Two new articles addressing effects of lactoferrin. Both used bovine lactoferrin (bLF), one was in humans, the other in piglets.
In case you haven’t been following closely, lactoferrin is an iron transport protein that has multiple anti-infective properties, against bacteria, fungi and viruses. It reduces the formation of biofilms, and also has some immune modulatory effects. A single large (470 infants in 3 groups) multicenter RCT by Paolo Manzoni and his colleagues showed a major (80%) reduction in nosocomial sepsis with bovine lactoferrin prophylaxis among very preterm infants. Another trial in infants in Peru by Theresa Ochoa and others has also been presented, but not yet published, and also showed a reduction in late onset sepsis; they had a more modest 40% reduction in combined probable and possible sepsis, and they included babies with birth weights of 500 to 2500 g, mostly the babies were over 1000g.
At least 3 other large RCTs are starting up to see whether the effects can be confirmed.
In the meantime other smaller studies looking at mechanisms are being produced.
The study in piglets examined the effects of bovine lactoferrin in 3 different doses. The control diet of sow milk replacer already contains some bLF, giving about 100 mg/kg/d, compared to the 2 other groups that received 3 times as much or 10 times as much. The spleen cells from the highest dose group produced much more interleukin10 and TNFalpha than the controls, and lymph node cells also produced more IL-6 in response to being stimulated with endotoxin.
The other article is a very small RCT (25 per group, <32 weeks gestation or VLBW) that was not powered to examine differences in the incidence of sepsis even though that was the stated primary outcome. Secondary outcomes included changes in regulatory T cell populations. The number of babies who had at least one sepsis episode was not statistically different between groups (8 controls and 4 lactoferrin babies), Many of the control babies had a second sepsis, so when analyzed as sepsis episodes per 1000 patient days there were less frequent sepsis episodes in bLF-treated infants (4.4 vs. 17.3/1,000 patient days, p = 0.007) with none developing NEC, compared to 5 controls who had NEC (20% NEC under 32 weeks being an enormously high incidence).
This article needed some serious editing: The consort flow diagram in this article includes the term ‘give reason’ about 8 times. I guess the authors cut and pasted this from somewhere and didn’t realize that they were supposed to replace ‘give reasons’ with the actual reasons! The diagram also doesn’t say which group is which, they are both ‘intervention’. They also use terms in the text that I don’t understand such as ‘inappropriate sample’ (as a reason to not be enrolled in the study) and there are a few other sentences whose meaning is not clear.
Most importantly they also excluded 3 babies from analysis in the lactoferrin group as they are said to have become infected before they got the lactoferrin, infants were randomized before 72 hours, but only started getting the bLF when they were getting 20 mL/kg/d of enteral feeds, this is an unfortunate abrogation of the Intention To Treat principle; if those babies are included as they should be, then there is obviously no difference at all in sepsis episodes between groups. At least one of the babies in the control group also had a sepsis at 4 days of age also, but was not excluded from analysis.
The first and major analysis for a clinical trial has to be to include all the babies randomized in the group that they were randomized to. Otherwise this is not a fair test of whether using bLF in this way is actually effective. For mechanistic secondary analyses, sometimes a by treatment analysis can be appropriate, even then you should delete control babies if they became septic before getting placebo.
The other data presented are interesting, the authors showed that Treg levels at birth and discharge were similar, while preterm infants showed significantly lower levels than term controls. However, when they analyzed the percentage change in Treg levels, they were higher in the bLF group. Although this is soft data, it does suggest some effects of bLF on immune modulation.