate of ICU admission and neither did the analysis performed by Wang et al. 56, 58 The research by Teshome et al did find 1 study that determined that patients with a vitamin D deficiency had a greater tendency to be admitted to the ICU. 55 There were 6 articles that evaluated vitamin D levels and the incidence of mortality. Four of the studies determined that there was an increased risk of death in patients with a vitamin D deficiency while the other 2 studies did not find an association. 44, 48, 49, 47, 62, 66 AlSafar et al concluded that individuals with a vitamin D level less than 12 ng/mL had a significantly greater risk of mortality while Angelidi et al found a correlation between mortality rate and patients with vitamin D levels under 30 ng/mL. 62, 66 As the research related to vitamin D status and mortality is limited and inconsistent, metaanalysis studies were assessed. There were 7 out of the 10 meta-analysis reviews that discussed the association between vitamin D status and risk of death. Six studies found a correlation between a vitamin D deficiency and an increased risk of mortality and 1 found no association. 53, 55, 56, 57, 58, 59, 60 The meta-analysis by Pereira et al and Wang et al evaluated 3 and 15 studies respectively and found a significant risk of mortality with a vitamin D deficiency while the review by Crafa et al documented 9 studies that found no relation between vitamin D status and mortality. 53, 56, 60 Kazemi et al assessed 13 studies and determined that 9 correlated a vitamin D deficiency with a higher potential for mortality. 58 The research by Kazemi et al demonstrated that the degree of deficiency influenced the outcome of the infection. 58 The investigators documented that serum vitamin D levels less than 10 ng/mL had a 50% chance of mortality while those with serum vitamin D over 10 ng/mL had a 5% mortality rate. 58 In an article reviewed by Teshome et al, patients with a vitamin D deficiency had a seven-fold increase in the incidence of death. 55 The data from Rizki Akbar et al showed a 55% probability of death with lower levels of vitamin D compared to a 27% probability of death with normal vitamin D status in 6 studies and a 29% probability of death with low serum vitamin D compared to a 12% probability of death in patients with normal vitamin D levels in 8 studies included in their analysis. 59 Consequently, vitamin D status may have an impact on the survival rate of individuals infected with COVID-19 as there is a multitude of research that demonstrates that patients that are deficient have a greater potential to develop a serious infection. People with a more severe infection may be more susceptible to the development of SARSs, which was documented in several articles. 45, 47, 58 However, other factors may have a stronger influence on mortality. There are certain characteristics and comorbidities of an individual that may increase the susceptibility of a person to develop a severe infection and death. The factors that may influence the course of the infection to a greater degree than vitamin D status are older than over 50 years of age, obesity, male gender, living in poverty, immunosuppression and having a preexisting medical condition such as a malignancy, chronic obstructive pulmonary disorder or end-stage renal disease. 44, 47, 62, 66 There were 7 articles that discussed the treatment of CoV with vitamin D. All 7 of the publications documented an improvement in the clinical outcome of COVID-19 infections with the treatment of different dosages of vitamin D. 67, 68, 69, 70, 71, 72, 73 Only 2 of the studies were randomized clinical trials, 4 were retrospective studies and 1 was a case series. In 4 of the studies, supplementation with vitamin D reduced the severity of the infection. 68, 69, 72 Sabico et al utilized 1,000 or 5,000 IU of vitamin D in the form of Cholcaciferol once a day. 68 The investigators found that 1,000 IU of vitamin D was inadequate to diminish the severity of the infection while cough and loss of taste resolved 2.9 and 5.5 days earlier in the group receiving 5,000 IU per day. 68 Annweiler et al administered 80,000 IU of vitamin D3 in a single dose every 2-3 months and found it decreased the severity of the patient's symptoms. 69 Entrenas et al treated subjects with 21,280 IU of vitamin D as calcifediol upon admission to the hospital and 10,640 IU on days 3 and 7 each and then weekly until discharge. 72 Of the participants in the control group, 50% were transferred to the ICU while only 1 of the patients receiving vitamin D necessitated transfer to the ICU accounting for 2% of the sample. 72 The study by Ohaegbulam et al supplemented patients with either 50,000 IU ergocalciferol or 1,000 IU of cholecalciferol each day for 5 days. After the 5 th day of treatment, the participants given 50,000 IU of ergocalciferol fully recovered while the group receiving 1,000 IU of cholecalciferol experienced a minimal improvement in their vitamin D status and their symptoms steadily declined resolving on day 13 or 14. 73 There were 5 articles that concluded that treatment with vitamin D reduced the risk of mortality. Similar to the Entrenas et al study Alcala-Diaz et al utilized dosages of 21,280 IU of vitamin D in the form of 25-hydroxyvitamin D3 at admission and 10,640 IU on days 3 and 7 weekly until discharge for 1 group and standard care for the control group. 67 The mortality rate in their study was recorded at 5% for the group that received 25-hydroxyvitamin D3 and 20% for those that received standard care. 67 In the study by Entrenas et al, the mortality rate was 7.6% for the control group and 0% for individuals receiving calcifediol. 72 Ling et al administered a treatment dose or a maintenance dose of cholecalciferol that ranged from 20,000-40,000 IU per day for 1 to 2 weeks, 20,000, 40,000 or 50,000 IU per week, 20,000 IU 2 times a week or 20,000 IU every 2 weeks. 71 The majority of patients were receiving either 40,000 IU weekly or 20,000 IU 2 times a week accounting from 76.7% of the sample. 71 The investigators deduced that supplementing with vitamin D at a high dose was positively correlated with a reduction in mortality. 71 There were 2 articles by Annweiler et al. In the first study, individuals either supplemented with 50,000 IU each month or received 80,000-1000,000 IU of vitamin D3 every 2-3 month or did not supplement and were administered 80,000 IU within hours of a positive COVID-19 diagnosis. 70 The last group was the control group that received standard care. The research indicated that consistent supplementation with vitamin D3 had the lowest level of mortality at 6.9%, which was followed by the group administered vitamin D3 upon diagnosis at 18.8% and the control group at 31.3%. 70 There was not a statistical difference between the morality rates between the second and third groups. 70 Consequently, the investigators surmised that supplementing with high dose vitamin D upon admission was not adequate to prevent death. 70 However, it should be noted that in general symptoms were less severe and the mortality rate was lower. From the other studies, it appears that consistent supplementation with vitamin D is necessary to reduce the morality rate.

