1611065
©1991 S. Karger AG, Basel 0379-8305/91 /0174-0144S2.75/0
Dev Pharmacol Ther 1991;17:144-149
Intravenous Immunoglobulin for Prophylaxis of Infection in Preterm Infants 1 Giorgio Rondini, Gaetano Chirico, Alberto G. Ugazio Division of Neonatal Intensive Care, Policlinico San Matteo IRCCS, Pavia; Department of Pediatrics, University of Brescia, Italy
Key Words. Immunoglobulin • Infection • Preterm infants Abstract. Immunodeficiency, particularly antibody deficiency, is a crucial contributory factor to the increased susceptibility to infections in preterm infants. Availability of the recent preparation of intravenous immunoglobulin (ivIgG) led several authors to evaluate the safety and effectiveness of ivlgG for prophylaxis of infection in preterm infants. The results of these studies, although controversial, have pointed out two common findings: (1) ivlgG prophylaxis seems to be effective only in the very preterm infants, with mean birth weight below about 1,300 g; (2) ivlgG seems to be well tolerated by newborn infants.
The neonatal age is characterized by a delicate process of adaptation from intra- to extrauterine life. The immune system is par ticularly subject to problems of adaptation. In fact, a mature immune competence could cause unfavorable effects due to maternalfetal antigenic incompatibility and is unnec essary to the fetus, who develops in a highly protective germ-free environment. The new born infant, on the other hand, must be capable to defend himself against hostile mi1 Presented at the Second European Neonatal Workshop, Klingenthal, France, June 15, 1991.
croorganisms in the environment. As a result of these contradictory physiological require ments, the immune system is incompletely developed at birth [1], The relatively high incidence of infectious disease (e.g. 1 % of septicemia) in the perinatal period bears tes timony to the fact that the host-parasite bal ance is precarious in the neonate. The immu nodeficiency is particulary severe and pro longed in preterm infants, and it is responsi ble for an incidence of systemic infection of about 32% with a mortality rate of 33% [2].
Some typical consequences of the neona tal immaturity of the immune system are: increased incidence of bacterial infection, Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
Introduction
often caused by microorganisms generally considered to be of low pathogenicity (such as Staphylococcus epidermidis)\ increased in cidence and long duration of viral infection; reduced inflammatory response and diffi culty to delimit the focus of infection. Both the nonspecific and antigen-specific components of host defense mechanisms are compromised in the neonate [3, 4],
Neonatal Immunodeficiency
Polymorphonuclear Leukocytes Over the past decade several develop mental deficiencies of neonatal phagocytes have been described. Chemotaxis is significantly impaired both in term and preterm infants. The de creased migration correlates with several functional abnormalities of neonatal neutro phils: (1) decreased binding of certain chemotactic factors; (2) decreased adherence to surfaces under resting and stimulated condi tions; (3) irreversible aggregation in response to chemotactic factors; (4) decreased cell deformability, resulting in decreased ability to migrate through small-pore filters in vitro and probably through capillary endothelial cells in vivo; (5) decreased movement to ward chemotactic stimuli despite normal orientation toward the stimulus; (6) reduced expression of complement and Fc receptors. These deficiencies are usually marked and have been confirmed [3], Phagocytosis by neonatal neutrophils has been reported to be reduced under ‘stress conditions’ in vitro or in vivo (sick or pre mature infants). Results obtained in studies of bactericidal activity of neonatal neutrophils are similar to those found in phagocytosis, i.e. normal
145
bactericidal activity in healthy infants and in favorable in vitro conditions, and, on the other hand, depresssed bactericidal activity in sick or premature infants or in conditions of‘stress’ obtained in vitro. Bactericidal ac tivity in healthy term infants is related to postnatal age, being normal at birth and transiently defective during the subsequent 2 weeks of life. The impairment of bactericidal activity is severe in premature infants - the more immature the infant, the greater the deficiency - and may persist after the neona tal period [5]. Furthermore, neonatal neutro phil viability and the reserve and storage pool are reduced. The Complement System Several studies have reported reduced ac tivity of both classical and alternative path ways of complement in term newborns, as compared to their mothers or adult