Lactoferrin as potential supplementary nutraceutical agent in COVID-19 patients: in vitro and in vivo preliminary evidences
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Abstract
Lactoferrin, a multifunctional cationic glycoprotein, secreted by exocrine glands and neutrophils, possesses an antiviral activity extendable to SARS-CoV-2.
We performed in vitro assays proving lactoferrin antiviral activity through direct attachment to both virus and cell surface components. This activity varied according to concentration (100/500μg/ml), multiplicity of infection (0.1/0.01) and cell type (Vero E6/Caco-2 cells).
Interestingly, the in silico results strongly supported the hypothesis of a direct recognition between the lactoferrin and the Spike S glycoprotein, thus hindering the viral entry into the cells.
Hence, we conducted a clinical trial to investigate effect and tolerability of a liposomal lactoferrin formulation as a supplementary nutraceutical agent in mild-to-moderate and asymptomatic COVID-19 patients.
A total of 92 mild-to-moderate (67/92) and asymptomatic (25/92) COVID-19 patients were recruited and divided in 3 groups according to the administered regimen. Thirty-two patients, 14 hospitalised and 18 in home-based insolation received oral and intranasal liposomal bovine lactoferrin (bLf), 32 hospitalised patients were treated with standard of care treatment (hydroxychloroquine, azitromicin and lopinavir/darunavir), and 28, in home-based isolation, did not take any medication. Furthermore, 32 COVID-19 negative, not-treated, healthy subjects were added as a control group for ancillary analysis.
bLf-supplemented COVID-19 patients obtained an earlier and significant (p < 0,0001.) median rRT-PCR SARS-COV-2 RNA negative conversion than standard of care-treated and non-treated COVID-19 patients (14.25 vs 27.13 vs 32.61 days, respectively).
In addition, bLf-supplemented COVID-19 patients showed significant fast clinical symptoms recovery than standard of care-treated and non-treated COVID-19 patients. Moreover, in bLf-supplemented patients, a significant decrease of either serum ferritin or IL-6 levels or host iron overload, all parameters characterizing inflammatory processes, were observed. Serum D-dimers was also found significantly decreased following bLf supplement. No adverse events were reported.
These in vitro and in vivo observations led us to speculate a potential and safe supplementary role of Blf in the management of mild-to-moderate and asymptomatic COVID-19 patients.
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SciScore for 10.1101/2020.08.11.244996: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell culture and virus: The African green monkey kidney-derived Vero E6 and human colon carcinoma-derived Caco-2 cells were provided by American Type Culture Collection (ATCC). Vero E6suggested: RRID:CVCL_XD71)In order to investigate the putative interaction of bLf with viral particles and/or host cells, the following different experimental approaches in both Vero E6 and Caco-2 cells were performed. Caco-2suggested: None… SciScore for 10.1101/2020.08.11.244996: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell culture and virus: The African green monkey kidney-derived Vero E6 and human colon carcinoma-derived Caco-2 cells were provided by American Type Culture Collection (ATCC). Vero E6suggested: RRID:CVCL_XD71)In order to investigate the putative interaction of bLf with viral particles and/or host cells, the following different experimental approaches in both Vero E6 and Caco-2 cells were performed. Caco-2suggested: NoneSoftware and Algorithms Sentences Resources Both docking procedures were performed using Frodock’s (http://frodock.chaconlab.org/) web-server. Frodock’ssuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:One of the limitations of our study was the small sample size of the clinical trial. Further studies, both in vitro and in vivo are needed to better deepen Lf placement against COVID-19, both as a preventive, adjunctive or in monotherapy. Nevertheless, we achieved a statistical significance in the crucial blood parameters related to disease evolution and we still observed an improving trend in all other analysed markers. Further studies on larger samples are needed to better evaluate the role Lf in treating SARS-CoV-2. Considering the risk of COVID-19 relapse [86], we also suggest additional long-term studies to evaluate the maintenance of viral clearance with Lf continuous administration. Lf could be considered as an effective supplement in mild to moderate and asymptomatic COVID19 patients, which are not clearly included in therapeutical guidelines, allowing improvement of patient outcomes and prevention of hospital recovery, but also prevention of the chronic consequences of infection as well as prevention of transmission by shortening the time length of infectiousness. This study is part of the GEFACOVID2.0 research program coordinated by the Tor Vergata University of Rome.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04475120 Completed Efficacy and Safety of Liposomal Lactoferrin in COVID-19 Pat… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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