key: cord-1052000-793erl3u authors: Ahmed, A.; Abdelseed, H.; Albalawi, Y.; Almutairi, Y.; Alsalameen, E.; Alkattan, A. title: Evaluation of the Effect of Zinc, Quercetin, Bromelain and Vitamin C on COVID-19 Patients date: 2020-12-24 journal: nan DOI: 10.1101/2020.12.22.20245993 sha: 2589c62f147e3a264abe04fe11f00cdc6c94257f doc_id: 1052000 cord_uid: 793erl3u Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new strain of coronavirus. There are three phases of COVID-19: early infection stage, pulmonary stage and hyper-inflammation stage respectively. It is important to prevent lung or other organs injuries by preventing phase-II and phase-III via pharmacological or non-pharmacological treatments. This was a case series study done on twenty-two patients confirmed to be infected with SARS-CoV-2 and diagnosed with COVID-19. Patients in this study have been used quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg and ascorbic acid 1 g once daily as supplements for 3 to 5 days during SARS-CoV-2 infection. The aim of this study is to evaluate the safety and efficacy of quercetin, bromelain, zinc and ascorbic acid combination supplements on patients with COVID-19. The mean levels of WBC, ANC, ALC, AMC and AST were normal among all included patients before and after taking quercetin, bromelain, zinc and ascorbic acid supplements (P-value > 0.05). Quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg and ascorbic acid 1 g once daily supplements were safe for patients infected with SARS-CoV-2 and may prevent poor prognosis. Randomized clinical trials needed in the future to ensure the efficacy of quercetin, bromelain, zinc and vitamin c combination. Coronavirus disease 2019 (COVID- 19) is an infectious disease caused by a new strain of coronavirus. ]1[ More than thirty million people around the world have been infected and got COVID-19, and at least one million of them died because of the disease complication including acute respiratory distress syndrome (ARDS) and cytokine storm. ]2[ There are three phases of COVID-19: phase-I (early infection stage); in which SARS-CoV-2 starts to spread and proliferate and innate immunity activated. Phase-II (pulmonary stage); characterized by lung tissue injury and increased leucocytes recruitment. Phase-III (hyperinflammation stage); which various organs could be damaged and there is an extreme exacerbation of immune response. In order to treat COVID-19 patients; it is important to prevent lung or other organs injury by preventing phase-II and phase-III via pharmacological or nonpharmacological treatments. ]3[ Quercetin is a natural flavonoid molecule that distributed broadly in many fruits and vegetables including red onion, cranberry, kale, tomatoes, Hungarian wax and watercress. ]4[ It was revealed in previous studies that quercetin has an anti-inflammatory and anti-hypersensitivity effect by preventing pro-inflammatory prostaglandins and leukotrienes through inhibiting of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, therefore; quercetin was used as an extract in various trials to treat different infectious and non-infectious diseases. ]5[ In addition, quercetin showed to reduce tumor necrosis factor-alpha (TNF-α) production with chronic inflammation. ]6[ Reduction in the ratio of CD4 + :CD8 + T cells and suppression of macrophages, dendritic, mast cells and interleukin-6 (IL-6) levels were revealed after a specific tissue was treated with quercetin in pre-clinical studies (see figure.1 ). ]7-8[ Besides, quercetin expected to has antiviral activity by acting as a zinc chelator and as a zinc ionophore as well. ]9[ However, because most of these studies were done by using quercetin in-vitro with high concentration and in-vivo studies cannot use the same doses; it's showed minimum effect during clinical trials. The available data clarifies that quercetin is a very safe molecule and used as a nutritional supplement with a dose reached 1500 mg divided per day. ]10[ Bromelain is a protein enzyme that found mainly in the stem of the pineapple plant. The bioavailability of bromelain was high through the oral route, and was safe even when consumed more than 11 grams per day. ]11[ In vitro studies showed that bromelain exerts anti-inflammatory effects through reducing bradykinin serum ]12[ and modulating the expression of some genes related to inflammation. ]13[ Three genes related to inflammation including TLR4, TNF-α and IL-8 were found to be less expressed after bromelain treatment (see figure. 