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
Jocelyn Dupuis, Pierre Laurin, Jean-Claude Tardif, Leslie Hausermann, Camille Rosa, Marie-Claude Guertin, Karen Thibaudeau, Lyne Gagnon, Frank Cesari, Martin Robitaille, John E Moran
Evidence-Based Complementary and Alternative Medicine, doi:10.1155/2022/3125662
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. Tirteen symptoms were recorded after 3, 7, 10, and 14 days. Te 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). Te 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.
Disclosure Te other funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of Interest
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DOI record:
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"abstract": "<jats:p>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, <jats:inline-formula>\n <a:math xmlns:a=\"http://www.w3.org/1998/Math/MathML\" id=\"M1\">\n <a:mi>p</a:mi>\n <a:mo>=</a:mo>\n <a:mn>0.23</a:mn>\n </a:math>\n </jats:inline-formula>). 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, <jats:inline-formula>\n <c:math xmlns:c=\"http://www.w3.org/1998/Math/MathML\" id=\"M2\">\n <c:mi>p</c:mi>\n <c:mo>=</c:mo>\n <c:mn>0.03</c:mn>\n </c:math>\n </jats:inline-formula>). 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 (<jats:inline-formula>\n <e:math xmlns:e=\"http://www.w3.org/1998/Math/MathML\" id=\"M3\">\n <e:mi>p</e:mi>\n <e:mo>=</e:mo>\n <e:mn>0.29</e:mn>\n </e:math>\n </jats:inline-formula>). 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) (<jats:inline-formula>\n <g:math xmlns:g=\"http://www.w3.org/1998/Math/MathML\" id=\"M4\">\n <g:mi>p</g:mi>\n <g:mo>=</g:mo>\n <g:mn>0.92</g:mn>\n </g:math>\n </jats:inline-formula>). 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.</jats:p>",
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