In contrast to the previous study, the second study by Annweiler et al analyzed the mortality rate of subjects administered 80,000 IU of vitamin D3 on the week or month prior to the onset of COVID compared to a control group that did not receive vitamin D3. 69 The researchers documented that individuals in the group that received vitamin D3 were consistently administered 80,000 IU of vitamin D3 every 2-3 months. 69 The mortality rate was 55.6% for the control group and 17.5% for the treatment group. 69 As with previous data presented by Ma There were 2 meta-analysis reviews that discussed the treatment of patients with vitamin D. Both publications noted that supplementation with vitamin D in the form of 25hydroxycholcalciferol reduced the incidence of admission into the ICU. 58, 74 In addition, Kazemi et al determined that the average duration of the infection was shorter in the individuals that received vitamin D. 58 Unfortunately, a dosage range of the 4 studies analyzed was not specified. Shah et al evaluated 3 studies treating patients with COVID-19 with vitamin D. The first was Entrenas et al, which was discussed above. 74 The investigators concluded that the data from this study was relevant with a low level of bias. 74 The second utilized a single dosage of 200,000 IU upon admission to the hospital. In this study, the rate of admittance into the ICU of those that were infected was 15.83% for those that were supplemented with vitamin D and 20.83% for those that did not supplement. 74 However, the mortality rate for those receiving the single large dose was 6.67% compared to 5% in the control group, which is consistent with data showing habitual use of vitamin D being more effective for limiting mortality that a 1 time high dose at the onset of infection. 51, 52, 70, 74 There was not a dosage range included in the last trial evaluated. The research indicated that the rate of admission to the ICU was 5.26% for those administered vitamin D and 25.38% for the control, yet the mortality rate for the control and supplementation group was 10.15% and 10.53% respectively. 74 This data may reflect that treatment with vitamin D can have a positive impact on the severity of the infection, but other factors probably have a more substantive role in determining the outcome of the case. This is exemplified by the article published by De Smet et al. The investigators documented a stronger association between an increased mortality rate and over 50 years of age, obesity, male gender, living in poverty, immunosuppression and having a preexisting medical condition such as a malignancy, chronic obstructive pulmonary disorder or end-stage renal disease. 44, 47, 62, 66 

We considered if zinc may be an adjunct for the treatment of CoV infections as it has the ability to mitigate the activity of inflammatory chemicals activated by the virus. This metal can reduce the gene expression of NF-κB attenuating the inflammatory cascade and mitigating the production of inflammatory mediators TNF-α, IL-1, IL-6 and IL-8 and increasing IL-10. 75, 76, 77 In addition, zinc suppresses the release of MCP-1. 78 Unfortunately, there is no evidence related to the impact of zinc on PAI-1 activity.

According to Mocchegiani et al, inadequate dietary intakes of zinc occur in developing and developed countries contributing to the potential for a zinc deficiency especially in elderly patients. 79 Zinc has an important function for the establishment and maintenance of immune responses controlled by the innate and adaptive immune systems. 79 This metal is an essential nutrient for the synthesis of DNA and division of immune cells and is involved with the transcription of immune proteins. 79 Inadequate dietary intake of zinc can result in an impaired immune response. 4 As Ling et al found that there is a higher mortality rate after age 74, low levels of serum zinc could predispose an elderly patient to a greater risk of a severe infection. 71 The literature review revealed 2 studies assessing the activity of zinc against CoV infections including 1 study related to COVID-19. The first article was a case series with 4 patients that tested positive for COVID-19. The first patient was a 63-year-old male prescribed 23 mg of zinc citrate 3 times the first day of his infection. 80 He experienced a worsening of symptoms. 80 Over the next 24 hours in intervals of a few hours, he ingested a total daily value of 207 mg of zinc citrate and his symptoms began to improve. 80 He continued to supplement with 184 mg of zinc citrate each day until resolution of his infection on day 10. 80 The second case consisted of a 57-year-old female that ingested 23 to 46 mg of zinc citrate daily for 10 days and experienced a progressive worsening of her symptoms that eventually climaxed with a severe cough and neck pain, chest pain, a headache, fever and shortness of breath (SOB). 80 At this point, she proceeded to ingest 23 mg of zinc citrate every hour for a 7 hour period totaling 161 mg, which drastically improved her SOB and cough. 80 The next day she resumed consuming 46 mg of zinc a day and her cough began to intensify again. 80 She then selfadministered an additional 69 mg and her symptoms subsided. 80 She continued to self-medicate with 115 mg of zinc citrate daily and her symptoms dissipated and eventually resolved after 10 days. 80 The third case was a 41-year-old female who experienced a progressive aggravation of her symptoms over the first 9 days of her infection culminating in an intense cough, SOB and body aches. 80 On day 9, she began taking 23 mg of zinc citrate/zinc gluconate every 4 hours for a total of 138 mg daily. 80 The severity of her symptoms began to improve the next day. 80 She continued to ingest 138 mg of supplement until her symptoms resolved on day 19 of her illness. 80 The last patient was a 26-year-old female that suffered from a moderate intensity infection for a week before developing SOB and severe fatigue the second week. 80 The third week her symptoms manifested as a severe cough and fatigue with body aches. 80 At the beginning of the fourth week of her infection she ingested 15 mg of zinc acetate every two hours, which equated to 150 mg daily. 80 Twenty-four hours after supplementation her symptoms improved until she fully recovered on day 14 after ingestion of zinc acetate. 80 This case series provides new information related to the therapeutic value of zinc for the treatment of infections with CoV specifically COVID-19. With each case, low dosages of zinc were unable to reduce the severity of the symptoms of the infection. However, as the patients increased the dosage and the frequency of administration, the symptoms became less pronounced and eventually resolved in all cases. This is evident as the symptoms of each patient began to dissipate after consuming high amounts of zinc regardless of its form. It appears as if the optimal results were observed with the consumption of over 100 mg of zinc. The second case exemplifies the importance of the dosage as the patient began to improve and lowered the dose from 161 mg to 46 mg and her symptoms began to intensify again. The potential medicinal properties can be noted in the fourth case as well. This patient had a severe infection for several weeks and after 24 hours of a high daily dosage of zinc her symptoms began to abate. The data collected from this study may signify that continuous low dose supplementation accumulating to over 100 mg of zinc each day could diminish the severity of COVID and promote its resolution. Additional research with a much larger sample size is necessary before accurate conclusions can be achieved.

The other article related to zinc was a double-blind, randomized clinical trial in neonatal calves afflicted with the bovine CoV. The bovine CoV is a type of β-CoV. 81 The primary reservoir of β-CoV infections is bats. 5 According to the Centers of Disease Control and Prevention, COVID-19 is believed to have been spread from a bat and is a β-CoV. 82 The bovine CoV targets the pulmonary or gastrointestinal tract. 81 Since the bovine CoV can infect a broad spectrum of domesticated ruminant species, experts have hypothesized that there may be the potential for the development of a zoonotic infections. 82 In addition, treatment of CoV in animals may provide details related to therapies that may be effective in humans. 4 In the clinical trial, 37 calves were enrolled that were afflicted with neonatal enteritis from the CoV. The neonates were treated with either a placebo, zinc oxide or zinc methionine. Both dosages administered were equivalent to 80 mg of zinc. 83 The outcome revealed a cure rate of 80%, 81.81% and 90.9% for the calves in the placebo, zinc methionine and zinc oxide groups respectively. 83 There was not a significant difference between the groups. 83 Although statistical significance was not observed in this case, there was a 10.9% higher cure rate in the zinc oxide group, which may indicate that it is the more proficient form to use during a CoV infection. The reasons for the nonsignificant results may have been due to a small sample size or a low dosage of zinc administered. As was observed with the case series utilizing zinc, lower dosages were less effective. Supplementing with zinc more frequently to increase the overall daily dosage may have demonstrated a better clinical outcome in this study.

