Prophylactic rG-CSF for Preterm Neonates with Neutropenia
Prophylactic rG-CSF for Preterm Neonates with Neutropenia
Abstract & Commentary
By Hal B. Jenson, MD, FAAP, Professor of Pediatrics, Tufts University School of Medicine, and Chief Academic Officer, Baystate Medical Center, Springfield, MA, is Associate Editor for Infectious Disease Alert.
Dr. Jenson reports no financial relationships relevant to this field of study.
Synopsis: The prophylactic administration of rG-CSF to preterm infants with neutropenia has a modest benefit on reducing nosocomial infections at two weeks following administration, but no significant benefit at four weeks on either the incidence of nosocomial infections or survival.
Source: Kuhn P, et al. A multicenter, randomized, placebo-controlled trial of prophylactic recombinant granulocyte-colony stimulating factor in preterm neonates with neutropenia. J Pediatr. 2009;155:324-330.
A randomized, double-blind, placebo-controlled, multicenter study was conducted from 2002-2006 at 25 institutions in France of the effect of prophylactic recombinant granulocyte-colony stimulating factor (rG-CSF) on nosocomial infections and survival among preterm neonates with persistent neutropenia. Neutrophil counts were obtained at birth, day four of life, and weekly thereafter. Preterm infants of gestational age < 33 weeks (or 35 weeks for birth weight < 1500 g) with peripheral blood neutrophil count < 1500 cells/mm3 for at least 24 hours during the first three weeks of life were randomized to receive either rG-CSF (Neupogen [filgrastim]; Amgen) or placebo. The rG-CSF was administered intravenously as a single daily dose of 10 µg/kg/day for three consecutive days, starting no later than 48 hours after persistent neutropenia was identified.
A total of 200 newborns with neutropenia of at least 24 hours duration, and who are not considered to be infected, were randomized with 102 in the rG-CSF group and 98 in the placebo group. Demographic, obstetrical, and neonatal characteristics, including age at treatment (4.5 ± 2.8 days in the rG-CSF group, and 4.9 ± 4.0 days in the placebo group), were similar in both groups. There were a total of 47 cases of confirmed infection (42 septicemia and five pneumonia) and 45 unconfirmed infections (30 cases of clinical sepsis and 15 possible infections), which was not significant either in the first two weeks or during the entire four weeks of surveillance (p = 0.24). Survival free of confirmed nosocomial infection at four weeks did not differ significantly between two groups: 74/102 (73%) in the rG-CSF group and 66/98 (67%) in the placebo group (p = 0.42). There was a significant protective effect on survival without confirmed infection at two weeks after completion of treatment: 86/102 (84%) in the rG-CSF group and 70/98 (71%) in the placebo group (p = 0.028). There was also a significant protective effect at two weeks for any type of infection, confirmed plus unconfirmed: 70/102 (69%) in the rG-CSF group and 54/98 (55%) in the placebo group (p = 0.049).
There were no toxicities observed and no significant differences in growth, mortality, or incidence of necrotizing enterocolitis, retinopathy of prematurity, or cerebral abnormalities identified by cerebral ultrasound.
Commentary
Neutropenia is common among preterm newborns and, in most cases (83%), is transient. Persistent neutropenia is a significant risk factor for neonatal nosocomial infections. rG-CSF has selective and rapid action in promoting differentiation and proliferation of neutrophils, enhancing function, and correcting neutropenia in preterm newborns. The study found that there was no significant effect on the incidence of nosocomial infections or survival at four weeks following prophylactic administration of rG-CSF in preterm newborns with neutropenia.
Interestingly, a significant effect on the incidence of nosocomial infections was detected at two weeks after administration, which reflects the expected maximal effect of rG-CSF on neutrophil count, of approximately seven days. Despite this benefit, at two weeks following treatment, there was an absence of any significant benefit at four weeks, which likely reflects the benefits of antimicrobial treatment and additional supportive therapies. It is unlikely that a second course of rG-CSF treatment would be beneficial because the neutropenia resolves within 24 hours of rG-CSF administration, and from 4-12 days even without treatment.
The effect of prophylactic rG-CSF in this study is moderate at two weeks, and short-lived. The clinical relevance of this finding is modest because neither mortality nor prematurity-associated morbidity at four weeks after administration was affected. Whether fewer nosocomial infections at two weeks after administration avoid excessive inflammatory stimuli that may have beneficial long-term effects on brain and lung development remains speculative.
A randomized, double-blind, placebo-controlled, multicenter study was conducted from 2002-2006 at 25 institutions in France of the effect of prophylactic recombinant granulocyte-colony stimulating factor (rG-CSF) on nosocomial infections and survival among preterm neonates with persistent neutropenia.Subscribe Now for Access
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