Quercetin for COVID-19: real-time analysis of all 13 studies

Quercetin for COVID-19: real-time meta analysis of 6 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for ICU admission, hospitalization, recovery, cases, and viral clearance. 6 studies from 4 different countries show statistically significant improvements in isolation (1 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 58% [2‑82%] improvement. Results are slightly worse for peer-reviewed studies. Early treatment is more effective than late treatment.

• Currently there is limited data, with a total of only 35 control events for the most serious outcome in trials to date.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 50% of quercetin studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments may be more effective.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.

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

	Studies	Early treatment	Late treatment	Prophylaxis	Patients	Authors
All studies	6	79% [-82‑98%]	31% [-42‑67%]	92% [21‑99%]	996	70
Peer-reviewed	5	79% [-82‑98%]	31% [-42‑67%]		883	63
RCTs	6	79% [-82‑98%]	31% [-42‑67%]	92% [21‑99%]	996	70
Percentage improvement with quercetin treatment

Covid Analysis et al., 1/5/2022, preprint, 1 author.

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 (Peer Reviewed) (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.

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 (Peer Reviewed)

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, Middle East, peer-reviewed, mean age 50.9 (treatment) 52.7 (control), 8 authors.

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

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

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 (Peer Reviewed)

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, Europe, 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 (Peer Reviewed)

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 [1].

[1] 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, North America, 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 (Peer Reviewed)

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 virological cure, 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 virological cure, 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, South Asia, peer-reviewed, 12 authors.

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 (Peer Reviewed)

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, South Asia, peer-reviewed, 19 authors.

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 (Peer Reviewed)

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) (Peer Reviewed)

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, Europe, 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.

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.

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

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

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

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) (Peer Reviewed)

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)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption