Lactoferrin for COVID-19: real-time analysis of all 12 studies

Lactoferrin for COVID-19: real-time meta analysis of 4 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvement is seen for viral clearance. 2 studies from 2 independent teams (both from the same country) show statistically significant improvements in isolation (1 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 48% [30‑62%] improvement. Results are worse for Randomized Controlled Trials and similar after exclusions. Early treatment is more effective than late treatment.

• Currently there is limited data, with only 786 patients in trials to date.

• No treatment, vaccine, or intervention is 100% effective and available. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments may be more effective. Only 25% of lactoferrin studies show zero events with treatment. The quality of non-prescription supplements can vary widely [Crawford, Crighton].

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 20 Sep 2022, preprint, 1 author.

An overview on in vitro and in vivo antiviral activity of lactoferrin: its efficacy against SARS-CoV-2 infection

Rosa et al., BioMetals, doi:10.1007/s10534-022-00427-z (Review)

Review of the antiviral activity of lactoferrin and efficacy for SARS-CoV-2.

Rosa et al., 3 Aug 2022, peer-reviewed, 6 authors.

Lactoferrin binding to Sars-CoV-2 Spike glycoprotein protects host from infection, inflammation and iron dysregulation.

Cutone et al., Research Square, doi:10.21203/rs.3.rs-1605740/v1 (Preprint) (In Vitro)

Vero E6, Caco-2, and THP-1 In Vitro study showing lactoferrin inhibited SARS-CoV-2 spike pseudovirus. Nutraceutically available bovine lactoferrin was more effective than human lactoferrin.

Cutone et al., 17 May 2022, Italy, preprint, 12 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Lactoferrin Inhibition of the Complex Formation between ACE2 Receptor and SARS CoV-2 Recognition Binding Domain

Piacentini et al., International Journal of Molecular Sciences, doi:10.3390/ijms23105436 (In Vitro)

Biolayer interferometry and turbidimetry study showing lactoferrin inhibits ACE2 - SARS-CoV-2 RBD binding.

Piacentini et al., 13 May 2022, Italy, peer-reviewed, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells

Ostrov et al., Pathogens, doi:10.3390/pathogens10111514 (In Vitro)

Vero E6 and H23 In Vitro study finding SARS-CoV-2 antiviral activity associated with agonism of the sigma-1 receptor, ligation of the sigma-2 receptor, and a combination of the two. Authors identify synergistic effects with the combination of diphenhydramine and lactoferrin.

Ostrov et al., 20 Nov 2021, peer-reviewed, 16 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Hepatic and gastrointestinal disturbances in Egyptian patients infected with coronavirus disease 2019: A multicentre cohort study

Shousha et al., World Journal of Gastroenterology, doi:10.3748/wjg.v27.i40.6951

Retrospective 547 hospitalized COVID+ patients in Egypt, showing lower mortality with lactoferrin treatment (without statistical significance).

risk of death, 79.1% lower, RR 0.21, p = 0.11, treatment 1 of 46 (2.2%), control 52 of 501 (10.4%), NNT 12, unadjusted.

Excluded in after exclusion results of meta analysis: confounding by indication, unadjusted results and treatment used selectively per official protocol, unadjusted results with no group details.

Shousha et al., 28 Oct 2021, retrospective, Egypt, peer-reviewed, 18 authors, study period 15 April, 2020 - 29 July, 2020.

Lactoferrin as Antiviral Treatment in COVID-19 Management: Preliminary Evidence

Campione et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph182010985

Small prospective study in Italy with 32 lactoferrin patients, 32 SOC, and 28 patients with no treatment, showing significantly faster viral clearance and improved recovery with treatment. Oral and intranasal lactoferrin.

time to viral-, 47.5% lower, relative time 0.53, p < 0.001, treatment 32, control 32, vs. SOC.

time to viral-, 56.3% lower, relative time 0.44, p < 0.001, treatment 32, control 28, vs. untreated.

Campione et al., 19 Oct 2021, prospective, Italy, peer-reviewed, 32 authors.

Ambulatory COVID-19 Patients Treated with Lactoferrin as a Supplementary Antiviral Agent: A Preliminary Study

Rosa et al., Journal of Clinical Medicine, doi:10.3390/jcm10184276

Retrospective survey based study in Italy with 82 patients treated with lactoferrin, and 39 control patients, showing significantly faster viral clearance with treatment. There was no significant difference in recovery time overall, however the treatment group had significantly more moderate condition patients (39% versus 8%), and improved recovery was seen with treatment as age increased. Median dose for asymptomatic patients was 400mg/day, for paucisymptomatic patients 600mg/day, and for moderate condition patients 1000mg three times a day.

risk of hospitalization, 75.6% lower, RR 0.24, p = 0.32, treatment 0 of 82 (0.0%), control 1 of 39 (2.6%), NNT 39, relative risk is not 0 because of continuity correction due to zero events.

recovery time, 40.0% higher, relative time 1.40, p = 0.50, treatment 82, control 39, excluded in exclusion analyses: excessive unadjusted differences between groups.

time to viral-, 39.4% lower, relative time 0.61, p = 0.02, treatment 82, control 39, inverted to make RR<1 favor treatment, Cox regression, primary outcome.

