Quercetin for COVID-19: real-time analysis of all 21 studies

Quercetin for COVID-19: real-time meta analysis of 9 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for ICU admission, hospitalization, recovery, cases, and viral clearance. 9 studies from 8 independent teams in 6 different countries show statistically significant improvements in isolation (3 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 63% [27‑81%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, similar for peer-reviewed studies, and similar after excluding studies using combined treatment.

• Studies typically use advanced formulations for greatly improved bioavailability.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 44% of quercetin studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments may be more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 8/16/2022, preprint, 1 author.

Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors

Chellasamy et al., Journal of King Saud University - Science, doi:10.1016/j.jksus.2022.102277

In Silico study of SARS-CoV-1&2 endodomains and ezrin docking, identifying ivermectin, quercetin, calcifediol, calcitriol, selamectin, and minocycline as potential therapeutic drugs with strong ezrin binding which may restrict viral endodomain interaction while also stabilizing ezrin, thereby reducing virus fusion and infection.

Chellasamy et al., 8/10/2022, peer-reviewed, 2 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Evaluation of the Clinical Effects of an Antiviral, Immunostimulant and Antioxidant Phytotherapy in Patients Suffering from COVID-19 Infection: An Observational Pilot Study

Ortore et al., International Journal of Translational Medicine, doi:10.3390/ijtm2020022

Retrospective case series of 240 patients in Italy in 2020, up to 96 years old, showing no mortality and 1.6% hospitalization with early treatment including vitamin C, quercetin, and green tea and red wine polyphenols.

The formulation was based on SARS-CoV-2 molecular docking studies. Low bioavailability is a known issue for polyphenols. Authors note that bioavailability may be improved with combinations of polyphenols which may have a synergistic effect, and via consumption with dietary fat.

Ortore et al., 6/16/2022, Italy, peer-reviewed, 12 authors, study period September 2020 - December 2021.

The pharmacological mechanism of quercetin as adjuvant therapy of COVID-19

Rizky et al., Life Research, doi:10.53388/life2022-0205-302 (Review)

Review of in silico and clinical evidence supporting the use of quercetin for COVID-19.

Rizky et al., 5/15/2022, peer-reviewed, 5 authors.

Oral Co-Supplementation of Curcumin, Quercetin, and Vitamin D3 as an Adjuvant Therapy for Mild to Moderate Symptoms of COVID-19—Results From a Pilot Open-Label, Randomized Controlled Trial

Khan et al., Frontiers in Pharmacology, doi:10.3389/fphar.2022.898062

RCT 50 COVID+ outpatients in Pakistan, 25 treated with curcumin, quercetin, and vitamin D, showing significantly faster viral clearance, significantly improved CRP, and faster resolution of acute symptoms (p=0.154). 168mg curcumin, 260mg quercetin and 360IU cholecalciferol.

risk of no recovery, 33.3% lower, RR 0.67, p = 0.15, treatment 10 of 25 (40.0%), control 15 of 25 (60.0%), NNT 5.0.

relative CRP reduction, 39.1% better, RR 0.61, p = 0.006, treatment 25, control 25.

risk of no viral clearance, 50.0% lower, RR 0.50, p = 0.009, treatment 10 of 25 (40.0%), control 20 of 25 (80.0%), NNT 2.5.

Khan et al., 5/1/2022, Randomized Controlled Trial, Pakistan, peer-reviewed, 7 authors, study period 2 September, 2021 - 28 November, 2021, this trial uses multiple treatments in the treatment arm (combined with curcumin and vitamin D) - results of individual treatments may vary, trial NCT05130671 (history).

The Therapeutic and Prophylactic Potential of Quercetin against COVID-19: An Outlook on the Clinical Studies, Inventive Compositions, and Patent Literature

Imran et al., Antioxidants, doi:10.3390/antiox11050876 (Review)

Review of the evidence supporting the use of quercetin for COVID-19 from clinical studies and patents.

Imran et al., 4/29/2022, peer-reviewed, 10 authors.

Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants

Goc et al., European Journal of Microbiology and Immunology, doi:10.1556/1886.2021.00022 (In Vitro)

In Vitro study testing combinations of plant extracts and micronutrients with several variants of SARS-CoV-2. A combination of vitamin C, N-acetylcysteine, curcumin, quercetin, resveratrol, theaflavin, naringenin, baicalin, and broccoli extract showed the highest inhibition of RBD binding, and also decreased RdRp, furin, and cathepsin L activity.

