Effect of lactoferrin treatment on symptoms and physical performance in long COVID patients: a randomised, double-blind, placebo-controlled trial.

Background: Long COVID is a heterogeneous condition with a variety of symptoms that persist at least 3 months after SARS-CoV-2 infection, often with a profound impact on quality of life. Lactoferrin is an iron-binding glycoprotein with anti-inflammatory and antiviral properties. Current hypotheses regarding long COVID aetiology include ongoing immune activation, viral persistence and auto-immune dysregulation. Therefore, we hypothesised that long COVID patients may potentially benefit from lactoferrin treatment. The aims of the present study were to investigate the effect of lactoferrin on various long COVID domains: fatigue, anxiety, depression, cognitive failure and muscle strength. Methods: We performed a randomised, double-blind, placebo-controlled trial in long COVID patients aged 18-70 years within 12 months after proven SARS-CoV-2 infection. Patients were randomised (1:1) to 6 weeks of lactoferrin (1200 mg daily) or placebo. At three hospital visits (T0, T6 and T12 weeks), patient-reported outcome measures were collected, physical performance tests were performed and blood was drawn. The difference in fatigue at T6 was the primary outcome. Results: 72 participants were randomised to lactoferrin (n=36) or placebo (n=36). We found a significant decrease in fatigue, as measured with the Fatigue Assessment Scale, between T0 and T6 in both study arms, but without significant difference between the study arms (lactoferrin: 3.9, 95% CI 2.3-5.5, p=0.007; placebo: 4.1, 95% CI 2.3-5.9, p=0.013). No significant differences were found in any of the other outcomes in favour of the lactoferrin arm at T6 or T12. Conclusion: Although both long COVID arms showed improved clinical outcomes at T6, the improvement did not continue until T12. Lactoferrin provided no benefit in terms of fatigue, other patient-reported outcome measures or physical functioning.