Fermented Carica papaya and Morinda citrifolia as Perspective Food Supplements for the Treatment of Post-COVID Symptoms: Randomized Placebo-Controlled Clinical Laboratory Study

Abstract

Food supplements based on fermented Carica papaya and Morinda citrifolia, known for their immune modulating, redox balancing, and anti-inflammatory effects, were added to conventional treatment protocols prescribed to patients recovering after severe and moderate COVID-19 disease in order to alleviate long-lasting post-COVID symptoms. A randomized single-center placebo-controlled clinical laboratory study was designed and performed (total number of participants 188, with delta variant of virus 157, with omicron 31). Clinical statuses were assessed using computer tomography, electrocardiography, a questionnaire, and physical endurance. Plasma cytokines (IL-6, IL-8, IL-17A, and INF-gamma), nitrate/nitrite ratio, antioxidant activity (AOA), and polymorphonuclear leukocyte (PMN) ATP levels were determined before and 20 days following the addition of 28 g of fermented supplements twice per day. The capacity of PMN to phagocyte and the oral-nasal-pharyngeal microbiota were assessed. Clinical symptoms, IL-6, IL-8, and nitric oxide metabolites diminished significantly compared to the placebo group and their background expression. The PMN capacity to phagocyte, AOA, and ATP content remarkably increased. The oral-nasal-pharyngeal microbiota were unchanged. On these grounds, we suggest that fermented tropical fruits could efficiently diminish post-COVID clinical symptoms through several immune-modulating, redox balancing, and pro-energy mechanisms.

Keywords: ATP; Carica papaya; Morinda citrifolia; antioxidant activity; fermented food supplements; nitrates/nitrites; oral-nasal-pharyngeal microbiota; phagocytosis; post-COVID symptoms; pro-inflammatory cytokines.

Figure A1

Examples of ECG in post-COVID period before and after clinical trial on the efficacy of FFS. (a) Left ECG-bradycardia of post-COVID patient A-va (severe COVID) at the 30th day after discharge from the hospital. Right ECG-normal ECG of the same patient at the 50th day after 20 days of FFS supplementation. (b) Left ECG-partial blockade of the left bundle of Hiss in post-COVID patient B-ev (severe COVID) at the 40th day after discharge from the hospital. Right panel-normal ECG of the same patient at the 60th day after 20 days of FFS supplementation. (c) Left ECG-dysmetabolic changes in myocardium of post-COVID patient L-ova (moderate COVID) at the 30th day after discharge from the hospital. Right panel normal ECG of the same patient at the 50th day after 20 days of FFS supplementation.

Figure 1

Phagocytosis parameters of circulating polymorphonuclear leukocytes (PMN) before and after the clinical trial. (a) Number of engulfed bacteria per single cell; (b) actively phagocytosing PMN, phagocytosis index (%); (c) intensity of intracellular killing (%). * FFS-Fermented fruit supplement, 28 g daily for 20 days; ** Placebo-diluted 5% honey 28 g daily for 20 days. Grey area covers normal range of values. ¹ p < 0.01 vs. post-COVID severe placebo group before supplementation; ² p < 0.01 vs. post-COVID severe FFS group before supplementation; ³ 0.05 < p < 0.1 vs. post-COVID severe placebo group before supplementation; ⁴ 0.05 < p < 0,1 vs. post-COVID severe FFS group before supplementation; ⁵ p < 0.01 vs. post-COVID moderate placebo group before supplementation; ⁶ p < 0.01 vs. post-COVID moderate FFS group before supplementation; ⁷ 0.05 < p < 0.1 vs. post-COVID moderate placebo group; ⁸ 0.05 < p < 0.1 vs. post-COVID moderate FFS group before supplementation; ⁹ p < 0.01 vs. donors; ¹⁰ 0.05 < p < 0.1 vs. donors.

Figure 2

Polymorphonuclear leukocyte (PMN) levels of ATP in post-COVID period of the Fermented Fruits Supplemented (FFS) groups. Area coloured in beige covers normal range of values. ¹ p < 0.01 versus normal values; ² p < 0.01 versus post-COVID severe form; ²* 0.05 < p < 0.1 versus post-COVID moderate form group before FFS supplementation.

Figure 3

Plasma interleukin levels (pg/mL) in post-COVID period of the FFS and placebo groups. (a) IL-6 at the admission to the hospital; (b) IL-6 in the post-COVID period before and after supplementation with FFS or placebo; (c) IL-8 in the post-COVID period before and after supplementation with FFS or placebo; (d) IL-17A in the post-COVID period before and after supplementation with FFS or placebo; (e) INF-γ in the post-COVID period before and after supplementation with FFS or placebo. * FFS-Fermented fruit supplement, 28 g for 20 days; ** Placebo-diluted 5% honey 28 g for 20 days. Grey area covers normal range of values. ¹ p < 0.01 vs. post-COVID severe form, FFS; ² p < 0.01 vs. post-COVID severe form, 30–40 days after infection (before FFS); ²* 0.05 < p < 0.1 vs. post-COVID severe form, FFS; ³ p < 0,01 vs. post-COVID moderate form, placebo; ⁴ p < 0.01 vs. post-COVID moderate form, 30–40 days after infection (before FFS); ⁵ p < 0.01 vs. donors.

Figure 4

Plasma levels of (a) nitrites-nitrates and (b) plasma antioxidant capacity (AOA) in post-COVID period of the FFS and placebo groups. * FFS—Fermented fruit supplementation, 28 g for 20 days; ** Placebo-diluted 5% honey, 28 g for 20 days; Grey area covers normal range of values. ¹ p < 0.01 versus post-COVID severe form, FFS; ² p < 0,01 versus post-COVID severe form, before FFS supplementation; ³ p < 0.01 versus post-COVID moderate form, FFS; ⁴ p < 0.01 versus post-COVID moderate form, before FFS supplementation; ⁵ p < 0.01 versus donors.