Goc et al., 1/21/2022, peer-reviewed, 5 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Promising Effects of 3-Month Period of Quercetin Phytosome® Supplementation in the Prevention of Symptomatic COVID-19 Disease in Healthcare Workers: A Pilot Study

Rondanelli et al., Life, doi:10.3390/life12010066

RCT 120 healthcare workers, 60 treated with quercetin phytosome, showing lower risk of cases with treatment. Quercetin phytosome 250mg twice a day.

risk of symptomatic case, 92.9% lower, HR 0.07, p = 0.04, treatment 1 of 60 (1.7%), control 4 of 60 (6.7%), adjusted, inverted to make RR<1 favor treatment, Cox proportional risk.

Rondanelli et al., 1/4/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Italy, peer-reviewed, 12 authors, trial NCT05037240 (history).

Quercetin and Luteolin Are Single-digit Micromolar Inhibitors of the SARS-CoV-2 RNA-dependent RNA Polymerase

Munafò et al., Research Square, doi:10.21203/rs.3.rs-1149846/v1 (Preprint) (In Vitro)

In Vitro and In Silico study showing quercetin and luteolin inhibiting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).

Munafò et al., 12/28/2021, preprint, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The spike protein of SARS-CoV-2 virus induces heme oxygenase-1: Pathophysiologic implications

Singh et al., Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, doi:10.1016/j.bbadis.2021.166322 (In Vitro)

In Vitro study transfecting SARS-CoV-2 viral spike protein in kidney cell lines, showing syncytia formation and upregulation of the cytoprotective gene HO-1, and that quercetin, which induces HO-1, can reduce syncytia formation. Authors conclude that quercetin may be protective for AKI in COVID-19.

Singh et al., 12/14/2021, peer-reviewed, 9 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Retrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis of Early COVID-19 and Treated at Home Within 3 Days or After 3 Days of Symptom Onset with Prescribed and Non-Prescribed Treatments Between November 2020 and August 2021

Fazio et al., Medical Science Monitor, doi:10.12659/MSM.935379

Retrospective 158 COVID-19 patients in Italy treated with hesperidin, quercetin, indomethacin, aspirin, omeprazole, azithromycin, LMWH, and betamethasone (treatment specific for each patient), showing significantly lower hospitalization and faster recovery with early treatment.

Fazio et al., 12/8/2021, retrospective, Italy, peer-reviewed, 6 authors.

The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: A randomized controlled trial

Shohan et al., European Journal of Pharmacology, doi:10.1016/j.ejphar.2021.1746158

Small RCT with 60 severe hospitalized patients in Iran, 30 treated with quercetin, showing shorter time until discharge. All patients received remdesivir or favipiravir, and vitamin C, vitamin D, famotidine, zinc, dexamethasone, and magnesium (depending on serum levels). Quercetin 1000mg daily for 7 days. IRCT20200419047128N2.

risk of death, 85.7% lower, RR 0.14, p = 0.24, treatment 0 of 30 (0.0%), control 3 of 30 (10.0%), NNT 10.0, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 40.0% lower, RR 0.60, p = 0.71, treatment 3 of 30 (10.0%), control 5 of 30 (16.7%), NNT 15.

days from end of intervention to discharge, 32.4% lower, relative time 0.68, p = 0.04, treatment 30, control 30.

Shohan et al., 12/2/2021, Randomized Controlled Trial, Iran, peer-reviewed, mean age 50.9 (treatment) 52.7 (control), 8 authors, average treatment delay 7.8 days.

Inhibition of the SARS-CoV-2 3CLpro main protease by plant polyphenols

Bahun et al., Food Chemistry, doi:10.1016/j.foodchem.2021.131594 (In Vitro)

In Silico and In Vitro study of plant polyphenols identifying quercetin, curcumin, ellagic acid, epigallocatechin gallate and resveratrol as SARS-CoV-2 3CL^pro inhibitors with IC₅₀ between 11.8µM and 23.4µM. Real-time binding was analyzed with surface plasmon resonance spectroscopy.

