The Journal of Pediatrics
Volume 151, Issue 3 , Pages 232-234, September 2007

Specific Immune Globulin Therapy for Prevention of Nosocomial Staphylococcal Bloodstream Infection in Premature Infants: Not What We Hoped for!

  • M. Teresa de la Morena, MD

      Affiliations

    • Corresponding Author InformationReprint requests: M. Teresa de la Morena, MD, Division of Allergy and Immunology, University of Texas Southwestern Medical Center in Dallas, 1935 Motor St, Dallas, TX 75235.

Division of Allergy and Immunology, University of Texas Southwestern Medical Center, Dallas, Texas

Article Outline

Abbreviations: CoNS, Coagulase-negative staphylococci, IVIG, Intravenous immune globulin, LOS, Late-onset sepsis, MRSA, Methicillin-resistant Staphylococcus aureus, NRN, Neonatal Research Network, VLBW, Very low birth weight

 

Advances in medical knowledge coupled with the proliferation of capable neonatal intensive care units have been instrumental in the survival of infants born prematurely. Yet, premature birth remains an important contributor to overall infant death (>30% of all infant deaths).1 In this issue of The Journal, DeJonge et al2 describe the important negative findings of a study that attempted to use a pathogen-specific antibody for prevention of nosocomial infections in very low birth weight infants (VLBW; <1500 g; <32 weeks gestation).

See related article, p 260

In 1986, in response to the growing population of preterm infants, the National Institutes of Child Health and Human Development created the Neonatal Research Network (NRN), a group of academic centers working in collaboration, with the goal of reducing neonatal morbidity and mortality rates and improving outcomes. Spurred on by this initiative, a series of carefully conducted observational studies and randomized clinical trials have been performed in the past decade that have not only allowed the recognition of risk factors but also provided an infrastructure to systematically analyze potential therapeutic interventions with adequate numbers of subjects. Consequently, as expected, infections are recognized as an important problem for VLBW infants.3 Since the early 1990s the NRN has been monitoring both early-onset sepsis (occurring before 72 hours of life) and late-onset sepsis (LOS; positive blood culture after 72 hours of life) in VLBW infants and its impact on comorbidities, survival, and long-term outcomes. The incidence of sepsis occurring early is 2% versus 25% if the child survives past 72 hours of life. The most common organisms causing LOS are Gram-positive pathogens (70%), and coagulase-negative staphylococci (CoNS) represented 48% of all infections.4, 5 Taken together, VLBW infants with LOS have longer hospitalizations, high morbidity and mortality rates, and care costs resulting in a societal economic burden that reached $26.2 billion in 2005.6 Addressing prevention and treatment of LOS in these infants is imperative.

Antibodies are the effector molecules of the adaptive humoral immune response. Their physiological function is defense against extracellular microbes and microbial toxins through mechanisms of opsonization, neutralization, complement activation, and antibody-dependent cellular toxicity. Recognizing that transplacental transfer of maternal antibodies occurs after 32 to 35 weeks gestation, it was reasonable to hypothesize a benefit for intravenous administration of immune globulin (IVIG) to VLBW infants to prevent or treat infection. Since the late 1980s, more than a dozen studies and meta-analyses on the benefits of immune globulin therapy have been published. In general, studies agree on the safety of appropriate doses of IVIG in such small infants. However, benefits and efficacy varied. Baker et al7 studied 588 infants (500 to 1750 g) who were randomized to receive periodic infusions of IVIG. An important initial observation was a decrease in risk of first nosocomial infection in IVIG recipients compared with control subjects (RR 0.7; 95% CI) and trend to less necrotizing enterocolitis. Two years later, Weisman et al8 studied 753 babies (500-2000 g; <34 weeks;<12 hours of life) who were randomized to receive a single infusion of IVIG. Despite maintaining higher immunoglobulin G levels, bloodstream infection, and overall morbidity and death caused by sepsis were not affected by IVIG. In 1994, Fanaroff et al9 in a collaborative NRN effort, published the results of a randomized placebo-controlled trial of IVIG (phase I/II) for 2416 infants (501-1500 g). IVIG failed to reduce the incidence of nosocomial infections. Subsequently, studies and meta-analyses of use of IVIG for adjunctive therapy in infants with suspected/confirmed infection were published. These studies varied in IVIG product, age, birth weight, and sample size. When death was reported as an outcome, borderline statistical significance was noted in groups treated with IVIG compared with placebo (RR 0.63; 95% CI; 0.40, 1.00).10