We considered if vitamin A may assist with the resolution of symptomatology associated with the CoV. This vitamin can suppress the activity of transcription factor NF-κB and has been shown to significantly reduce the production of IL-1, IL-6 and TNF-α while increasing IL-10 secretion. 84, 85, 86, 87 Vitamin A can down-regulate the expression of MCP-1 and PAI-1 attenuating their physiologic effects. 88, 89 Research indicates that vitamin A can regulate T cell activation and the response of antiviral T cells, which can lower the risk of excessive systemic inflammation and tissue injury. 33 In addition, vitamin A can activate the adaptive immune system by promoting the release of IL-2 and potentiating communication between T lymphocytes. 90 IL-2 promotes the propagation of T lymphocytes and enhances cytotoxicity. 90 Metabolites of vitamin A can increase the proliferation of B lymphocytes, which secrete antibodies to fend of invading pathogens. 90 Reducing inflammation and up-regulating the immune response as well as the acting as an anticoagulant may improve the course of CoV infections.

There was 1 article that met the inclusion criteria for the literature review. The article discusses the use of vitamin A for the treatment of the porcine epidemic diarrhea virus (PEDV), which is an α-CoV. 91 The primary host infected by this virus is a piglet. 91 PEDV is a virus that causes enteropathy resulting in diarrhea. 92 It has the capacity to infect a variety of different cell lines including humans and is believed to have the potential for cross-species transmission. 92 In the experiment, infected animals were placed into four groups: infected pigs, infected pigs with daily dose of vitamin A, infected pregnant pigs in their third trimester and infected pregnant pigs in their third trimester receiving daily vitamin A. The dosage utilized with supplementation was 15,000 IU twice daily as retinyl acetate. The investigators found that vitamin A supplementation reduced the rate of RNA shedding in the non-pregnant pigs, which could signify a lower rate of infectivity to a new host. 91 The severity of diarrhea was significantly reduced in the group of non-pregnant pigs receiving vitamin A. 91 The mortality rate of pigs receiving vitamin A was 25.8% compared to 44.1% in the control group. 91 The survival rate of the piglets born to infected sows was not considered significant at 8.3% for those receiving vitamin A and 5.7% for those that were not supplemented. 91 The data collected from this study may demonstrate that vitamin A can reduce the potential for transmission of the virus between hosts, the severity of the infection and the mortality rate, but did not have a significant effect on infant survival rate.

The botanical S nigra may provide a therapeutic benefit as an adjunct for the treatment of CoV infections. S nigra can deactivate the transcription factor NF-κB. 93 Evidence exists demonstrating that S nigra increases proinflammatory cytokines IL-1, IL-6, IL-8 and TNF-α and anti-inflammatory cytokine IL-10. 94, 95 The investigators proposed that the elevation of these mediators stimulated the immune response. 94 In an experiment, the herb was shown to increase the inflammatory mediators while simultaneously alleviating symptoms associated with the influenza virus. 94 However, another study found that this botanical reduces the levels of TNF-α and IL-6. 96 This may signify that S nigra has a regulatory function related to inflammatory mediators. 94, 95, 96 Additional research is required to determine the exact effects of S nigra on inflammatory mediators during an infection.

One of the reasons S nigra may reduce symptomatology associated with infections is that it may act as an immunostimulatory agent. 97 However, the evidence related to the influence of S nigra on the immune system is lacking. The improvement in symptomatology is more likely due to its antiviral effects. There is no data related to the physiological impact of S nigra on MCP-1 or PAI-1.

There was 1 study related to the employment of S nigra for the treatment of the avian infectious bronchitis virus (AIBV), which is a Gamma-CoV that infects the lining of the respiratory tract in chickens. Although Gamma-CoVs do not typically infect humans, the investigators believe that the data obtained from this study can help to determine herbal extracts that can impede the replication of different strains of the CoV. The data from this study could be used to devise treatment strategies for CoV, that affects the human population. 4 The plant extract was prepared with an 80% ethanol solution. S nigra generated antiviral effects inhibiting the replication of the AIBV by physically damaging the membranous envelope of the virion. 4 In the first part of the experiment, the cells were treated with the plant extract before infection and after the infection for 24 hours and the virus was incubated with the extract for 20 minutes prior to inducing the infection. At a low and high multiplicity of infection, S nigra decreased viral titers by 6 and 4 orders of magnitude respectively. 4 In the second part of the experiment, cells were treated with the extract prior to infection, the virus was treated with the plant isolate before the infection or the cells were treated post-infection. The results indicated that treating the cells with S nigra after the infection caused a reduction in the levels of the virus by 3 times. 4 However, the virus that was exposed to the plant extract prior to infection demonstrated a decrease in viral titers by 3 orders of magnitude indicating it had a more pronounced effect. 4 Consequently, S nigra may possess antiviral activity against CoV, which could prove to be beneficial as a therapeutic treatment. Caution should be taken with S nigra for the treatment of severe cases of CoV infections until more evidence is available as the CoV can induce a severe inflammatory state and the plant extract may increase the production of certain inflammatory mediators.

We considered if the addition of A satvium may enhance the therapeutic value of standard treatment for CoV infections. Multiple studies indicate that the constituents of A sativum can deactivate NF-κB, down-regulating the inflammatory cascade. 98, 99, 100 The oil and organosulfur components can attenuate the production of IL-1, IL-6, IL-8 and TNF-α and stimulate the synthesis of IL-10. 101, 102, 103 An extract of A sativum inhibited the effects of PAI-1. 104 A sativum can enhance immune function by increasing T lymphocyte and natural killer cell proliferation and activating macrophages. 105 There is no research related to the impact of A sativum on MCP-1. These actions demonstrate that A sativum may reduce the pathophysiology of CoV infections and be an advantageous adjunct therapy.