Bahun et al., 11/14/2021, peer-reviewed, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

In silico identification of SARS-CoV-2 cell entry inhibitors from selected natural antivirals

Şimşek et al., Journal of Molecular Graphics and Modelling, doi:10.1016/j.jmgm.2021.108038

In Silico study identifying quercetin derivatives as SARS-CoV-2 spike protein, ACE2, and neuropilin inhibitors.

Şimşek et al., 9/29/2021, peer-reviewed, 3 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Quercetin effectiveness in patients with COVID-19 associated pneumonia

Zupanets et al., Zaporozhye Med. J., doi:10.14739/2310-1210.2021.5.231714

RCT 200 patients in Ukraine, 99 treated with IV quercetin/polyvinylirolidone followed by oral quercetin/pectin, showing improved recovery with treatment.

risk of no recovery, 29.4% lower, RR 0.71, p = 0.50, treatment 9 of 99 (9.1%), control 13 of 101 (12.9%), NNT 26.

recovery time, 18.2% lower, relative time 0.82, p = 0.03, treatment 99, control 101.

Zupanets et al., 9/1/2021, Randomized Controlled Trial, Ukraine, peer-reviewed, 14 authors.

20-Week Study of Clinical Outcomes of Over-the-Counter COVID-19 Prophylaxis and Treatment

Margolin et al., Journal of Evidence-Based Integrative Medicine, doi:10.1177/2515690X211026193

Retrospective 113 outpatients, 53 (patient choice) treated with zinc, quercetin, vitamin C/D/E, l-lysine, and quina, showing lower cases with treatment. Results are subject to selection bias and limited information on the groups is provided. See [journals.sagepub.com].

1. journals.sagepub.com, https://journals.sagepub.com/doi/full/10.1177/2515690X211058417.

risk of case, 94.4% lower, RR 0.06, p = 0.003, treatment 0 of 53 (0.0%), control 9 of 60 (15.0%), NNT 6.7, relative risk is not 0 because of continuity correction due to zero events.

risk of COVID-19 or flu-like illness, 81.1% lower, RR 0.19, p = 0.01, treatment 2 of 53 (3.8%), control 12 of 60 (20.0%), NNT 6.2.

Margolin et al., 7/6/2021, retrospective, USA, peer-reviewed, 5 authors, this trial uses multiple treatments in the treatment arm (combined with zinc, vitamin C/D/E, l-lysine, and quina) - results of individual treatments may vary.

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

Di Pierro et al., International Journal of General Medicine, doi:10.2147/IJGM.S318949

RCT 42 outpatients in Pakistan, 21 treated with quercetin phytosome, showing faster viral clearance and lower symptom severity with treatment.

risk of death, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 21 (0.0%), control 1 of 21 (4.8%), NNT 21, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 21 (0.0%), control 1 of 21 (4.8%), NNT 21, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 21 (0.0%), control 1 of 21 (4.8%), NNT 21, relative risk is not 0 because of continuity correction due to zero events.

risk of no viral clearance, 73.7% lower, RR 0.26, p < 0.001, treatment 5 of 21 (23.8%), control 19 of 21 (90.5%), NNT 1.5, day 7.

risk of no viral clearance, 88.9% lower, RR 0.11, p = 0.11, treatment 0 of 21 (0.0%), control 4 of 21 (19.0%), NNT 5.2, relative risk is not 0 because of continuity correction due to zero events, day 14.

Di Pierro et al., 6/24/2021, Randomized Controlled Trial, Pakistan, peer-reviewed, 12 authors, trial NCT04861298 (history).

Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2

Kandeil et al., Pathogens, doi:10.3390/pathogens10060758 (In Vitro)

Vero E6 In Vitro study showing curcumin, hesperidin, and quercetin significantly inhibited SARS-CoV-2 replication, and In Silico analysis with promising M^pro and spike docking results.

Kandeil et al., 6/15/2021, peer-reviewed, 11 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

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

Di Pierro et al., International Journal of General Medicine, doi:10.2147/IJGM.S318720

RCT 152 outpatients in Pakistan, 76 treated with quercetin phytosome, showing lower mortality, ICU admission, and hospitalization with treatment.

risk of death, 85.7% lower, RR 0.14, p = 0.25, treatment 0 of 76 (0.0%), control 3 of 76 (3.9%), NNT 25, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 94.1% lower, RR 0.06, p = 0.006, treatment 0 of 76 (0.0%), control 8 of 76 (10.5%), NNT 9.5, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization, 68.2% lower, RR 0.32, p = 0.003, treatment 7 of 76 (9.2%), control 22 of 76 (28.9%), NNT 5.1.