In spite of the lack of clear benefit of IVIG, previous successful experience with pathogen-specific immune globulin for respiratory syncytial virus prophylaxis11 suggested a potential role for the development of pathogen-specific IVIG preparations. Because CoNS is the most common organism causing LOS, staphylococcal binding proteins C1fA and SdrG were selected as possible targets. These proteins are surface adhesins, present on >98% of Staphylococcus aureus and most strains of Staphylococcus epidermidis and play a critical role in the attachment of bacteria to host tissue, an important pathogenic step for entry. In 2005, Bloom et al12 published a phase II, multicenter, double-blind clinical trial of INH-A21, a plasma-derived, donor-selected polyclonal antistaphylococcal human immune globulin. The study was sponsored by the manufacturer and the Office of Orphan Product Development of the US Food and Drug Administration. Plasma concentrations of the staphylococcal-specific antibody necessary to achieve protection were unknown, so the trial was designed to identify a dose for future analysis. A total of 512 infants (500-1250 grams; >72 hours to 7 days of age) were randomized to 250, 500, and 750 mg/kg/dose of INH-A21. No differences in incidence of any staphylococcal (CoNS or S. aureus) infections was identified.

The study by DeJonge et al2 is the subsequent phase III analysis: A multicenter (95 different centers within the United States and Canada), randomized double-blind, placebo-controlled clinical trial. A total of 1983 neonates (500-1250 g) received either placebo or study drug INH-A21. Because the phase II study only demonstrated possible activity of INH-A21 against S. aureus LOS, this study’s primary outcome was LOS caused by S. aureus, with CoNS infections as a secondary outcome. Sepsis was clearly defined by the authors. Incidence of LOS due to S. aureus was no different between the groups (5% in the placebo vs 6% in the INH-A21 group). No association was found between the number of infusions and infections. The lack of clinical benefit is disappointing, particularly as an increase in methicillin-resistant S. aureus (MRSA) strains emerged within the study neonatal intensive care units (23% of S. aureus were MRSA2).

For the past decades, knowledge of the neonatal human immune response has derived from analyses of the immunologic status of the mother, the role of the placenta in the transfer of antibodies, the in vitro analysis of cord and newborn peripheral blood cell, from study of patients and inferred from studies using mouse models.13 This knowledge underestimates the complexity of the immune response. For example, the B-lymphocyte system is fully developed at birth; fetal bone marrow B lymphocyte pools are similar in size to those of adults and preterm infants are capable of forming specific antibodies with comparable isotype diversity as adults.14 Control of staphylococcal infections requires not only humoral, but cellular and phagocytic responses for effective killing. The lack of efficacy of antibody therapies may relate to confounding mechanisms necessary for clearance of pathogens by the host. The extent to which neonatal deficiencies of neutrophil function, complement, or antibody contribute to the increased risk of infection remains unknown, even though these factors are important in vitro for opsonophagocytic killing of Escherichia coli, group B Streptococcus, and Candida species.

Answers may lie in expanding our knowledge and therapeutic approaches to stimulate/enhance innate components of the immune response. Antimicrobial products, receptors capable of recognizing pathogen-associated molecular patterns, phagocytic cells, complement proteins, dendritic and natural killer cells are all essential components of the innate immune response and constitute the first line of defense against invading pathogens. The skin is the most important barrier against pathogens invasion. Epithelial cells are capable of secreting 2 classes of antimicrobial peptides: defensins and cathelicidins.15 Interestingly, during the third trimester of pregnancy, the fetus becomes covered by the vernix caseosa that contains antimicrobial peptides including α-defensins and LL-37, a human cathelicidin. Vernix extracts exhibited both antibacterial activity against gram-negative bacteria, and antifungal properties against Candida albicans.16 Intriguingly, psoriasis and atopic dermatitis, are 2 inflammatory skin conditions associated with skin breakdown. However, although infection is rarely associated with psoriasis, patients with atopic dermatitis are commonly infected with S. aureus. Human β-defensin 2 and the cathelicidin LL-37 appear to be strongly expressed in psoriasis and not in eczematous skin. Interleukin 13, produced under atopic conditions, suppresses the induction of these antimicrobial peptides.17 Furthermore, LL-37 has also been identified in the ductal epithelium of salivary and sweat glands, suggesting a role in the protection of the gland itself from microbial invasion.18

Finally, the molecular biology of staphylococcal infections provides hints for the interactions of innate and adaptive immune responses. In vitro and in vivo experiments demonstrate that exposure of S. aureus to host cells induces the antimicrobial products β-defensins and LL-37/CAP-18 but vary among stains of S. aureus, with MRSA exhibiting lower susceptibility.19

The publication by The Journal of this well-conducted study with negative results is essential as the accumulation of new findings that do support perceived knowledge advance the field.

