Lactoferrin and COVID-19

In 2020 lactoferrin looked like a reasonable COVID-19 candidate. It had shown antiviral activity against SARS-CoV-2 in laboratory work, and it was already sold as a supplement. Several groups ran randomized trials. Their results agree with each other, and every one of them is null.

The hospital trial

The LAC trial is the strongest test. It enrolled 218 adults in Italian hospitals with moderate to severe COVID-19 and randomized them to 800 mg a day of oral bovine lactoferrin or to placebo for 30 days, on top of standard care. Patients and investigators were both blinded.

Neither primary outcome moved. For death or admission to intensive care, the risk ratio was 1.06 (95% CI 0.63 to 1.79). For discharge, or a NEWS2 early warning score of 2 or less, within 14 days, it was 0.85 (95% CI 0.70 to 1.04). The authors reported that lactoferrin was well tolerated, and concluded that their results do not support its use in this population.

The trial set its size in advance. Its larger scenario called for 97 patients per arm, enough to detect a rise in 14-day discharge from 60% to 80%. Both arms passed that figure. A smaller benefit than that cannot be ruled out by this trial alone.

The prevention trial

LF-COVID, run in two hospitals in Lima, Peru, asked whether lactoferrin could stop health care staff catching the virus. It gave 600 mg a day or placebo for 90 days, with weekly symptom screening and an antibody test at the end.

Infection occurred in 11 of 104 people taking lactoferrin (10.6%) and 9 of 105 taking placebo (8.6%). The incidence rate ratio was 1.23 (95% CI 0.51 to 3.06). Time to symptomatic infection did not differ either.

This trial was stopped early, when vaccines became available in Peru. With 20 infections in total it had little power, and on its own it would earn an Insufficient grade for prevention. It does not point towards a benefit either: the point estimate slightly favors placebo.

Long COVID, and a pilot study

A Dutch trial randomized 72 people with long COVID to 1,200 mg a day or placebo for six weeks. Fatigue was the primary outcome. It fell by a similar amount in both arms (3.9 points on lactoferrin, 4.1 on placebo), and no other symptom score or physical test favored lactoferrin at six or twelve weeks.

An earlier pilot in Egypt randomized 54 patients with mild to moderate disease to standard treatment alone or with lactoferrin at one of two doses for seven days. It found no significant difference in symptom recovery or laboratory measures.

Why the grade is Not supported

The grade rests mainly on the LAC trial: blinded, placebo-controlled, sized in advance, with pre-specified outcomes, and null. The three smaller trials cover other settings and agree with it. Across 553 randomized participants no trial found an effect on any primary outcome.

The grade has limits, and they are specific. Prevention was tested in one trial that ended early. None of the trials could detect a small effect. And each tested oral bovine lactoferrin at a single dose range, 600 to 1,200 mg a day, for weeks rather than months.

What the laboratory work showed about the virus still stands. The step from a cell culture to a patient is the one that failed here, as it did for infection in preterm infants. The wider record on lactoferrin holds claims graded higher than this one, and others graded lower.