Efficacy of Brazilian Green Propolis (EPP-AF®) as an adjunct treatment for hospitalized COVID-19 patients: a randomized, controlled clinical trial

Silveira, Marcelo Augusto Duarte; Jong, David De; Berretta, Andresa Aparecida; Galvão, Erica Batista dos Santos; Ribeiro, Juliana Caldas; Cerqueira-Silva, Thiago; Amorim, Thais Chaves; Conceição, Luis Filipe Miranda Rebelo da; Gomes, Marcel Miranda Dantas; Teixeira, Maurício Brito; Souza, Sergio Pinto de; Santos, Marcele Helena Celestino Alves dos; Martin, Raissa Lanna Araújo San; Silva, Márcio de Oliveira; Lírio, Monique; Moreno, Lis; Sampaio, Julio Cezar Miranda; Mendonça, Renata; Ultchak, Silviana Salles; Amorim, Fabio Santos; Ramos, João Gabriel Rosa; Batista, Paulo Benigno Pena; Guarda, Suzete Nascimento Farias da; Mendes, Ana Verena Almeida; Passos, Rogerio da Hora

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes challenging immune and inflammatory phenomena. Though various therapeutic possibilities have been tested against coronavirus disease 2019 (COVID-19), the most adequate treatment has not yet been established. Propolis is a natural product with considerable evidence of immunoregulatory and anti-inflammatory activities, and experimental data point to potential against viral targets. We hypothesized that propolis can reduce the negative effects of COVID-19. METHODS: In a randomized, controlled, open-label, single center trial, hospitalized adult COVID-19 patients were treated with a standardized green propolis extract (EPP-AF®️) as an adjunct therapy. Patients were allocated to receive standard care plus an oral dose of 400 mg or 800 mg/day of green propolis for seven days, or standard care alone. Standard care included all necessary interventions, as determined by the attending physician. The primary end point was the time to clinical improvement, defined as the length of hospital stay or oxygen therapy dependency duration. Secondary outcomes included acute kidney injury and need for intensive care or vasoactive drugs. Patients were followed for 28 days after admission. RESULTS: We enrolled 124 patients; 40 were assigned to EPP-AF®️ 400 mg/day, 42 to EPP-AF®️ 800 mg/day, and 42 to the control group. The length of hospital stay post-intervention was shorter in both propolis groups than in the control group; lower dose, median 7 days versus 12 days (95% confidence interval [CI] -6.23 to -0.07; p=0.049) and higher dose, median 6 days versus 12 days (95% CI -7.00 to -1.09; p=0.009). Propolis did not significantly affect the need for oxygen supplementation. In the high dose propolis group, there was a lower rate of acute kidney injury than in the controls (4.8 vs 23.8%), (odds ratio [OR] 0.18; 95% CI 0.03 to 0.84; p=0.048). No patient had propolis treatment discontinued due to adverse events. CONCLUSIONS: Addition of propolis to the standard care procedures resulted in clinical benefits for the hospitalized COVID-19 patients, especially evidenced by a reduction in the length of hospital stay. Consequently, we conclude that propolis can reduce the impact of COVID-19.