2). On the other hand, PPARγ gene expression was elevated after treatment with bromelain. ]14[ Therefore, bromelain may have a role in reducing inflammations during various disorders and may be used in combination with other analgesics and anti-inflammatory drugs. Since the inflammatory status of patients during COVID-19 may lead to severe consequences and even death if not prevented or treated adequately; it is important to ensure high quality care to patients and provide evidence-based prophylaxis and treatment. The aim of this study is to evaluate the efficacy of quercetin, bromelain, zinc and ascorbic acid supplements on patients with COVID-19. This was a case series study conducted between June and September 2020 on twenty-two patients confirmed to be infected with SARS-CoV-2 and diagnosed with COVID-19. The study subjects included are adults and hospitalized in Imam Abdulrahman Alfaisal Hospital in Riyadh. COVID-19 patients in this study have been used quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg and ascorbic acid 1 g once daily as supplements for 3 to 5 days during SARS-CoV-2 infection. A number of laboratory tests were done for all patients included in this study. These tests include absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), hemoglobin (Hb), platelets (Plts), potassium (K), aspartate aminotransferase (AST), oxygen saturation percentage (SaO2), D-dimer and white blood cells (WBCs). In addition, medical and medication history were reported. The primary endpoint was to ensure the efficacy of quercetin, bromelain, zinc and ascorbic acid supplements by evaluating the laboratory results pre-and post-supplements. Paired t-test was used to reveal the differences between different lab tests before and after quercetin, bromelain, zinc and vitamin c combination supplement among patients. Institutional review board (IRB) was obtained from the Saudi ministry of health on the 7 th of June 2020 with the central IRB log number: 20-95M. Twenty-two hospitalized patients diagnosed with COVID-19 were enrolled in this study, all of them were taking quercetin, bromelain, zinc and ascorbic acid as supplements. The mean age of patients was 49.27 years, and 59% of them were older than 50 years old. The percentage of male patients was 68.18%. More than 13% of the patients were having chronic diseases. About half of the patients were receiving antibacterial and antiviral medications during hospitalization, and 63.63% of total patients were on anti-coagulants. Days of stay average was 9 days (see table.1). The mean D-dimer level at admission was elevated (1.0082 mcg/ml). Mean WBCs levels at admission and at discharge were 7440 and 8550 cells/mm 3 respectively (P-value = 0.34). Mean ANC at admission and at discharge were 5570 and 5800 cells/microliter respectively (P-value = 0.86). O2sat% mean was less than 94% at admission, and was more than 94% at discharge (Pvalue = 0.83). AST mean levels were slightly elevated at admission and at discharge (46 and 44.8 U/L respectively, P-value = 0.9). Mean ALC was 1240 at admission and was 1740 cells/microliter at discharge (P-value = 0.11). Mean platelets count at admission and at discharge were 243830 and 304200 cells/microliter respectively (P-value = 0.45). The mean AMC was 456 at admission and 587 cells/microliters (P-value = 0.09). Regarding hemoglobin mean levels, it was 13.68 at admission and 13.24 g/dl at discharge (P-value = 0.78). Mean potassium concentration at admission and at discharge were 4.53 and 4.38 mmol/l (P-value = 0.45) (see table. 2). In this study, the mean D-dimer level of patients diagnosed with COVID-19 was more than 0.5 mcg/ml; which indicates that their condition was not mild and need hospitalization based on the Chinese study. In addition to quercetin and bromelain supplements, most of the twenty-two patients were on hospital medications which include vitamin C, zinc, enoxaparin, drugs expected to have an anti-SARS-CoV-2 effect (ribavirin, hydroxychloroquine or lopinavir-ritonavir) and antibacterial drugs. As shown in the results, all the patients' lab tests done at admission and at discharge were not significantly different and the mean days of stay at the hospital was 9 days. These results reveal that quercetin 800 mg once daily with bromelain 165 mg, in addition to zinc acetate 50 mg and vitamin c 1 g supplements are safe with COVID-19 patients who were on multiple therapies including antivirals and antibacterial medications. The efficacy of quercetin, bromelain, zinc and ascorbic acid combination was not clear in this study, because of lacking placebo or comparable group; however, their efficacy in preventing severe consequences of SARS-CoV-2 infections cannot be ruled out based on previous studies (see figure. 3). Large comparable studies need to be done about quercetin and bromelain to confirm their efficacy in treating COVID-19 cases. Quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg and ascorbic acid 1 g once daily as supplements for 3 to 5 days were safe for patients infected with SARS-CoV-2 and may prevent poor prognosis through restraining from hyper-inflammation and cytokine storm. Randomized All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 24, 2020. ; clinical trials are needed in the future to ensure the efficacy of quercetin, bromelain, zinc and ascorbic acid combination. Anti-platelet or anti-coagulant use (%) 63.63 Mean Days of hospital stay 9 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 24, 2020. ; https://doi.org/10.1101/2020.12.22.20245993 doi: medRxiv preprint Figure. 1 Role of quercetin in inhibiting inflammation by blocking the activity of COX (cyclooxygenase) enzymes and LOX (lipoxygenase) enzyme, in addition to reducing TNF-α (tumor necrosis factor-alpha) and macrophages levels. 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Virol Sin Prophylactic Efficacy of Quercetin 3-β-O-d-Glucoside against Ebola Virus Infection Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry The authors have no conflict of interest.