controls [6], Complement activity is lower in prema ture infants, with a close relationship to ges tational age and birth weight. Kinetic studies have shown a considerable delay in comple ment activation, particularly in preterm in fants [6], Furthermore, no C3 and factor B are synthesized by neonatal monocytes in response to lipopolysaccharide challenge [1]. This complex deficiency of the complement system, in addition to fibronectin and anti body deficiency, causes a significant reduc tion of opsonic activity in neonatal serum. Cellular Immunity Cell-mediated immunity is incompletely developed at birth, as proved by a different distribution of subpopulations of T, B and natural killer cells, as compared to adult con trols, and by the presence of subsets of lym phocytes bearing markers of immaturity on the membrane surface [1], Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
Immunoglobulin Prophylaxis in Infants
146
Rondini/Ch i rico/Ugazio
Specific Humoral Immunity Several factors are responsible for the marked antibody deficiency in the neonate. The immaturity of T and B lymphocytes and of macrophages causes a delayed switch from IgM to other immunoglobulin isotypes (only low levels of IgM are produced during the first month of life in response to anti genic challenge; no response to lipopolysac charide antigen may be observed); levels of IgG are low in preterm infants because trans placental passage from the mother occurs almost exclusively during the last 6 weeks of gestation; the neonate may lack pathogenspecific IgG, particularly those restricted to the IgG2 subclass, such as antibody specific for streptococcal carbohydrate or Haemophi lus influenzae type b capsular polysaccharide [8]. The interplay of these factors with the neonatal deficiency of complement activity and neutrophil activity results in increased susceptibility to systemic infections from en capsulated pathogens, such as group B strep tococci, straphylococci and Klebsiella sp., that require opsonization for efficient phagocytosis and killing.
Intravenous Immunoglobulin Therapy
The observation that neonatal opsonic deficiency is partly correctable with immu noglobulin led some authors to study the intramuscular use of human immune serum globulin for prophylaxis of infection in pre
mature infants. The results of these studies failed to show a significant beneficial effect, probably because of the disadvantages of in tramuscularly administered immunoglobu lin therapy: uneven absorption, slow avail ability, tissue damage and pain, with resul tant problems in administering adequate amounts. Intramuscular preparations of im munoglobulin cannot be administered intra venously because they contain aggregates of IgG that activate complement and may cause dangerous anaphylactoid reactions. Better preparations of immunoglobulin have recently been obtained by removal of aggre gates; these can be administered intrave nously in high doses, contain intact antibody molecules and maintain normal biologic ac tivities of the Fc fragment, such as comple ment activation, binding to cell surface re ceptors, catabolization and opsonic activity, although with significant variability among available preparations [9]. Furthermore, the IgG subclass distribution is similar to that found in normal serum and includes anti bodies to most of the pathogens found in neonatal infections. We performed a controlled study to eval uate the safety and effectiveness of intrave nously administered immunoglobulin ther apy for prophylaxis of infection in 83 neo nates with birth weight < 1,500 g and gesta tional age 1,500 g receiving intensive
147
care and assisted ventilation. No immediate side effects were observed after ivIgG ad ministration; no difference in serum biliru bin and transaminase values was recorded between treated and control infants at 2 and 4 months of age. These data show that ivIgG therapy is both safe and effective for prophy laxis of infection in preterm infants with very low birth weights. Following this report, several other stud ies have been performed on the prophylactic use of ivIgG in preterm infants, with both positive and negative results [12-16], These studies cannot be compared because of the different methods used for patient selection, the different methods of care, the different study designs and the different ivIgG prepa rations and dosages used. In one report, for instance, the ivIgG dosage has been individ ually regulated to maintain IgG serum levels >700 mg/dl [17], However, these studies have pointed out two common findings: (1) the efficacy of ivIgG for prophylaxis of infection seems to be strictly related to birth weight; in fact, positive results have been observed in