The literature review revealed 2 studies that met inclusion criteria. AIBV was the type of CoV researched. This study consisted of 7 groups composed of embryonic chicken eggs that were infected with 1 of 2 strains of AIBV known as Intervet4/91 and M41. 106 In this experiment, the treatment groups were inoculated with the virus at low, medium, moderate and high concentrations and exposed to an extract of A sativum. 106 The strain of Intervet4/91 slowed the growth of the embryos, but were otherwise unaffected. 106 The M41 strain of the virus killed all the embryos in the groups with the high and moderate concentrations of the virus within 4 days and the medium dilution group by day 8 of the study. 106 A sativum prevented the Intervet4/91 strain from impeded the growth of the embryos. 106 All of the embryos treated with A sativum that were exposed to the high concentration of the virus died. 106 However, only 10% of the embryos in the moderate dilution group died and none of the embryos in the medium dilution group died. 106 An in vitro study incorporated a nucleotide sequence encoding the SARS-CoV-2 into bacteria, which was exposed to phytochemicals extracted from A sativum. The investigators found that the whole herb extract at a dosage of 0.5 mg/mL completely inhibited the replication of SARS-CoV-2 with an IC 50 at 137±10 µg/mL. 107 Tannic acid, Puerarin and daidzein were isolated and utilized against the virus. 107 These active constituents prevented the replication of the virus with IC 50 concentrations of 9 µg/mL, 42±2 µg/mL and 56 µg/mL respectively. 107 There were 13 additional phytochemicals that impeded replication by over 50%. 107 The research from these studies provides a limited amount of information requiring more investigation. However, the data may indicate that A sativum possesses antiviral activity that could have a role in the treatment of mild to moderate CoV infections. Although in severe cases of the infection as represented by the high dilution group, A sativum appears not to be effective.

We considered G glabra as an adjunct therapy to attenuate the pathophysiology of CoV infections through the mitigation of inflammatory mediators generated as a result of an infection. There is currently not any research on the effect of G glabra on PAI-1. However, the expression of NF-κB is down-regulated by G glabra. 108 The inflammatory activity of TNF-α, IL-1 and IL-6 is diminished by the botanical as well. 108, 109 An active constituent of the herb known as licochalcone had the ability to reduce the secretion of IL-8 and MCP-1. 110, 111 The primary antiviral component glycyrrhizin enhanced the synthesis of IL- 10. 112 In addition, glycyrrhizin can augment the proliferation of T lymphocytes especially CD4, CD40 and CD86 T cells and the production of interferon (INF)-γ. 108, 111 Elevating CD4 and CD40 T cells may be an essential component to the treatment strategy as individuals with COVID-19 have lower levels of CD4 T cells and CD40 T cells are produced in higher quantities, which may indicate that CD40 T cells are involved in combating the virus. 113, 114 The positive attribution of CD86 T cell activity for CoV infections is not known. However, this immunoglobulin activates T lymphocytes that can defend the host against the infection. 108 CD40 T cells can potentiate the differentiation of B lymphocytes and activate monocytes and macrophages while INF-γ promotes immune function by activating T lymphocytes and natural killer cells and mobilizing white blood cells associated with the immune response. 108, 112 The transcription of major histocompatibility complex (MHC) II, which initiates the generation of dendritic cells, macrophages and B lymphocytes, is increased by this botanical. 108 Lastly, G glabra may act as a weak regulator of cortisol levels. 108 Research demonstrates that the botanical can decrease 11-β-hydroxysteroid dehydrogenase and 5-β-reductase activity. 108 These enzymes are responsible for the metabolism of cortisol. 108 Consequently, this increases cortisol levels, which may be able to attenuate the intense inflammatory state associated with CoV infections.

Evidence exists that G glabra can act as a potent antiviral for the treatment of the SARS-CoV. 115 There were 2 articles that met inclusion criteria. One study involved cells infected with SARS CoV, which is the agent responsible for COVID-19, exposed to components of G glabra. Of the phytochemicals tested, ribavirin and mycophenolic acid were ineffective against the virus while 6-azauridine, pyrazofurin and glycyrrhizin were capable of down-regulating viral replication at 104 mg/L, 52 mg/L and 300 mg/L. 116 The experiment revealed that glycyrrhizin diminished the ability of the virus to attach to the host cell, which could allow it to act as a prophylactic, when administered at 300 mg/L. 116 The mechanism of action has not been elucidated.

A similar experiment was performed using cell cultures. In this study, an aqueous extract of G glabra was preincubated with the virus at dosages ranging from 0.004-4.0 mg/mL. 117 Inhibition of viral replication was observed at 2 mg/mL, which was lower than the traditional dose of 12.5 mg/mL found in infusions. 117 In the second part of the experiment, glycyrrhizin mitigated the replication of SARS-CoV-2 at a dosage of 0.5 mg/mL when preincubated prior to cellular exposure and 1 mg/mL when administered after the cells were infected without producing cytotoxic effects. 117 The mechanism of action was the inhibition of the primary proteinase that controls viral replication known as M pro . 117 This may indicate that G glabra could be administered as an adjunct therapy for CoV infections, but more research is required.

We considered if the administration of U dioica in conjunction with standard therapy may be a treatment strategy for infections of the CoV. The botanical can suppress the expression of NF-κB and the activity of pro-inflammatory cytokines TNF-α, IL-1 and IL-6. 118, 119, 120 There is limited information on the physiologic effect of the herb on IL-8. One study in rainbow trout infected with parasites found that U dioica increased the synthesis and release of TNF-α, IL-1, IL6 and IL-8 while reducing the severity of the condition and mortality rate. 121 Consequently, as with S nigra, U dioica may be a modulator of inflammatory cytokines, which in certain cases may be essential for the immune response. Research regarding the influence of the botanical on IL-10, MCP-1 and PAI-1 is not available.

Evidence has shown that U dioica can act as an immunomodulator. 122 The herb can bolster the nonspecific and cell mediated immune response. 123 This may be accomplished by the botanical increasing the production of neutrophils and T lymphocytes. 124, 125 U dioica may be an effective adjunct therapy for the treatment of CoV infections as it can regulate inflammation and the immune function.

There were 3 studies that met the inclusion criteria for the literature review related to the effects of U dioica against the SARS-CoV. In the first article, the genera of the virus was not specified. However, the investigators noted that it was a strain that could impact the human population. The first part of the experiment utilized human cell cultures infected with Urbani SARS-CoV and exposed it to the botanical extract. 126 U dioica agglutinin demonstrated a 90% reduction of viral replication. 126 In addition, the extract had the ability to down-regulate the replication of the strains of SARS-CoV obtained from Frankfurt, Hong Kong and Toronto by 90%. 126 In the second part of the experiment, mice were infected with the SARS-CoV. U dioica agglutinin was administered through intraperitoneal injection at a dosage of 5-10 mg/kg/day. 126 The mortality rate of the virus in the mice was measured at 90-100%. 126 The botanical preparation significantly reduced the severity of the infection and prevented the serious weight loss observed in the placebo group. 126 In addition, the mortality rate was 10% or less for the mice receiving the plant extract. 126 The outcome of this study may be explained through the examination of the lung tissue of infected mice. In mice given the placebo, necrotic damage was observed in the capillary walls of the alveolar cells resulting in hemorrhages. 126 Mice that received the plant extract showed a significant degree of protection demonstrated by a reduction in inflammation and number of cell surface hemorrhages. 126 The investigators found that pretreating the virus with the herbal extract prior to the virus entering the cells reduced its replication by 3 times. 126 However, injecting the herb into the cells 24 hours after infection produced minimal effects. 126 The virus was inoculated into viable cell cultures and the herbal extract was used to treat the cells. Viral replication was analyzed every 2 hours for 24 hours. U dioica inhibited replication in hours 1-12, but not after 20 hours. 126 Consequently, U dioica may be most efficacious to utilize as a prophylactic or in the early stages of the infection to reduce replication. Although it did not have an impact on viral replication after the initial stages, the herbal extract may still attenuate the symptomatology of the host through its anti-inflammatory and immunostimulating activity.

