Fourteen-Day Evolution of COVID-19 Symptoms during the Third Wave in Nonvaccinated Subjects and Effects of Hesperidin Therapy: A Randomized, Double-Blinded, Placebo-Controlled Study

Abstract

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once daily for 14 days in 216 symptomatic nonvaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10, and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath, or anosmia. At the baseline, symptoms in decreasing frequency were as follows: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%), and irritability/confusion (3.2%). Group A symptoms in the placebo vs. hesperidin group were 88.8% vs. 88.5% (day 1) and reduced to 58.5 vs. 49.4% at day 14 (OR 0.69, 95% CI 0.38–1.27, p = 0.23 ). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing “no symptoms” to missing values, the hesperidin group showed reduction of 14.5% of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32–0.96, p = 0.03 ). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% to 25.3% in the hesperidin group vs. 32.6% in the placebo group ( p = 0.29 ). The mean number of symptoms in the placebo and hesperidin groups was 5.10 (SD 2.26) vs. 5.48 (SD 2.35) (day 1) and 1.40 (SD 1.65) vs. 1.38 (SD 1.76) (day 14) ( p = 0.92 ). In conclusion, most nonvaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1 g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

Bioinformatics-based investigation on the genetic influence between SARS-CoV-2 infections and idiopathic pulmonary fibrosis (IPF) diseases, and drug repurposing

“…An in-vitro study found that the drug molecule 'simeprevir' significantly decreases the SARS-CoV-2 viral load 152 . In a double-blind placebo-controlled trial, the drug 'Hesperidin 1000 mg daily may help decrease fever, cough, shortness of breath, or anosmia symptoms of nonvaccinated COVID-19 infected patients 169 . In histopathological, biochemical, and micro-CT analyses on rat, Hesperidin successfully reduced the severity of lung injury caused by BLC, a model for IPF 168 .…”

Hesperidin, a Potential Antiviral Agent against SARS-CoV-2: The Influence of Citrus Consumption on COVID-19 Incidence and Severity in China

“…The studies conducted by Dupuis et al [ 36 ] presented the findings of a randomized, double-blinded, placebo-controlled study conducted to investigate the evolution of COVID-19 symptoms over a 14-day period in nonvaccinated COVID-19 individuals. The intervention involved administering hesperidin at 1000 mg once daily for 14 days, while the control group received a matching placebo.…”

A Comprehensive Review of Natural Flavonoids with Anti-SARS-CoV-2 Activity

“…Hesperidin also blocks the AKT pathway and inhibits Ang II-induced collagen expression and cardiac fibroblast proliferation during COVID-19 infection [ 121 ]. Clinical studies have also shown that hesperidin can reduce some of the clinical symptoms of COVID-19, such as shortness of breath, cough, decreased or even absent taste, and fever [ 122 ].…”