infants with mean birth weight below 1,300 g, while, when infants with higher birth weight were considered, the re sults have been unsatisfactory (fig. 1); (2) no significant immediate or late side effects have been recorded after treatment, which indicates that ivIgG are well tolerated by preterm infants. It has been reported that high doses of ivIgG can reduce the penicillin bactericidal activity against group B Strepto coccus and the neutrophil opsonophagocytosis activity, probably because of membrane receptor inhibition. However, such an effect has been observed in animal experiments only after the administration of very high doses of ivIgG (2.7 g/kg) and not after treat ment with the lower doses (0.68 g/kg) which Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
Immunoglobulin Prophylaxis in Infants
148
Rondini/Chirico/Ugazio
Chirico et al. [10] -
Baker [12] Stabile et al. [16] -
■v«
Chirico et al. [10] Haque et al. [15] Baker [12] Bussei et al. [13] -
■>
f
1,000
1,250
1,500
1,750
2,000
2,250
Mean birth weight, g
are commonly used in preterm infants [18]. Furthermore, we showed that ivlgG do not interfere with natural killer cell activity in preterm infants [19], Von Murait and Sidiropoulos [20] reported that the ivlgG therapy in the neonatal period does not cause a de pression of immune response or a sensitiza tion to polyclonal IgG. Few and inconclusive data are available on the use of ivlgG for therapy of sepsis, because of the difficulty to evaluate an ade quate number of septicemic infants with ho mogeneous characteristics for a reliable sta tistical analysis. The doses of ivlgG used were either 1 g/day for 6 days in term infants and 0.5 g/day for 6 days in preterm infants [20], 0.8 g/kg/day [21] or 250 mg/kg/day for 4 days of IgM-enriched IvlgG (Pentaglobin) [22], An intravenous preparation of mono clonal antibody against endotoxin has re cently proven useful for the treatment of Gram-negative bacteremia and septic shock in adults: similar positive results may be expected in the treatment of neonatal infec tions [23].
Fig. 1. Positive (+) or nega tive (-) results of the studies on prophylaxis of infection with in travenous immunoglobulin in relation to birth weight.
References 1 Burgio GR. Hanson LA, Ugazio AG (eds): Immu nology of the Neonate. Berlin, Springer, 1987. 2 Usher RH: The special problems of the premature infant; in Avery GB (ed); Neonatology, Patho physiology and Management of the Newborn. Philadelphia, Lippincott, 1987. 3 Miller ME; Immunodeficiencies of immaturity; in Stiehm ER (cd): Immunologic Disorders in In fants and Children, ed 3. Philadelphia. Saunders, 1990. 4 Wilson CB: Developmental immunology and role of host defenses in neonatal susceptibility: in Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infant, ed 3. Philadel phia, Saunders, 1990. 5 Chirico G, Marconi M, De Amici M, et al: Defi ciency of neutrophil bactericidal activity in term and preterm infants. Biol Neonate 1985;47:125— 129. 6 Notarangelo LD, Chirico G. Chiara A, et al: Ac tivity of classical and alternative pathways of complement in preterm and small for gestational age infants. Pediatr Res 1984;18:281-285. 7 Ugazio AG, Chirico G, Plebani A, et al: Immunity and infection in term and preterm newborns; in Xanthou M, Bracci R (ed): Neonatal Haemato logy and Immunology. Amsterdam, Elsevier Science Publishers, 1990. Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
Clapp et al. [14]
Immunoglobulin Prophylaxis in Infants
17 Kyllonen KS, Clapp DW, Kliegman RM, et al: Dosage of intranvenously administered immuno globulin and dosing interval required to maintain target levels of immunoglobulin G in low birth weight infants. J Pediatr 1989:115:1013-1016. 18 Weisman LE, Lorenzetti PM: High dose human intravenous immunoglobulins suppress neonatal group B streptococcal immunity in rats. J Pediatr 1989:115:445-450. 19 Chirico G, Maccario R, Montagna D. et al: Natu ral killer cell activity in preterm infants: Effect of intravenous immune globulin administration. J Pediatr 1990;1 17:465-466. 20 Von Murait G, Sidiropoulos D: Prenatal and post natal prophylaxis of infections in preterm neo nates. Pediatr Infect Dis J 1988;7:S72—S78. 21 Fischer GW: Use of intravenous immunoglobulin during the treatment of infection in low birth w'eight infants. Proc NIH Consensus Dev Conf Intravenous Immunoglobulin: Prevention and Treatment of Disease. Bethesda. 1990. 22 Haque KN, Zaidi MH, Bahakim H: IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Am J Dis Child 1988;142:1293-1296. 23 Ziegler EJ, Fisher CJ, Sprung CL, et al: Treatment of gram-negative bacteremia and septic shock with Ha-1A human monoclonal antibody against endotoxin. N Engl J Med 1991;324:429-435.