In the second study, Van Der Meer et al used the active constituent N-acetylglucosamine extracted from U dioica and tested its antiviral capacity against a variety of strains of CoV including AIBV, transmissible gastroenteritis virus (TGEV), mouse hepatitis virus (MHV) and feline CoV. Research indicates that the AIBV, TGEV and MHV share 39%, 44% and 50% of the amino acid sequence of the SARS-CoV that infects humans. 127 As the amino acid sequence shares some similarities, researchers have proposed that antiviral therapies effective against these strains could be utilized against human strains of the CoV including COVID-19. 127 Although there is no evidence of the transmission of feline CoV to humans, a broad-spectrum antiviral drug decreased antiviral activity against human and feline strains of CoV. 128 This may signify that agents capable of inhibiting the replication of feline CoV strains may have the ability to reduce the replication of species of CoV that infect humans.

Cell cultures were infected with various strains of the virus and treated with different test compounds including N-acetylglucosamine. The data revealed that N-acetylglucosamine possessed antiviral properties against AIBV, TGEV, MHV and feline CoV. 129 Replication of the AIBV, TGEV, MHV and 3 isolates of the feline CoV were inhibited by 50% at 0.05±0.05 µM, 0.08±0.07 µM, 0.53±0.02 µM, 0.023±0.012 µM, 0.24±0.14 µM and 0.11±0.03 µM respectively. 129 This data reflects that N-acetylglucosamine extracted from U dioica can impede the replication of a broad-spectrum of strains of CoV, which may have implications for human infections.

The third article was conducted by Van der Meer et al as well. The investigators evaluated the inhibitory nature of N-acetylglucosamine extracted from U dioica against strains of the CoV. Isolates of the feline CoV and MHV were selected for this study. As with the previous study, the CoV was used to infect cell cultures and then exposed to the herbal extract at a dosage of 6.25 mg/L. In the first part of the experiment, it was found that N-acetylglucosamine was capable of significantly reducing the formation of the syncytium. 130 The synthesis of the syncytium is initiated by the S proteins responsible for fusion that allows the virus to infiltrate the host cell. 131 Decreasing the number of syncytia produced may reduce the pathophysiology of the virus.

The second part of the experiment analyzed the action of N-acetylglucosamine on M protein for the MHV. As discussed previously, M protein controls the replication and transcription of the virus. 13 The phytochemical was able to interfere with the function of M protein at 0.7±0.2 mg/L, 2.8±2.2 mg/L and 2.7±1.3 mg/L for all 3 strains of the virus. 130 Through the mitigation of the activity of M protein, U dioica may reduce the ability of the virus to replicate decreasing the severity of the infection.

The capacity of the virus to enter the host cell was evaluated. N-acetylglucosamine inhibited the entry of the virus into the cell after it had been attached. 130 However, the investigators noted that the presence of N-acetylglucosamine during the attachment phase of the infection enhanced its entry into the cell. 130 In the final portion of the experiment, N-acetylglucosamine was able to down-regulate the replication of the isolates of the virus tested. 130 The studies analyzed in this literature review demonstrate that U dioica may act as an effective adjunct therapy for the treatment of various strains of the CoV. In each of the studies analyzed, the botanical was capable of inhibiting the replication of multiple strains of the virus. 126, 127, 130 Although the reduction in reproductive capacity was only seen in the first 12 hours of the study conducted by Kumaki et al and exposure of the virus to the herb during attachment to the host cell by van der Meer et al, this may be due to the utilization of a cell culture or in the case of van der Meer, only utilizing a single component of the plant. 126, 130 Consequently, the botanical diminished the replication and M protein activity suggesting that it may be effective to control the spread of the virus. This is apparent in the animal study conducted by Kumaki et al. In this experiment, an attenuation of the symptoms and mortality rate was observed. The morality rate in the placebo group was 90-100% and was decreased to less than 10% with the administration of U dioica), which may indicate it could be a valuable adjunct to conventional care. 126 Unfortunately, there have not been any clinical trials performed evaluating the therapeutically effective dosage of the botanical for the treatment of CoV infections. However, the recommended therapeutic dosage of the dried extract is between 460-600 mg. 132

We considered if NAC may be an effective adjunct therapy to standard care for the treatment of CoVinfections. This amino acid derivative can mitigate the expression of NF-κB. 133 Evidence demonstrates that NAC can reduce the synthesis of IL-1, IL-6, IL-8 and TNF-α while potentiating the production of IL-10. 133, 134, 135 This nutraceutical has the ability to down-regulate the expression of MCP-1. 136 Although research does not signify that NAC has a direct effect on PAI-1, data reflects an indirect inhibition of its synthesis. 137, 138, 139 Data shows that NAC may act as an immunostimulant. 140 This agent can up-regulate the replication and differentiation of lymphocytes. 140 This is exemplified by the enhancement of the proliferation of CD4+ and CD8+ lymphocytes amplifying the immune response. 140 Enhancing the formation of CD4+ and CD8+ lymphocytes as their levels are diminished in patients with COVID. 113 Additionally, NAC can increase the production of IL-2. 141 IL-2 promotes the formation of T and B lymphocytes optimizing immune function. 142 The culmination of the antiinflammatory and immune up-regulating activity may indicate that NAC could be an efficacious adjunct therapy for the treatment of CoV infections. NAC has been proposed by experts as a possible treatment strategy for COVID-19. 143 NAC is the precursor to the antioxidant compound glutathione. Glutathione may help to eliminate the high levels of oxidative damage that has been observed in cases of COVID-19. 143 In addition, NAC can inhibit ACE activity, which may impede the ability of the virus to infiltrate the host potentially reducing the risk or severity of the infection. 143 Unfortunately, the literature review did reveal any studies demonstrating this concept.

Quercetin may improve patient care as an adjunct to standard therapy. This flavonol has the ability to down-regulate the expression of NF-κB and the subsequent inflammatory cascade. 144 The phytochemical can further reduce inflammation through the mitigation of TNF-α, IL-1, IL-6 and IL-8 and increased IL-10. 144, 145, 146 Research indicates that quercetin can abate the levels of MCP-1 and PAI-1. 148, 149 Although data is limited, quercetin can act as an immunostimulant and has antiviral properties. 150, 151 This flavonoid can promote the phagocytotic activity of macrophages and enhance the function of natural killer cells. 152 The combination of these effects may improve the outcome of a CoV infection.