Rosa et al., 21 Sep 2021, retrospective, Italy, peer-reviewed, 8 authors, study period October 2020 - March 2021.

Lactoferrin reduces the risk of respiratory tract infections: A meta-analysis of randomized controlled trials

Ali et al., Clinical Nutrition ESPEN, doi:10.1016/j.clnesp.2021.08.019

Meta analysis of 6 RCTs, showing lower risk of respiratory tract infections with lactoferrin.

Ali et al., 3 Sep 2021, peer-reviewed, 4 authors.

Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19

Mirabelli et al., Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2105815118 (In Vitro)

In Vitro study testing 1,425 compounds for SARS-CoV-2 antiviral activity, identifying 17 dose-responsive compounds with IC₅₀ values <1μM. Lactoferrin inhibited SARS-CoV-2 in the nanomolar range in all cell models with multiple modes of action.

Mirabelli et al., 19 Aug 2021, peer-reviewed, 23 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

The Prospect of Lactoferrin Use as Adjunctive Agent in Management of SARS-CoV-2 Patients: A Randomized Pilot Study

Algahtani et al., Medicina, doi:10.3390/medicina57080842

RCT 54 hospitalized patients in Egypt, showing no significant differences in recovery with lactoferrin treatment. 200mg lactoferrin orally once daily (group 1) or 200mg lactoferrin orally twice daily (group 2).

risk of unresolved fever, 25.0% lower, RR 0.75, p = 1.00, treatment 3 of 36 (8.3%), control 2 of 18 (11.1%), NNT 36, day 7.

risk of unresolved fatigue, 33.3% lower, RR 0.67, p = 0.67, treatment 4 of 36 (11.1%), control 3 of 18 (16.7%), NNT 18, day 7.

risk of unresolved cough, no change, RR 1.00, p = 1.00, treatment 8 of 36 (22.2%), control 4 of 18 (22.2%), day 7.

risk of unresolved headache, no change, RR 1.00, p = 1.00, treatment 4 of 36 (11.1%), control 2 of 18 (11.1%), day 7.

risk of unresolved loss of smell/taste, 25.0% lower, RR 0.75, p = 0.72, treatment 6 of 36 (16.7%), control 4 of 18 (22.2%), NNT 18, day 7.

Algahtani et al., 19 Aug 2021, Randomized Controlled Trial, Egypt, peer-reviewed, 6 authors, study period 8 July, 2020 - 18 September, 2020.

Natural resources to control COVID-19: could lactoferrin amend SARS-CoV-2 infectivity?

Mattar et al., PeerJ, doi:10.7717/peerj.11303 (Review)

Review of the mechanisms of action and evidence for beneficial effects of lactoferrin for COVID-19.

Mattar et al., 14 Apr 2021, peer-reviewed, 5 authors.

Molecular Mechanisms Behind Anti SARS-CoV-2 Action of Lactoferrin

Miotto et al., Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.607443

In Silico study of possible molecular mechanisms for anti-SARS-CoV-2 action of lactoferrin.

Miotto et al., 15 Feb 2021, peer-reviewed, 6 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Protective Effects of Lactoferrin against SARS-CoV-2 Infection In Vitro

Salaris et al., Nutrients, doi:10.3390/nu13020328 (In Vitro)

Caco-2 and Vero E6 In Vitro study showing lactoferrin enhances the antiviral immune response, partially inhibits SARS-CoV-2 infection in Caco-2 intestinal epithelial cells, and modulates cytokine production.

Salaris et al., 23 Jan 2021, peer-reviewed, 9 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Lactoferrin as potential preventative and adjunct treatment for COVID-19

Chang et al., International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106118 (Review)

Review of the antiviral, anti-inflammatory, and immunomodulatory effects of lactoferrin and the potential benefit for COVID-19.

Chang et al., 30 Sep 2020, peer-reviewed, 3 authors.

Lactoferrin as Protective Natural Barrier of Respiratory and Intestinal Mucosa against Coronavirus Infection and Inflammation

Campione et al., International Journal of Molecular Sciences, doi:10.3390/ijms21144903 (Review)

Review of the mechanisms of action and potential benefits of lactoferrin for COVID-19. Authors propose designing a trial combining an intranasal spray and oral administration (which they later performed).

Campione et al., 11 Jul 2020, peer-reviewed, 8 authors.

Liposomal Lactoferrin as Potential Preventative and Cure for COVID-19

Serrano et al., International Journal of Research in Health Sciences, doi:10.5530/ijrhs.8.1.3

Prospective study of treatment with lactoferrin, vitamin C, and zinc, reporting recovery for all patients within 5 days. Depending on symptoms, lactoferrin nasal drops, mouth spray, or nebulization was also used.

Serrano et al., 1 Apr 2020, prospective, Spain, peer-reviewed, 7 authors.