Prof. G. Rondini Divisione di Patologia Neonatale Policlinico San Matteo 1-27100 Pavia (Italy)
Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
8 Einhorm MS, Granoff DM, Nahm MH, et al: Concentrations of antibodies in paired maternal and infant sera: Relationship to IgG subclass. J Pediatr 1987;111:783-788. 9 Givner LB: Human immunoglobulins for intrave nous use: Comparison of available preparations for group B streptococcal antibody levels, opsonic activity and efficacy in animal models. Pediatrics 1990;86:955-962. 10 Chirico G, Rondini G, Plebani A, et al: Intrave nous gammaglobulin therapy for prophylaxis of infection in high-risk neonates. J Pediatr 1987; 110:437-442. 11 Eibl MM, Wolf HM, Furnkranz H. et al: Pre vention of necrotizing enterocolitis in low-birthweight infants by IgA-IgG feeding. N Eng J Med 1988;319:1-7. 12 Baker CJ: Intravenous immunoglobulin in low birth weight infants: Prevention. Proc NIH Con sensus Dev Conf Intravenous Immunoglobulin: Prevention and Treatment of Disease. Bethesda, 1990. 13 Bussei JB, LaGamma EF. Giuliano M: Intrave nous gammaglobulin prophylaxis of late sepsis in VLBW infants: A randomized placebo controlled trial. Pediatr Res 1988;23:471 A. 14 Clapp DW, Kliegman RM, Baley JE, et al: Use of intravenously administered immunoglobulin to prevent nosocomial sepsis in low birth weight infants: Report of a pilot study. J Pediatr 1988; I 15:973-978. 15 Haque K.N, Zaidi MH, Haque SK. et al: Intrave nous immunoglobulin for prevention of sepsis in preterm and low birth weight infants. Pediatr In fect Dis J 1986;5:622-625. 16 Stabile A, Miceli Sopo S, Romanelli V, et al: Intra venous immunoglobulin for prophylaxis of neona tal sepsis in premature infants. Arch Dis Child 1988:63:441-443.
149
©1991 S. Karger AG, Basel 0379-8305/91 /0174-0144S2.75/0
Dev Pharmacol Ther 1991;17:144-149
Intravenous Immunoglobulin for Prophylaxis of Infection in Preterm Infants 1 Giorgio Rondini, Gaetano Chirico, Alberto G. Ugazio Division of Neonatal Intensive Care, Policlinico San Matteo IRCCS, Pavia; Department of Pediatrics, University of Brescia, Italy
Key Words. Immunoglobulin • Infection • Preterm infants Abstract. Immunodeficiency, particularly antibody deficiency, is a crucial contributory factor to the increased susceptibility to infections in preterm infants. Availability of the recent preparation of intravenous immunoglobulin (ivIgG) led several authors to evaluate the safety and effectiveness of ivlgG for prophylaxis of infection in preterm infants. The results of these studies, although controversial, have pointed out two common findings: (1) ivlgG prophylaxis seems to be effective only in the very preterm infants, with mean birth weight below about 1,300 g; (2) ivlgG seems to be well tolerated by newborn infants.
The neonatal age is characterized by a delicate process of adaptation from intra- to extrauterine life. The immune system is par ticularly subject to problems of adaptation. In fact, a mature immune competence could cause unfavorable effects due to maternalfetal antigenic incompatibility and is unnec essary to the fetus, who develops in a highly protective germ-free environment. The new born infant, on the other hand, must be capable to defend himself against hostile mi1 Presented at the Second European Neonatal Workshop, Klingenthal, France, June 15, 1991.
croorganisms in the environment. As a result of these contradictory physiological require ments, the immune system is incompletely developed at birth [1], The relatively high incidence of infectious disease (e.g. 1 % of septicemia) in the perinatal period bears tes timony to the fact that the host-parasite bal ance is precarious in the neonate. The immu nodeficiency is particulary severe and pro longed in preterm infants, and it is responsi ble for an incidence of systemic infection of about 32% with a mortality rate of 33% [2].