There were 2 studies that met the inclusion criteria of the literature review. The first article was a randomized trial consisting of 152 subjects that tested positive for and were afflicted with a mild to moderate case of COVID-19. 153 The patients were all receiving standard care according to hospital guidelines. The intervention group received 1,000 mg of quercetin 2 times a day for 30 days. 153 The investigators documented a significant reduction in hospital admissions, requirement for ventilation, ICU admission, the duration of need for hospitalization and mortality. 153 In the group receiving standard therapy, 28.9% were hospitalized, 19.7% required ventilation, 10.5% were admitted into the ICU and 3.9% died while 9.2% and 1.3% of those in the quercetin treatment group were hospitalized or required ventilation respectively and none of the subjects in the quercetin group were admitted to the ICU or died. 153 The duration of hospitalization was 6.77±3.08 days in the standard therapy group compared to 1.57±0.53 days in the quercetin group. 153 The investigators did note that there was an imbalance between the two groups in relation to comorbidities. 153 In the standard therapy group, 59.2% of individuals had a comorbidity compared to 38.2% in the quercetin group. 153 To compensate, the researchers evaluated the impact of quercetin supplementation compared to standard therapy on infected subjects without comorbidities. After the adjustment, the data reflected that 22.6%, 12.9%, 6.5% and 6.5% of otherwise healthy individuals in the standard therapy group were hospitalized, required oxygen, were sent to the ICU or died while 8.5% of those in the quercetin group were admitted to the hospital and none of these individuals required oxygen, were sent to the ICU or died. 153 The duration of hospital stays for individuals that were otherwise healthy was 5.14±2.79 days for the standard therapy group and 1.25±0.5 for treatment group. 153 Consequently, after adjusting for comorbidities, quercetin remained a significantly effective adjunct therapy.

In the second study, 42 COVID-19 positive patients with a mild to moderate infection were randomly divided into groups to receive standard therapy according to hospital guidelines or 500 mg of quercetin 3 times a day for 7 days and 500 mg 2 times a day for an additional 7 days. 154 The demographics and comorbidities were equivalent between the groups except for age, which was on average 56.2±3.3 years in the standard therapy and 42.5±3.3 years in the treatment group. 154 The data showed that quercetin significantly increased viral clearance by 76% in the first week compared to 9.5% in the standard therapy group. 154 In the treatment group, 57% of the patients experienced a complete resolution of symptoms at day 7 versus 19% in the standard therapy group. 154 One patient in the standard therapy group was hospitalized, admitted to the ICU and died. 154 The group receiving quercetin did not have any of the patients hospitalized or admitted to the ICU and none of them died. 154 The results of this study are a good indication that quercetin may be an effective adjunct therapy. Additional research needs to be conducted prior to making conclusions.

We considered if selenium may be advantageous as an adjunct to standard therapy for CoV infections as it is an anti-inflammatory and antioxidant nutraceutical. This mineral can reduce the expression of the inflammatory transcription factor NF-κB. 155 The inflammatory markers TNF-α, IL-1, IL-6 and IL-8 were decreased and IL-10 increased with supplementation with selenium. 156, 157, 158, 159 Supplementation with selenium can diminish MCP-1 and PAI-1 activity, 160, 161 Research indicates that selenium can enhance immune function and combat viral infections. This mineral can potentiate the proliferation of T lymphocytes and the secretion of INF-γ, which activates T lymphocytes and natural killer cells and enhancing the overall immune response. 108, 162 The secretion of IL-4 by T lymphocytes was up-regulated. 163 IL-4 attenuates the inflammatory response during an infection. 164 In a study with cases of an upper respiratory tract infection, selenium increased antibody release fortifying immune response. 163 There were 3 articles that met the inclusion criteria for selenium. All of the studies were related to selenium status and the potential to develop COVID-19 infection. Two of the studies found that lower levels of selenium was associated with an increased mortality rate from COVID-19. 165, 166 One of the studies, compared the cure rates and death rates of COVID-19 in different regions of China related to selenium status. The investigators determined that there was a positive correlation between the regions of the country with low selenium status and a lower cure rate and higher death rate. 166 The other study found that selenium status was higher over time in patients that survived a COVID-19 infection compared to those that did not. 165 There was not an association between the incidence rate of COVID-19 and a selenium deficiency in the third study. 167 Although the data is limited, supplementing with selenium may reduce inflammation and stimulate the immune function to assist in the resolution of a CoV infection. Only a small amount of research has been conducted related to the effects of selenium on CoV. However, some evidence demonstrates that individuals with a low selenium status may be at increased risk. This seems probable as impaired immune function and lower levels of IgG and IgM has been observed in individuals with a selenium deficiency. 163 More research and clinical trials are required to determine the extent of the benefit of selenium as an adjunct therapy.

There are several limitations to this exploratory study. Our goal was to consider antiinflammatory and antioxidant nutraceuticals as potential adjunctive therapies for CoV and therefore not to suggest using them replace mainstream treatments that have been proven to be effective through rigorous clinical research. Our search criteria spanned 15 years, thus content may have not been included. Another limitation is that several of the articles available were not clinical, and were either cell culture studies or animal trials. This was a necessity as the data published related to human test subjects was minimal. Clinical trials for each nutraceutical will be necessary to determine the impact of the natural remedy as an adjunct treatment strategy. The review assesses several different species of the CoV, which are not all capable of infecting humans. However, understanding the impact of certain nutraceuticals on carious strains of CoV could provide insight into possible treatment strategies for species that do infect humans. This review was limited in that it only sought to explore the topic, not to make conclusive clinical recommendations. Our review demonstrates that further students are needed to consider how anti-inflammatory and antioxidant non-pharmaceuticals may be used as potential adjunctive therapies for CoV infections in humans.

In this exploratory review, we identified non-pharmaceutical supplements (Vitamin D, zinc, vitamin A, S nigra, A sativum, G glabra and U dioica) which may have the potential to provide support for those with coronavirus infections. However, rigorous clinical studies need to be performed before any clinical recommendations can be made at this time.

No funding sources or conflicts of interest were reported for this study.

