Quercetin–bromelain supplementation and clinical outcomes of COVID-19: a randomized, double-blind, placebo-controlled trial in hospitalized patients in Tunisia

Abstract Background Coronavirus disease 2019 (COVID-19) may be complicated by respiratory deterioration and cardiovascular events, especially in hospitalized patients with underlying comorbidities. Quercetin and bromelain have been investigated for their anti-inflammatory, antioxidant, and immunomodulatory properties and may represent potential adjunctive therapeutic agents in COVID-19. Objective To evaluate the effect of a quercetin–bromelain formulation on respiratory deterioration and clinical complications in hospitalized patients with COVID-19. Methods This prospective, randomized, double-blind, placebo-controlled trial enrolled 244 hospitalized adults with confirmed COVID-19. Participants were randomly assigned to receive the quercetin–bromelain formulation (1:1) in addition to standard supportive care (placebo). The intervention consisted of quercetin 800 mg/day for 10 days followed by 400 mg/day for 30 days and bromelain: each capsule contained 400 mg of quercetin and 100 mg of bromelain with an enzymatic activity of > 2,000 GDU (gelatin digesting units). The primary outcome was respiratory deterioration. Secondary outcomes included cardiac complications, in-hospital mortality, and length of hospital stay. Results Respiratory deterioration was significantly less frequent in the quercetin–bromelain group than in the placebo group (9.0% vs. 21.3%; RR, 0.42; 95% CI, 0.22–0.81; p = 0.007). Exploratory subgroup analyses found a lower overall complication rate among patients with < 40% pulmonary involvement on baseline chest CT (18.4% vs. 40.5%; p = 0.03) and fewer cardiac complications among patients with pre-existing comorbidities (4.4% vs. 14.0%; p = 0.02). These subgroup findings were exploratory, and caution should be exercised in interpreting them. Statistically significant differences were not observed between the groups for in-hospital mortality or length of hospital stay. Conclusion In this randomized, double-blind, placebo-controlled trial, treatment with a quercetin–bromelain formulation was associated with a lower incidence of respiratory deterioration among hospitalized patients with COVID-19. The exploratory subgroup analyses found potentially different effects according to baseline pulmonary involvement and comorbidity status, but these need to be confirmed in adequately powered studies. Since the intervention combined quercetin and bromelain, the effects could not be specifically attributed to quercetin alone. Larger, prospectively registered multicenter randomized controlled trials are needed to confirm these findings and clarify the individual and combined contributions of quercetin and bromelain. Trial registration The study was retrospectively registered in the Pan African Clinical Trial Registry (PACTR202406512501178) on 06 June 2024. Registration was done under a registry initiative, which allows inclusion of studies that were already in progress or completed. The retrospective status of registration is reported transparently in accordance with journal requirements.