Some typical consequences of the neona tal immaturity of the immune system are: increased incidence of bacterial infection, Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
Introduction
often caused by microorganisms generally considered to be of low pathogenicity (such as Staphylococcus epidermidis)\ increased in cidence and long duration of viral infection; reduced inflammatory response and diffi culty to delimit the focus of infection. Both the nonspecific and antigen-specific components of host defense mechanisms are compromised in the neonate [3, 4],
Neonatal Immunodeficiency
Polymorphonuclear Leukocytes Over the past decade several develop mental deficiencies of neonatal phagocytes have been described. Chemotaxis is significantly impaired both in term and preterm infants. The de creased migration correlates with several functional abnormalities of neonatal neutro phils: (1) decreased binding of certain chemotactic factors; (2) decreased adherence to surfaces under resting and stimulated condi tions; (3) irreversible aggregation in response to chemotactic factors; (4) decreased cell deformability, resulting in decreased ability to migrate through small-pore filters in vitro and probably through capillary endothelial cells in vivo; (5) decreased movement to ward chemotactic stimuli despite normal orientation toward the stimulus; (6) reduced expression of complement and Fc receptors. These deficiencies are usually marked and have been confirmed [3], Phagocytosis by neonatal neutrophils has been reported to be reduced under ‘stress conditions’ in vitro or in vivo (sick or pre mature infants). Results obtained in studies of bactericidal activity of neonatal neutrophils are similar to those found in phagocytosis, i.e. normal
145
bactericidal activity in healthy infants and in favorable in vitro conditions, and, on the other hand, depresssed bactericidal activity in sick or premature infants or in conditions of‘stress’ obtained in vitro. Bactericidal ac tivity in healthy term infants is related to postnatal age, being normal at birth and transiently defective during the subsequent 2 weeks of life. The impairment of bactericidal activity is severe in premature infants - the more immature the infant, the greater the deficiency - and may persist after the neona tal period [5]. Furthermore, neonatal neutro phil viability and the reserve and storage pool are reduced. The Complement System Several studies have reported reduced ac tivity of both classical and alternative path ways of complement in term newborns, as compared to their mothers or adult controls [6], Complement activity is lower in prema ture infants, with a close relationship to ges tational age and birth weight. Kinetic studies have shown a considerable delay in comple ment activation, particularly in preterm in fants [6], Furthermore, no C3 and factor B are synthesized by neonatal monocytes in response to lipopolysaccharide challenge [1]. This complex deficiency of the complement system, in addition to fibronectin and anti body deficiency, causes a significant reduc tion of opsonic activity in neonatal serum. Cellular Immunity Cell-mediated immunity is incompletely developed at birth, as proved by a different distribution of subpopulations of T, B and natural killer cells, as compared to adult con trols, and by the presence of subsets of lym phocytes bearing markers of immaturity on the membrane surface [1], Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
Immunoglobulin Prophylaxis in Infants
146
Rondini/Ch i rico/Ugazio
Specific Humoral Immunity Several factors are responsible for the marked antibody deficiency in the neonate. The immaturity of T and B lymphocytes and of macrophages causes a delayed switch from IgM to other immunoglobulin isotypes (only low levels of IgM are produced during the first month of life in response to anti genic challenge; no response to lipopolysac charide antigen may be observed); levels of IgG are low in preterm infants because trans placental passage from the mother occurs almost exclusively during the last 6 weeks of gestation; the neonate may lack pathogenspecific IgG, particularly those restricted to the IgG2 subclass, such as antibody specific for streptococcal carbohydrate or Haemophi lus influenzae type b capsular polysaccharide [8]. The interplay of these factors with the neonatal deficiency of complement activity and neutrophil activity results in increased susceptibility to systemic infections from en capsulated pathogens, such as group B strep tococci, straphylococci and Klebsiella sp., that require opsonization for efficient phagocytosis and killing.
