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Editor—Studies of human neonate granulopoiesis have been hampered by the lack of a marker of overall neutrophil cell mass. Assumptions about neonate granulopoiesis have therefore largely been extrapolated from rat data. Direct measurement of total neutrophil cell mass (in terms of neutrophils per g body weight) in newborn rats has shown that they have about one quarter the neutrophil mass of adult animals and that their neutrophil mass increases to adult levels by the time they are 4 weeks old.1 In addition, newborn rodents do not have the reserve pool of quiescent granulocyte progenitors, as found in adults, to recruit into production during sepsis. Circumstantial evidence for a similar immaturity of neutrophil production in human neonates comes from the low proportion of quiescent progenitors in cord blood2 and the frequent occurrence of postnatal neutropenia in preterm infants. Some additional insight comes from a study of mid-trimester abortuses,3 which showed minimal numbers of neutrophils in haemopoietic tissue before 24 weeks gestation. Until now, direct quantification of total body neutrophil cell mass in human neonates between 24 weeks and term has remained elusive.
In 1992 we reported4 that preterm neonates born before 32 weeks gestation have very low plasma concentrations of the soluble FcRIII receptor (sFcRIII). sFcRIII is the plasma form of the neutrophil membrane receptor FcγRIII which, together with other membrane receptors, is responsible for binding opsonised particles and initiating phagocytosis. We observed that, between 24 and 32 weeks gestation, sFcRIII concentrations are about 15% of normal adult values (mean (SE) 15.3 (1.3)%), while sFcRIII concentrations in fetal samples collected between 19 and 23 weeks are even lower (mean (SE) 8.3 (1.4)%). Between 33 and 36 weeks in utero, sFcRIII increases rapidly so that babies born at term have concentrations similar to adults. In babies born before 32 weeks, sFcRIII increases gradually after birth to achieve adult concentrations by the fourth week of postnatal life. At the time, we interpreted these data to indicate reduced FcRIII production by individual cells and thus immaturity of neonate neutrophil function.
Since we published these data, further work has clarified the origins and significance of plasma sFcRIII. These studies have shown that sFcRIII is derived from apoptotic neutrophils, and its concentration in plasma reflects the total body neutrophil cell mass as well as the overall production of neutrophils in the bone marrow.5 6
This new understanding of sFcRIII alters the interpretation of our original observation. It is now apparent that our data confirm what was previously only suspected: preterm human infants of less than 32 weeks gestation have reduced neutrophil production and a reduced total neutrophil cell mass at birth. Our data also show that neutrophil reserves remain low for about three weeks after preterm birth. Term infants, by contrast, have neutrophil production and stores that are similar to those of adults.
The reduced neutrophil mass of preterm neonates explains the common occurrence of postnatal and sepsis induced neutropenia. The relevance of this finding to the high sepsis incidence associated with prematurity is emphasised by a recent study of patients with idiopathic neutropenia, which has shown that a low sFcRIII concentration is a more accurate predictor of infection risk than the peripheral blood neutrophil count.7 Furthermore, this new insight into neonatal immune development suggests that stimulation of neutrophil production by colony stimulating factors early in postnatal life could reduce the incidence and severity of sepsis in preterm neonates by accelerating expansion of their deficient neutrophil reserves.
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