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106 Part III: Epochal Hematology Chapter 7: Hematology of the Fetus and Newborn 107

Pseudomonas, and other Gram-negative bacilli. Cellular defense mech- Chemotaxis Chemotactic function of leukocytes is low in neo-
anisms and humoral immunity of the newborn differ from those found nates, whereas random motility is normal. 172–174 Neonatal serum does
later in life, and these undoubtedly contribute to the unusual suscepti- not generate as much chemotactic factor as does adult serum, even after
bility to infection noted in the neonatal period. 146 the addition of purified C3. The defect in chemotaxis may be related to
Opsonins and Complement Engulfment and destruction of bac- decreased granulocyte deformability and impaired capping of cell sur-
teria by neutrophils depend on opsonic activity of the plasma and on face receptors. The role of observed cyclic adenosine monophosphate
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chemotaxis, phagocytosis, and the bacteriocidal capacity of the leuko- (cAMP) and membrane potential alterations in the defective chemo-
cyte. The serum factors necessary for optimal phagocytosis (opsonins) taxis is not clear. The ability of neutrophils to roll along the blood
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include the immunoglobulins and complement components. In term vessel endothelium also is impaired in neonates. Diminished upregu-
infants, opsonic activity is normal for Staphylococcus aureus, 147,148 but lation and surface migration of β integrins and fewer L-selectin recep-
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it is low for yeast and Escherichia coli. 147,148 Diminished opsonic anti- tors reduce the ability of neonatal neutrophils to interact with adhesion
body is associated with group B streptococcal infection and represents molecules on the endothelium. 139
one risk factor for neonatal infection. 150 The densities of the C3bi receptor (CD11b/CD18) and of the
In premature infants, opsonic activity is low for S. aureus and low-affinity receptor for immunoglobulin, FcRIII (CD16), are decreased
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Serratia marcescens, but is normal for Pseudomonas aeruginosa. on neutrophils of premature infants, whereas term infants’ cells show a
When serum concentrations of fibronectin and IgG subclasses C3 and lesser impairment. 176–178 The deficient upregulation of C3bi correlates
C4 were measured at birth, 1 month, 3 months, and 6 months, early with decreased adherence and chemotaxis by neonatal neutrophils.
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gestational age was correlated with lower initial levels. The decreased Low FcRIII is associated with impaired chemotaxis of neonatal neu-
opsonic activity for some organisms in premature infants is attributed to trophils, although decreased FcRIII might also be responsible for sub-
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diminished IgG levels, because additional IgG will correct the opsonic tle defects in adherence and subsequent phagocytosis of opsonized
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defect both in vivo and in vitro. The added IgG improves bacterial and unopsonized organisms by neutrophils.
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opsonization by serum of premature infants in part because comple- Adherence Neutrophil cell adhesion molecules are central to the
ment consumption and deposition of C3 on the bacterial surface are bonding of neutrophils to the vascular endothelium, and reduction
augmented. 153,154 of these molecules diminishes the capacity of neonatal neutrophils to
Complement components appear in fetal blood before 20 weeks’ properly adhere and migrate (Chap. 19). Although L-selectin, a key
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gestation and increase markedly during the third trimester. However, adhesion molecule, is expressed at high levels on hematopoietic pro-
in many newborns both the classical and alternative complement path- genitor cells, it decreases markedly during the first 3 days of life and
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ways are decreased in activity and in levels of individual components. remains low compared to adult levels during the first weeks, impairing
The mean level of C3, the first common component of the two pathways the neutrophil’s ability to “roll” as part of the adhesion process. Also,
of complement activation, is approximately 65 percent of that in nor- there are defects in expression of CD18/CD11b, which are members of
mal adults. 156–158 There is no transplacental transfer of this protein, and the β -integrin family of adhesion molecules. These characteristics
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levels in infants are lower than those in their mothers. Total serum likely contribute to the newborn susceptibility to bacterial infections.
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hemolytic complement (CH ) and alternative pathway activity (PH ) Phagocytic and Bactericidal Activity Phagocytosis of bacteria
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in newborns are lower than in adults, as are mean levels of C1q, C2–C9, and latex granules by neutrophils from premature and term infants is
properdin, and factors B, I, and H. 157–159 In general, the mean levels in normal. 147,151,184 Bactericidal activity varies according to the conditions
full-term infants are greater than 50 percent of those in normal adult of testing and the clinical status of the neonates. The intracellular killing
controls and may be somewhat less in premature infants. There is con- of S. aureus and S. marcescens in cells from most term and low-birth-
siderable overlap, however, between levels in infants and in controls. A weight infants is normal, 147,185 as is that of E. coli in term infants. Sim-
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functional deficiency in the alternative pathway has been detected in ilar studies have shown defective bactericidal activity against S. aureus
infants. 160 in some infants in the first 12 hours after birth, P. aeruginosa in cells
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Fibronectin mediates more efficient interactions between phago- from premature infants, and Candida albicans in granulocytes from
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cytes and infectious agents. Fibronectin, a 450-kDa glycoprotein found term and premature infants. With bacteria-to-neutrophil ratios of
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in plasma and in the intercellular matrix, promotes the attachment of 1:1, newborn cells kill S. aureus and E. coli as effectively as controls;
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staphylococci to neutrophils and enhances opsonic activity of anti- however, at the higher ratio of 100:1, killing and oxidative responses
bodies against group B streptococci. Because both these bacteria are as measured by chemiluminescence are markedly depressed, although
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common pathogens for neonates, the deficiency in fibronectin observed phagocytosis is normal. Depressed activity also has been found in
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in neonates may further compromise opsonic capacity and hence bac- cells from newborns who have had clinical stress, either from infection
tericidal activity in the neonate. or other disorders, shown both as decreased chemiluminescence and
The administration of intravenous IgG may be useful in the treat- impaired bactericidal activity against S. aureus, E. coli, and group B
ment or prophylaxis of infection in preterm infants based on the reduced streptococci. 187–189 The decreased granulocyte function shown in these
placental transfer of maternal antibody and the restricted endogenous studies also is found in liquid culture, where neutrophils from new-
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synthesis of IgG. IgG administered to septic neonates appears to borns do not survive as long as those from adults, perhaps because of
enhance serum opsonic capacity as well as to increase the quantity of decreased resistance to autoxidation. Although superoxide dismutase
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circulating neutrophils. In premature neonates, added IgG heightens levels are normal and superoxide production is normal or increased in
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granulocyte phagocytosis. 165,166 Intravenous IgG has been reported to neutrophils from newborns, glutathione peroxidase and catalase levels
effectively treat infected premature neonates, but these reports involved are decreased. 189,190 The relationship of these in vitro cellular defects to
small numbers of subjects. 167,168 The clinical efficacy of IgG prophylaxis bacterial infections in the newborn is still not clear.
against neonatal pathogens is not firmly established. 169,170 New IgG prep- Antimicrobial proteins and peptides are present in neutrophil
arations with consistent, adequate levels of antibodies directed against cytoplasmic granules. Bacterial permeability-increasing protein (BPI),
neonatal pathogens can be achieved by selection of sera with high levels located in the primary granules, is markedly lower in newborns, par-
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of functional antibodies, or potentially by the addition of monoclonal ticularly preterm newborns. 191,192 BPI is an antimicrobial protein that
antibodies, and these may prove more effective. binds and neutralizes endotoxin. Other granule components, such as
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