Intravenous Immunoglobulin Therapy
The observation that neonatal opsonic deficiency is partly correctable with immu noglobulin led some authors to study the intramuscular use of human immune serum globulin for prophylaxis of infection in pre
mature infants. The results of these studies failed to show a significant beneficial effect, probably because of the disadvantages of in tramuscularly administered immunoglobu lin therapy: uneven absorption, slow avail ability, tissue damage and pain, with resul tant problems in administering adequate amounts. Intramuscular preparations of im munoglobulin cannot be administered intra venously because they contain aggregates of IgG that activate complement and may cause dangerous anaphylactoid reactions. Better preparations of immunoglobulin have recently been obtained by removal of aggre gates; these can be administered intrave nously in high doses, contain intact antibody molecules and maintain normal biologic ac tivities of the Fc fragment, such as comple ment activation, binding to cell surface re ceptors, catabolization and opsonic activity, although with significant variability among available preparations [9]. Furthermore, the IgG subclass distribution is similar to that found in normal serum and includes anti bodies to most of the pathogens found in neonatal infections. We performed a controlled study to eval uate the safety and effectiveness of intrave nously administered immunoglobulin ther apy for prophylaxis of infection in 83 neo nates with birth weight < 1,500 g and gesta tional age 1,500 g receiving intensive
147
care and assisted ventilation. No immediate side effects were observed after ivIgG ad ministration; no difference in serum biliru bin and transaminase values was recorded between treated and control infants at 2 and 4 months of age. These data show that ivIgG therapy is both safe and effective for prophy laxis of infection in preterm infants with very low birth weights. Following this report, several other stud ies have been performed on the prophylactic use of ivIgG in preterm infants, with both positive and negative results [12-16], These studies cannot be compared because of the different methods used for patient selection, the different methods of care, the different study designs and the different ivIgG prepa rations and dosages used. In one report, for instance, the ivIgG dosage has been individ ually regulated to maintain IgG serum levels >700 mg/dl [17], However, these studies have pointed out two common findings: (1) the efficacy of ivIgG for prophylaxis of infection seems to be strictly related to birth weight; in fact, positive results have been observed in infants with mean birth weight below 1,300 g, while, when infants with higher birth weight were considered, the re sults have been unsatisfactory (fig. 1); (2) no significant immediate or late side effects have been recorded after treatment, which indicates that ivIgG are well tolerated by preterm infants. It has been reported that high doses of ivIgG can reduce the penicillin bactericidal activity against group B Strepto coccus and the neutrophil opsonophagocytosis activity, probably because of membrane receptor inhibition. However, such an effect has been observed in animal experiments only after the administration of very high doses of ivIgG (2.7 g/kg) and not after treat ment with the lower doses (0.68 g/kg) which Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
Immunoglobulin Prophylaxis in Infants
148
Rondini/Chirico/Ugazio
Chirico et al. [10] -
Baker [12] Stabile et al. [16] -
■v«
Chirico et al. [10] Haque et al. [15] Baker [12] Bussei et al. [13] -
■>
f
1,000
1,250
1,500
1,750
2,000
2,250
Mean birth weight, g
are commonly used in preterm infants [18]. Furthermore, we showed that ivlgG do not interfere with natural killer cell activity in preterm infants [19], Von Murait and Sidiropoulos [20] reported that the ivlgG therapy in the neonatal period does not cause a de pression of immune response or a sensitiza tion to polyclonal IgG. Few and inconclusive data are available on the use of ivlgG for therapy of sepsis, because of the difficulty to evaluate an ade quate number of septicemic infants with ho mogeneous characteristics for a reliable sta tistical analysis. The doses of ivlgG used were either 1 g/day for 6 days in term infants and 0.5 g/day for 6 days in preterm infants [20], 0.8 g/kg/day [21] or 250 mg/kg/day for 4 days of IgM-enriched IvlgG (Pentaglobin) [22], An intravenous preparation of mono clonal antibody against endotoxin has re cently proven useful for the treatment of Gram-negative bacteremia and septic shock in adults: similar positive results may be expected in the treatment of neonatal infec tions [23].
Fig. 1. Positive (+) or nega tive (-) results of the studies on prophylaxis of infection with in travenous immunoglobulin in relation to birth weight.