Evolutionary Trajectory for the Emergence of Novel Coronavirus SARS-CoV-2. Pathogens

SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview

Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication

Coronavirus and paramyxovirus in bats from Northwest Italy

Comparative Pathogenesis of Bovine and Porcine Respiratory Coronaviruses in the Animal Host Species and SARS-CoV-2 in Humans

COVID-19: a novel zoonotic disease caused by a coronavirus from China: what we know and what we don't

MERS-CoV Photos

Coronaviruses: an overview of their replication and pathogenesis

Coronavirus disease 2019 (COVID-19): current status and future perspectives

The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex

Monoclonal antibodies for the S2 subunit of spike of SARS-CoV-1 cross-react with the newly-emerged SARS-CoV-2

Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Pathogenic viruses: Molecular detection and characterization. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases

The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells

Lippincott's Illustrated Reviews Biochemistry

IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome

Overview of the IL-1 family in innate inflammation and acquired immunity

Recent advances in underlying pathologies provide insight into interleukin-8 expression-mediated inflammation and angiogenesis

Tumor necrosis factor

Role of plasminogen activator inhibitor-1 in coronary pathophysiology

Pulmonary embolism rate in patients infected with SARS-CoV-2

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status

COVID-19 Overview and Infection Prevention and Control Priorities in non-US Healthcare Setting. CDC. Retrieved on

Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? Med Hypotheses

Tocilizumab: A Review in Rheumatoid Arthritis

IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

Rapid review for the anti-coronavirus effect of remdesivir

Efficacy of COVID-19 vaccines: From clinical trials to real life

COVID-19 vaccines and decreased transmission of SARS-CoV-2

Trust in a COVID-19 vaccine in the U.S.: A social-ecological perspective

Retinoic Acid Modulates Hyperactive T Cell Responses and Protects Vitamin A-Deficient Mice against Persistent Lymphocytic Choriomeningitis Virus Infection

Vitamin D receptor inhibits nuclear factor κB activation by interacting with IκB kinase β protein

1,25-dihydroxy Vitamin D3 and Interleukin-6 Blockade Synergistically Regulate Rheumatoid Arthritis by Suppressing Interleukin-17 Production and Osteoclastogenesis

Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes

Vitamin D and 1,25(OH)2D regulation of T cells

25(OH)2 vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients

Vitamin D supplementation lowers thrombospondin-1 levels and blood pressure in healthy adults

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection

Immune Modulatory Effects of Vitamin D on Viral Infections

Vitamin D: Effect on Haematopoiesis and Immune System and Clinical Applications

Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results

Vitamin D and COVID-19 infection and mortality in UK Biobank

25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2

Vitamin D and Lung Outcomes in Elderly COVID-19 Patients

Severe vitamin D deficiency is not related to SARS-CoV-2 infection but may increase mortality risk in hospitalized adults: a retrospective case-control study in an Arab Gulf country

Vitamin D 25OH deficiency in COVID-19 patients admitted to a tertiary referral hospital

Vitamin D supplementation and outcomes in coronavirus disease 2019 (COVID-19) patients from the outbreak area of Lombardy

Vitamin D status of Arab Gulf residents screened for SARS-CoV-2 and its association with COVID-19 infection: a multi-centre case-control study

Habitual use of vitamin D supplements and risk of coronavirus disease 2019 (COVID-19) infection: a prospective study in UK Biobank

Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results

Vitamin D deficiency aggravates COVID-19: systematic review and metaanalysis

Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis

The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis. Front Public Health

Association of vitamin D deficiency with COVID-19 infection severity: Systematic review and meta-analysis

Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and metaanalysis of 43 observational studies

Association of Vitamin D Status with SARS-CoV-2 Infection or COVID-19 Severity: A Systematic Review and Meta-analysis

Low Serum 25-hydroxyvitamin D (Vitamin D) Level Is Associated With Susceptibility to COVID-19, Severity, and Mortality: A Systematic Review and Meta-Analysis. Front Nutr

Influence of 25-hydroxy-cholecalciferol levels on SARS-CoV-2 infection and COVID-19 severity: A systematic review and meta-analysis

Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality

COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents

Circulating Vitamin D levels status and clinical prognostic indices in COVID-19 patients

Immunobiology: The Immune System in Health and Disease 5th Ed

Vitamin D insufficiency as a potential culprit in critical COVID-19 patients

Vitamin D Status Is Associated With In-Hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients

Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study

Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial

Vitamin D and survival in COVID-19 patients: A quasi-experimental study

Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study

High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study

Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study

Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series

Vitamin D supplementation, COVID-19 and disease severity: a meta-analysis. QJM

Antioxidant and antiinflammatory effects of zinc. Zinc-dependent NF-κB signaling

Zinc supplementation and immune factors in adults: a systematic review and meta-analysis of randomized clinical trials

Zinc source modulates intestinal inflammation and intestinal integrity of broiler chickens challenged with coccidia and Clostridium perfringens

Zinc sulfate inhibited inflammation of Der p2-induced airway smooth muscle cells by suppressing ERK1/2 and NF-κB phosphorylation

Zinc: dietary intake and impact of supplementation on immune function in elderly

Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients

Comparative Pathogenesis of Bovine and Porcine Respiratory Coronaviruses in the Animal Host Species and SARS-CoV-2 in Humans

A double-blind block randomized clinical trial on the effect of zinc as a treatment for diarrhea in neonatal Holstein calves under natural challenge conditions

Vitamin A reduces lung granulomatous inflammation with eosinophilic and neutrophilic infiltration in Sephadextreated rats

Vitamin A supplementation and serum Th1-and Th2-associated cytokine response in women

Vitamin A differentially regulates cytokine expression in respiratory epithelial and macrophage cell lines

Role of vitamin A oral supplementation on oxidative stress and inflammatory response in the liver of trained rats

Tumorangiogenese und Immunsuppression. Strategische Angriffspunkte für neue Therapieansätze beim Plattenepithelkarzinom der Mundhöhle (HNSCC) [Antiangiogenic and antiimmunosuppressive therapeutic strategies in human head and neck squamous cell carcinoma

Amelioration of glomerulosclerosis with alltrans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin

Vitamin effects on the immune system: vitamins A and D take centre stage

Oral vitamin A supplementation of porcine epidemic diarrhea virus infected gilts enhances IgA and lactogenic immune protection of nursing piglets

Porcine Epidemic Diarrhea Virus and the Host Innate Immune Response

Inhibition of proinflammatory activities of major periodontal pathogens by aqueous extracts from elder flower (Sambucus nigra)

The effect of herbal remedies on the production of human inflammatory and anti-inflammatory cytokines

The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines

Sambucus nigra L.) Fruit Extract Alleviates Oxidative Stress, Insulin Resistance, and Inflammation in Hypertrophied 3T3-L1 Adipocytes and Activated RAW

Inhibition of microglial activation by elderberry extracts and its phenolic components

Anti-wrinkle and antiinflammatory effects of active garlic components and the inhibition of MMPs via NF-κB signaling

Diallyl Trisulfide can induce fibroblast-like synovial apoptosis and has a therapeutic effect on collagen-induced arthritis in mice via blocking NF-κB and Wnt pathways

Diallyl Disulfide (DADS), a Constituent of Garlic, Inactivates NF-κB and Prevents Colitis-Induced Colorectal Cancer by Inhibiting GSK-3β

Preventive Effect of Garlic Oil and Its Organosulfur Component Diallyl-Disulfide on Cigarette Smoke-Induced Airway Inflammation in Mice

Allyl methyl disulfide inhibits IL-8 and IP-10 secretion in intestinal epithelial cells via the NF-кB signaling pathway

Garlic increases IL-10 and inhibits TNFalpha and IL-6 production in endotoxin-stimulated human placental explants

Garlic extract favorably modifies markers of endothelial function in obese patients -randomized double blind placebo-controlled nutritional intervention

Immunomodulation and anti-inflammatory effects of garlic compounds

The effect of Allium sativum (Garlic) extract on infectious bronchitis virus in specific pathogen free embryonic egg

The Inhibitory Effects of Plant Derivate Polyphenols on the Main Protease of SARS Coronavirus 2 and Their Structure-Activity Relationship

Treatment of a Woman With Glycyrrhiza glabra for Acute Sinusitis: A Case Report

Effects of rhaponticum carthamoides versus glycyrrhiza glabra and punica granatum extracts on metabolic syndrome signs in rats

Role of licochalcone A on thymic stromal lymphopoietin expression: implications for asthma

Licochalcone A potently inhibits tumor necrosis factor alpha-induced nuclear factor-kappaB activation through the direct inhibition of IkappaB kinase complex activation

The effect of glycyrrhizin on maturation and T cell stimulating activity of dendritic cells

CD4+T, CD8+T counts and severe COVID-19: A meta-analysis

Memory B cells targeting SARS-CoV-2 spike protein and their dependence on CD4 + T cell help

Exploring the Pivotal Immunomodulatory and Anti-Inflammatory Potentials of Glycyrrhizic and Glycyrrhetinic Acids

Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus

Glycyrrhizin Effectively Inhibits SARS-CoV-2 Replication by Inhibiting the Viral Main Protease

The effect of stinging nettle (Urtica dioica) seed oil on experimental colitis in rats

The effect of hydro alcoholic Nettle (Urtica dioica) extracts on insulin sensitivity and some inflammatory indicators in patients with type 2 diabetes: a randomized double-blind control trial

Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB

Immunity and growth improvement of rainbow trout (Oncorhynchus mykiss) fed dietary nettle (Urtica dioica) against experimental challenge with Saprolegnia parasitica

Safety and efficacy of Setarud (IMOD TM ) among people living with HIV/AIDS: a review

Effects of drugs of plant origin on the development of the immune response

Biochemical and hemato-immunological parameters in juvenile beluga (Huso huso) following the diet supplemented with nettle (Urtica dioica)

Stimulation of lymphocyte proliferation and inhibition of nitric oxide production by aqueous Urtica dioica extract

Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin

Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs

Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anticoronaviral drug

Antiviral activity of carbohydratebinding agents against Nidovirales in cell culture

The carbohydrate-binding plant lectins and the non-peptidic antibiotic pradimicin A target the glycans of the coronavirus envelope glycoproteins

Syncytia formation by SARS-CoV-2-infected cells

Urtica dioica; Urtica urens (nettle). Monograph

N-acetyl cysteine inhibits lipopolysaccharide-mediated synthesis of interleukin-1β and tumor necrosis factor-α in human periodontal ligament fibroblast cells through nuclear factor-kappa B signaling

Suppression of methylmercury-induced IL-6 and MCP-1 expressions by N-acetylcysteine in U-87MG human astrocytoma cells

N-acetylcysteine modulates cyclophosphamide-induced immunosuppression, liver injury, and oxidative stress in miniature pigs

Effects of N-acetylcysteine on mRNA expression of monocyte chemotactic protein and macrophage inflammatory protein 2 in acute necrotizing pancreatitis

Reactive oxygen species mediate TGF-beta1-induced plasminogen activator inhibitor-1 upregulation in mesangial cells

Rho-kinase mediates hyperglycemia-induced plasminogen activator inhibitor-1 expression in vascular endothelial cells

N-acetylcysteine attenuates TNF-alpha induced changes in secretion of interleukin-6, plasminogen activator inhibitor-1 and adiponectin from 3T3-L1 adipocytes

A potential therapeutic agent for SARS-CoV-2

N-acetylcysteine enhances T cell functions and T cell growth in culture

Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19

Quercetin inhibits TNF-α induced HUVECs apoptosis and inflammation via downregulating NF-kB and AP-1 signaling pathway in vitro. Medicine (Baltimore)

Quercetin and Quercitrin Attenuates the Inflammatory Response and Oxidative Stress in LPS-Induced RAW264.7 Cells: In Vitro Assessment and a Theoretical Model

Quercetin Inhibits the Production of IL-1β-Induced Inflammatory Cytokines and Chemokines in ARPE-19 Cells via the MAPK and NF-κB Signaling Pathways

Quercetin protects against atherosclerosis by regulating the expression of PCSK9, CD36, PPARγ, LXRα and ABCA1

The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice

Polyphenols downregulate PAI-1 gene expression in cultured human coronary artery endothelial cells: molecular contributor to cardiovascular protection

The Pharmacological Activity, Biochemical Properties, and Pharmacokinetics of the Major Natural Polyphenolic Flavonoid

Targeting defective pulmonary innate immunity -A new therapeutic option? Pharmacol Ther

Quercetin inhibited murine leukemia WEHI-3 cells in vivo and promoted immune response

Possible Therapeutic Effects of Adjuvant Quercetin Supplementation Against Early-Stage COVID-19 Infection: A Prospective, Randomized, Controlled, and Open-Label Study

Potential Clinical Benefits of Quercetin in the Early Stage of COVID-19: Results of a Second, Pilot, Randomized, Controlled and Open-Label Clinical Trial

Dietary Selenium Supplementation Modulates Growth of Brain Metastatic Tumors and Changes the Expression of Adhesion Molecules in Brain Microvessels

Effect of dietary selenium yeast supplementation on porcine circovirus type 2 (PCV2) infections in mice

Selenium ameliorates Staphylococcus aureus-induced inflammation in bovine mammary epithelial cells by inhibiting activation of TLR2, NF-κB and MAPK signaling pathways

Selenium relieves oxidative stress, inflammation, and apoptosis within spleen of chicken exposed to mercuric chloride

Selenium supplementation has beneficial and detrimental effects on immunity to influenza vaccine in older adults

Selenium-Containing Amino Acids Protect Dextran Sulfate Sodium-Induced Colitis via Ameliorating Oxidative Stress and Intestinal Inflammation

Dietary supplementation with methylseleninic acid, but not selenomethionine, reduces spontaneous metastasis of Lewis lung carcinoma in mice

Selenium supplementation has beneficial and detrimental effects on immunity to influenza vaccine in older adults

Nutritional perspectives for the prevention and mitigation of COVID-19

National Library of Medicine 2021. Retrieved on July

Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker

Association between regional selenium status and reported outcome of COVID-19 cases in China

Hypozincemia in the early stage of COVID-19 is associated with an increased risk of severe COVID-19