Quercetin augments therapeutic benefit of antivirals for COVID-19

In patients hospitalized for severe COVID-19, adding the plant flavonoid quercetin to the antiviral drugs remdesivir or favipiravir reduced hospitalization period and levels of inflammatory markers related to the pathogenesis of SARS-CoV-2, thus preventing the progression of the disease into its critical phase, suggests an open-label study from Iran.

COVID-19 patients may develop severe lung infiltration, which could lead to the critical phase of the disease involving acute respiratory distress syndrome and multiple organ failure. [The Lancet 2020;395:497-506] “Immune dysregulation … drives the disease into cytokine storm and mortality phases,” said the researchers. “Given the importance of controlling the mortality rate, uncovering the cellular and molecular mechanisms involved in the progression of disease into the storm phase is necessary.”

Quercetin has been found to prevent sphingomyelinase activity and inhibit progression of lung oedema. [Molecules 2016;21:1739] Quercetin may thus be considered an inhibitor of the acid sphingomyelinase/ceramide system, which is involved in viral internalization into respiratory epithelial cells during SARS-CoV-2 infection. [Int J Mol Sci 2021;22:4794] Regulating this system may lead to prevention of SARS-CoV-2 entry into host epithelial cells and consequently inhibit clinical deterioration of SARS-CoV-2 infection.

Sixty non-ICU* admitted patients with severe COVID-19 were randomized 1:1 to receive remdesivir** or favipiravir*** either alone (control arm) or in combination with quercetin 1,000 mg daily (quercetin arm) for 7 days. [Eur J Pharmacol 2022;914:174615]

The addition of quercetin was associated with significantly fewer hospital days compared with using antivirals alone (mean, 3.13 vs 4.63 days; p=0.039). Day 7 also saw substantially lower serum levels of alkaline phosphatase (mean, 179 vs 202; p=0.002), quantitative C-reactive protein (mean, 21.4 vs 34.1; p=0.004), and lactate dehydrogenase (mean, 439 vs 537; p=0.032) in the quercetin vs the control arm.

Haemoglobin level, though within normal range, was statistically higher in the quercetin vs the control arm (mean, 13.5 vs 12.3; p=0.04), as was the respiratory rate (mean, 29 vs 25; p= 0.011).

However, no significant differences were observed between the quercetin and the control arms in terms of mortality (n=0 vs 3; p=0.07), duration of ICU admission (6–10 vs 8–15 days; p=0.05), and ICU admission rate (n=3 vs 5; p=0.44).

The current findings align with evidence substantiating the ability of quercetin to reduce hospital stay, need for noninvasive oxygenation, progression into ICU, and number of deaths, and improve clinical symptoms and laboratory parameters, in COVID-19 patients. [Int J Gen Med 2021;14:2359-2366; Int J Gen Med 2021;14:2807-2816] The results also boost the therapeutic ability of quercetin as complementary treatment when added to ascorbic acid, zinc acetate, and bromelain. [medRxiv 2020;doi.org/10.1101/2020.12.22.20245993]

“[Taken together, our findings suggest] that quercetin may be therapeutically effective in reducing time to clinical improvement upon combination with antiviral drugs,” said the researchers, who called for further investigation to arrive at a more definite conclusion, especially regarding the effect of quercetin on mortality. “[F]urther studies can be helpful to compensate [for] the limitations of our study and clarify the therapeutic potential of quercetin in COVID-19 treatments.”