References 1 Burgio GR. Hanson LA, Ugazio AG (eds): Immu nology of the Neonate. Berlin, Springer, 1987. 2 Usher RH: The special problems of the premature infant; in Avery GB (ed); Neonatology, Patho physiology and Management of the Newborn. Philadelphia, Lippincott, 1987. 3 Miller ME; Immunodeficiencies of immaturity; in Stiehm ER (cd): Immunologic Disorders in In fants and Children, ed 3. Philadelphia. Saunders, 1990. 4 Wilson CB: Developmental immunology and role of host defenses in neonatal susceptibility: in Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infant, ed 3. Philadel phia, Saunders, 1990. 5 Chirico G, Marconi M, De Amici M, et al: Defi ciency of neutrophil bactericidal activity in term and preterm infants. Biol Neonate 1985;47:125— 129. 6 Notarangelo LD, Chirico G. Chiara A, et al: Ac tivity of classical and alternative pathways of complement in preterm and small for gestational age infants. Pediatr Res 1984;18:281-285. 7 Ugazio AG, Chirico G, Plebani A, et al: Immunity and infection in term and preterm newborns; in Xanthou M, Bracci R (ed): Neonatal Haemato logy and Immunology. Amsterdam, Elsevier Science Publishers, 1990. Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
Clapp et al. [14]
Immunoglobulin Prophylaxis in Infants
17 Kyllonen KS, Clapp DW, Kliegman RM, et al: Dosage of intranvenously administered immuno globulin and dosing interval required to maintain target levels of immunoglobulin G in low birth weight infants. J Pediatr 1989:115:1013-1016. 18 Weisman LE, Lorenzetti PM: High dose human intravenous immunoglobulins suppress neonatal group B streptococcal immunity in rats. J Pediatr 1989:115:445-450. 19 Chirico G, Maccario R, Montagna D. et al: Natu ral killer cell activity in preterm infants: Effect of intravenous immune globulin administration. J Pediatr 1990;1 17:465-466. 20 Von Murait G, Sidiropoulos D: Prenatal and post natal prophylaxis of infections in preterm neo nates. Pediatr Infect Dis J 1988;7:S72—S78. 21 Fischer GW: Use of intravenous immunoglobulin during the treatment of infection in low birth w'eight infants. Proc NIH Consensus Dev Conf Intravenous Immunoglobulin: Prevention and Treatment of Disease. Bethesda. 1990. 22 Haque KN, Zaidi MH, Bahakim H: IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Am J Dis Child 1988;142:1293-1296. 23 Ziegler EJ, Fisher CJ, Sprung CL, et al: Treatment of gram-negative bacteremia and septic shock with Ha-1A human monoclonal antibody against endotoxin. N Engl J Med 1991;324:429-435.
Prof. G. Rondini Divisione di Patologia Neonatale Policlinico San Matteo 1-27100 Pavia (Italy)
Downloaded by: University of Exeter 144.173.6.94 - 6/9/2020 9:08:35 PM
8 Einhorm MS, Granoff DM, Nahm MH, et al: Concentrations of antibodies in paired maternal and infant sera: Relationship to IgG subclass. J Pediatr 1987;111:783-788. 9 Givner LB: Human immunoglobulins for intrave nous use: Comparison of available preparations for group B streptococcal antibody levels, opsonic activity and efficacy in animal models. Pediatrics 1990;86:955-962. 10 Chirico G, Rondini G, Plebani A, et al: Intrave nous gammaglobulin therapy for prophylaxis of infection in high-risk neonates. J Pediatr 1987; 110:437-442. 11 Eibl MM, Wolf HM, Furnkranz H. et al: Pre vention of necrotizing enterocolitis in low-birthweight infants by IgA-IgG feeding. N Eng J Med 1988;319:1-7. 12 Baker CJ: Intravenous immunoglobulin in low birth weight infants: Prevention. Proc NIH Con sensus Dev Conf Intravenous Immunoglobulin: Prevention and Treatment of Disease. Bethesda, 1990. 13 Bussei JB, LaGamma EF. Giuliano M: Intrave nous gammaglobulin prophylaxis of late sepsis in VLBW infants: A randomized placebo controlled trial. Pediatr Res 1988;23:471 A. 14 Clapp DW, Kliegman RM, Baley JE, et al: Use of intravenously administered immunoglobulin to prevent nosocomial sepsis in low birth weight infants: Report of a pilot study. J Pediatr 1988; I 15:973-978. 15 Haque K.N, Zaidi MH, Haque SK. et al: Intrave nous immunoglobulin for prevention of sepsis in preterm and low birth weight infants. Pediatr In fect Dis J 1986;5:622-625. 16 Stabile A, Miceli Sopo S, Romanelli V, et al: Intra venous immunoglobulin for prophylaxis of neona tal sepsis in premature infants. Arch Dis Child 1988:63:441-443.
149
