Table 1.

Nutraceuticals, relative antiviral properties, and eventual clinical evidence on SARS-CoV2.

Nutraceutical	In Vitro Effects	Main Viral Targets	Clinical Evidences Toward SARS-CoV2	Type of Study	Participants	Main Findings	Limitations
Probiotics and prebiotics	- Modulation of the innate (NK cells, macrophages, granulocytes, dendritic cells, and epithelial cells) and adaptive (Th1, Th2, Th17, Treg cells, and lymphocytes B) immune systems - Production of bacteriocins and short-chain fatty acids	Influenza viruses, Rhinovirus, Respiratory syncytial virus (RSV)	–		–
Resveratrol	- Modulation of the immune e antioxidant systems (NF-kB and Nrf2) - Inhibition of viral replication in vitro - Interaction with spike protein and human ACE2 receptor complex	VZV, Herpes simplex (HSV), Poliovirus, Influenza A, HIV	–		–
Hesperidin	- Enhancement of cell-autonomous immunity (p38 and JNK expression) - Inhibition of the release of pro-inflammatory cytokines - Interaction with ACE2 interface - Interaction with viral proteases involved in the processing of viral proteins in the host cell	Influenza viruses	Prophylactic administration due to the protective effect toward thromboembolism and fibrosis [70,77].	In vitro/In vivo	–
Quercetin	- Inhibition of JNK pathway- Antagonized HIV-luc/SARS pseudotyped virus entry	Influenza viruses (H1N1, H3N2, A/WS/33), VZV, Cytomegalovirus (CMV), OC43 and NCDCV	Clinical efficacy on prophylaxis and treatment of COVID-19 cases	Clinical Trial	447	Effective dosage of 500 and 1000 mg for prophylaxis and treatment, respectively	Low number of patients
Lactoferrin	- Enhancement of T and NK lymphocyte activity - Inhibition of SARS CoV2 entry and adhesion -Intracellular inhibition of replication - Spike protein block by ACE-2 independent pathway	CMV, HSV, HIV, HCV, HBV, HPV, Rotavirus, Poliovirus, RSV	–	In vitro/In vivo
				Many clinical studies [95]
Vitamin C	- Scavenger of free radicals and ROS - Modulation of immune system (decrease the release of inflammatory cytokines IFN-γ, IL-6 and TNFα) - Support of neutrophils-mediated kill pathogens phagocytosis	HSV, Influenza type 1, HIV, Rhinovirus	Clinical efficacy on prophylaxis and treatment of COVID-19	Multicenter, prospective randomized, placebo-controlled trial [240]	308 adult patients into ICU (Wuhan)	New potential therapy for COVID-19 by clarifying the effect of High dose of Intravenous Vitamin C on the prognosis of patients, especially on respiratory function Death or persistent organ dysfunction	Low number of recruited patients No effective standardized guideline for COVID-19 treatment at the early stage
				Many ongoing clinical studies [119]
Vitamin D	- Modulation of the immune and antioxidant systems - Stimulation of the synthesis of antimicrobial proteins (cathelicidins and LL37)	Respiratory viruses	Clinical data about adjuvant activity in prophylaxis or treatment of COVID-19	Retrospective observational study [157]	European population	Negative correlations between mean levels of vitamin D in each country and the number of COVID-19 cases	Number of tests performed is different among countries
				Retrospective observational study [156]	107 adult patients	Lower vitamin D levels in SARS-CoV2 infected	Low number of patients from a single hospital
				Pilot randomized clinical study [159]	76 adult patients	Administration of a high dose of Calcifediol reduced the need for ICU treatment of patients requiring hospitalization	Serum vitamin D levels were not measured before, during, or after the experiment
				Retrospective observational study [164]	689 patients	Vitamin D deficiency increases chance of hospitalization	Sample consisted of only one health system
				Retrospective observational study [162]	348,598 UK Biobank participants	No significant relationships between vitamin D levels in a sample of 449 SARS-CoV2 infected patients	Blood samples were collected from 2006 to 2010
				Metanalysis [163]	361,934 participants	Low vitamin D status might be associated with an increased risk of COVID-19 infection	No evaluation of clinical severity or prognosis
				Metanalysis [165]	372,332 participants	Vitamin D deficiency is not associated with a higher risk of SARS-CoV2 infection but with a more severe COVID-19	No stratification according to the sex of the participants
Zinc	- Improvement of mucociliary clearance	Influenza, Rhinovirus	–		–
Vitamin A	- Regulation of NK cells, macrophages, and neutrophils - Downregulation of IFNγ and upregulation of IL-5- Differentiation of dendritic cells’ precursors	Respiratory viruses	–		–
Omega-3 (Ω-3) Fatty Acids	- Production of pro-resolving mediators (resolvins, protectins, and maresins)	Respiratory viruses	–		–
Vitamin K	- Modulation of the immune response associated to vascular damage	–	–		–