Di Pierro et al., 6/8/2021, Randomized Controlled Trial, Pakistan, peer-reviewed, 19 authors, trial NCT04578158 (history).

Oral Quercetin in Adult Patients as a Potential Nutraceutical against Coronavirus Disease 2019 (COVID-19)

Aguilar et al., Journal of Advances in Medical and Pharmaceutical Sciences, doi:10.9734/jamps/2021/v23i330222

Prospective study of 52 patients treated with quercetin. There was no control group.

Aguilar et al., 4/8/2021, peer-reviewed, 3 authors.

Treatment of COVID-19 patients with quercetin: a prospective, single center, randomized, controlled trial

Onal et al., Turk. J. Biol., 45:518-529 (preprint 1/19/2021)

RCT 447 moderate-to-severe hospitalized patients in Turkey, 52 treated with quercetin, bromelain, and vitamin C, showing no statistically significant difference in clinical outcomes. NCT04377789.

risk of death, 29.3% higher, RR 1.29, p = 0.57, treatment 1 of 49 (2.0%), control 6 of 380 (1.6%).

risk of ICU admission, 94.0% lower, RR 0.06, p = 0.39, treatment 0 of 49 (0.0%), control 14 of 380 (3.7%), NNT 27, relative risk is not 0 because of continuity correction due to zero events.

risk of no hospital discharge, 77.8% lower, RR 0.22, p = 0.10, treatment 1 of 49 (2.0%), control 35 of 380 (9.2%), NNT 14.

Onal et al., 1/19/2021, Randomized Controlled Trial, Turkey, peer-reviewed, 10 authors, this trial uses multiple treatments in the treatment arm (combined with bromelain and vitamin C) - results of individual treatments may vary, trial NCT04377789 (history).

Synergistic Effect of Quercetin and Vitamin C Against COVID-19: Is a Possible Guard for Front Liners

Arslan et al., SSRN, doi:10.2139/ssrn.3682517 (Preprint)

Small prophylaxis RCT with 113 patients showing fewer cases with quercetin + vitamin C + bromelain prophylaxis. NCT04377789. Note that this paper disappeared from SSRN without explanation.

risk of case, 91.7% lower, RR 0.08, p = 0.03, treatment 1 of 71 (1.4%), control 9 of 42 (21.4%), NNT 5.0, adjusted, inverted to make RR<1 favor treatment.

Excluded in after exclusion results of meta analysis: paper no longer available at the source, and the contact does not reply to queries.

Arslan et al., 11/16/2020, Randomized Controlled Trial, Turkey, preprint, 7 authors, this trial uses multiple treatments in the treatment arm (combined with vitamin C and bromelain) - results of individual treatments may vary, trial NCT04377789 (history).

A role for quercetin in coronavirus disease 2019 (COVID-19)

Derosa et al., Phytotherapy Research, doi:10.1002/ptr.6887 (Review)

Review noting that quercetin has a theoretical, but significant, capability to interfere with SARS-CoV-2 replication, with results showing this to be the fifth best compound out of 18 candidates.

Derosa et al., 10/9/2020, peer-reviewed, 4 authors.

Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19)

Biancatelli et al., Frontiers in Immunology, doi:10.3389/fimmu.2020.01451 (Review)

Review of the evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients.

Biancatelli et al., 6/19/2020, peer-reviewed, 4 authors.

In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) from Natural Products: Quercetin, Hispidulin, and Cirsimaritin Exhibited Better Potential Inhibition than Hydroxy-Chloroquine Against COVID-19 Main Protease Active Site and ACE2

Sekiou et al., ChemRxiv, doi:10.26434/chemrxiv.12181404.v1 (Preprint)

In Silico study of natural compounds identifying quercetin, curcumin, hispidulin, cirsimaritin, sulfasalazine, and artemisin as potential compounds that inhibit SARS-CoV-2.

Sekiou et al., 4/24/2020, preprint, 4 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Antiandrogens	(meta)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bebtelovimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Cannabidiol	(meta)	Nitric Oxide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)
Lactoferrin	(meta)

Other Treatments		Global Adoption