Lactoferrin Supplementation to Prevent Nosocomial Infections in Preterm Infants

Abstract

THE STUDY BY MANZONI AND COLLEAGUES 1 IN THIS ISsue of JAMA represents an important step toward preventing infections that currently pose a major hurdle for preterm infants. The findings give insight into the role of lactoferrin in preventing infection, helping to define its importance in breast milk as well as the effect of daily supplementation with bovine lactoferrin (BLF) in preterm infants. The incidence of late-onset ( 72 hours of age) bloodstream infections in very low-birth-weight (VLBW) infants ( 1500 g) is approximately 20% and is complicated by high mortality and neurodevelopmental impairment. In the United States, nearly 65 000 VLBW infants are born each year, which translates into approximately 13 000 infections, 2300 deaths, and neurodevelopmental impairment in 3000 survivors. For the smallest infants of extremely low birth weight (ELBW) ( 1000 g), neurodevelopmental impairment occurs in 45% of those who survive bacteremia and 57% of those who survive fungemia. For VLBW infants, bloodstream infections increase hospital treatment costs and length of stay. Manzoni and colleagues performed a multicenter, double-blind, placebo-controlled, randomized trial in VLBW infants comparing administration of BLF alone or in combination with Lactobacillus rhamnosus GG (LGG) to placebo. Invasive infections (blood or cerebrospinal or peritoneal fluid) were significantly lower in the treatment groups (5.9% for BLF and 4.6% for BLF plus LGG, vs 17% for placebo). This effect was strongest for infants weighing less than 1000 g (11.3% for BLF and 11.1% for BLF plus LGG, vs 36.7% for placebo). There was an effect on infection-related mortality for both treatment groups (0% for BLF and 0.7% for BLF plus LGG, vs 4.8% for placebo), whereas the incidence of necrotizing enterocolitis was decreased in the BLF plus LGG group only (0% vs 6% in infants receiving placebo). The effect of BLF and BLF plus LGG was significant for ELBW infants (n=167), as well as those weighing less than 750 g (n=39) and of 27 weeks or fewer gestation (n=118), but not for infants weighing between 1000 and 1500 g (n=307). This may be explained in part by the dosing used in the study. The infants did not receive dosing based on their weight, but rather all infants received 100 mg per day; therefore, smaller infants received a higher dose per kilogram per day. For example, for infants weighing 500, 1000, and 1500 g, the dose per kg would be 200, 100, and 67 mg/kg, respectively. Extremely low-birth-weight infants also received study drug for 6 weeks compared with only 4 weeks for infants weighing 1000 to 1500 g. Thus, supplementation of BLF between 100 and 200 mg/kg per day and possibly for a longer period may be needed for all patients. Additionally, doses higher than 200 mg/kg per day may have a greater effect and need to be further studied. Post hoc analysis revealed that BLF decreased grampositive and fungal infections. This demonstrates the probable interaction of lactoferrin with the gastrointestinal tract microflora effecting common gram-positive skin and central venous catheter bloodstream infections, as central venous catheter days and time to reach full enteral feedings were similar between groups. While BLF did not change fungal colonization, it prevented progression to infection, thus potentially allowing fungi to maintain their symbiotic role in the gut and helping to maintain a balanced microflora. Fluconazole prophylaxis has demonstrated efficacy in reducing invasive Candida infections in single and multicenter randomized controlled trials. However, intravenous immunoglobulin products and colony-stimulating factors have not proven effective in preventing infections, largely because many elements of the immune system are underdeveloped in preterm infants. Lactoferrin has many functions and is a key link in several immune processes. This may in part explain the large effect demonstrated by Manzoni et al. Lactoferrin is the major whey protein in human milk and is involved in innate host defenses having antimicrobial and immunomodulation activities as well as promoting a mature and healthy gut. Bovine lactoferrin has activity against gram-positive and gram-negative bacteria, fungi, and viruses such as rotavirus, enterovirus, and adenovirus. This includes antilipopolysaccharide (against gram-negative