Back to Article Outline

References 

  1. Callaghan WM, MacDorman MF, Rasmussen SA, Qin C, Lackritz EM. The contribution of preterm birth to infant mortality rates in the United States. Pediatrics. 2006;118:1566–1573
  2. DeJonge M, Bloom BD, et al. Phase III, randomized, double-blind, placebo-controlled multi-center clinical trial of safety and efficacy of INH-A21 for the prevention of nosocomial staphylococcal sepsis in premature infants. J Pediatr. 2007;151:260–265
  3. Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network. Semin Perinatol. 2003;27:293–301
  4. Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR, et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr. 1996;129:63–71
  5. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110(Pt 1):285–291
  6. In:  Behrman RE,  Butler AS editor. Committee on Understanding Premature Birth and Assuring Healthy Outcomes, Board on Health Science Policy, Institute of Medicine. Preterm Births: Causes, Consequences, and Prevention. 2006;Brief Report July. http://www.iom.edu/object.file/Master/35/975/pretermbirth.pdf. Accessed August 8s, 2007
  7. Baker CJ, Melish ME, Hall RT, Casto DT, Vasan U, Givner LB. Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight neonates (The Multicenter Group for the Study of Immune Globulin in Neonates). N Engl J Med. 1992;327:213–219
  8. Weisman LE, Stoll BJ, Kueser TJ, Rubio TT, Frank CG, Heiman HS, et al. Intravenous immune globulin prophylaxis of late-onset sepsis in premature neonates. J Pediatr. 1994;125(Pt 1):922–930
  9. Fanaroff AA, Korones SB, Wright LL, Wright EC, Poland RL, Bauer CB, et al. A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants (National Institute of Child Health and Human Development Neonatal Research Network). N Engl J Med. 1994;330:1107–1113
  10. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev. 2004;1:CD001239
  11. The PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics. 1997;99:93–99
  12. Bloom B, Schelonka R, Kueser T, Walker W, Jung E, Kaufman D, et al. Multicenter study to assess safety and efficacy of INH-A21, a donor-selected human staphylococcal immunoglobulin, for prevention of nosocomial infections in very low birth weight infants. Pediatr Infect Dis J. 2005;24:858–866
  13. Bona C. Neonatal immunity. In:  Rose NR editors. Contemporary immunology. Totowa, NJ: Humana Press; 2005;p. 1–389
  14. Ballow M, Cates KL, Rowe JC, Goetz C, Desbonnet C. Development of the immune system in very low birth weight (less than 1500 g) premature infants: concentrations of plasma immunoglobulins and patterns of infections. Pediatr Res. 1986;20:899–904
  15. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, et al. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science. 1999;286(5439):525–528
  16. Yoshio H, Tollin M, Gudmundsson GH, Lagercrantz H, Jornvall H, Marchini G, et al. Antimicrobial polypeptides of human vernix caseosa and amniotic fluid: implications for newborn innate defense. Pediatr Res. 2003;53:211–216
  17. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–1160
  18. Murakami M, Ohtake T, Dorschner RA, Schittek B, Garbe C, Gallo RL. Cathelicidin anti-microbial peptide expression in sweat, an innate defense system for the skin. J Invest Dermatol. 2002;119:1090–1095
  19. Komatsuzawa H, Ouhara K, Yamada S, Fujiwara T, Sayama K, Hashimoto K, et al. Innate defenses against methicillin-resistant Staphylococcus aureus (MRSA) infection. J Pathol. 2006;208:249–260

PII: S0022-3476(07)00603-8

doi:10.1016/j.jpeds.2007.06.031

Refers to article:

  • Clinical Trial of Safety and Efficacy of IHN-A21 for the Prevention of Nosocomial Staphylococcal Bloodstream Infection in Premature Infants , 28 July 2007

    Mitchell DeJonge, David Burchfield, Barry Bloom, Maria Duenas, Whit Walker, Mark Polak, Elizabeth Jung, Dietra Millard, Robert Schelonka, Fabien Eyal, Amy Morris, Barry Kapik, Destrey Roberson, Karen Kesler, Joe Patti, Seth Hetherington
    The Journal of Pediatrics September 2007 (Vol. 151, Issue 3, Pages 260-265.e1)

The Journal of Pediatrics
Volume 151, Issue 3 , Pages 232-234, September 2007

Article Tools