Intravenous Immunoglobulin in Neonatal Sepsis

Address for correspondence Prof. Dr. Jiang Li Department of Paediatrics School of Medicine, ZhongDa Hospital, Southeast University, China E-mail: jiangli77777@126.com How to cite this article ? Li J, Gautam MK. Intravenous Immunoglobulin in Neonatal Sepsis. J Nepal Paediatr Soc 2013;33(2):125-128. This work is licensed under a Creative Commons Attribution 3.0 License. Intravenous Immunoglobulin in Neonatal Sepsis


Introduction
N eonatal sepsis is a clinical syndrome characterized by systemic signs of infection and accompanied by bacteremia in the fi rst month of life 1 .Sepsis occurring in the fi rst 72 hours of life is defi ned as early-onset sepsis (EOS) and that occurring beyond 72 hours as late-onset sepsis (LOS) 2 .Neonatal early onset sepsis is defi ned by Centers for Disease Control and prevention (CDC) as blood or cerebrospinal fl uid culture proven infection occurring in the newborn younger than 7 days of age.Neonatal late onset sepsis is usually defi ned as a culture-proven systemic infection in an infant between seven days and three months of age.For hospitalized VLBW infant, EOS is defi ned as culture-proven infection occurring at fewer than 72 hours of age 3 .Incidence of neonatal sepsis varies from 2.2/1000 live births in developed countries to 10-50/1000 live births in developing countries; though under reporting is common in both 4 .In China the incidence of neonatal sepsis accounts for 1%-10% of all neonates requiring medical attention and 13%-50% of all neonatal mortality cause 5 .The incidence of neonatal sepsis in India according to National Neonatal Perinatal Database is 30/1000 live births.Sepsis has been reported as cause of neonatal death in 20-50% cases in community based studies 6 .There is no national database mentioning incidence of neonatal sepsis in Nepal till date.Deaths occurring in the neonatal period each year account for 41% (3.6 million) of all deaths in children under fi ve years of age 7,8 .In Nepal, out of the total infant mortality rate of 46/1000 live births, more than two-third, i.e. 33/1000 live births is contributed by neonatal mortality.Both the incidence of sepsis, 1/230 live births versus 1-5/1000 live term births and mortality from sepsis between 18-20% remain unacceptably high in VLBW preterm infants 9,10 .
Neonates are comparatively immunocompromised in view of quantitative and qualitative defi ciency in their humoral immunity.In addition, very preterm infants have reduced complement factors, opsonic activity, and polymorphonuclear chemotaxis and are liable to exhaust their storage pools 10,11 .

Intravenous immunoglobulin
It has been more than 60 years since Ogden C. Bruton's reported use of human-plasma-derived IgG of an 8-year-old boy with agammaglobulinemia.IVIg has now become an important treatment option in a number of clinical indications beyond primary immunodefi ciency, Intravenous Immunoglobulin in Neonatal Sepsis including autoimmune and acute infl ammatory conditions 12 .Off-label prescribing has crossed over into almost every medical specialty including neonates.
Endogenous immunoglobulin synthesis does not begin until 24 weeks of life; young infants rely on in-utero maternally acquired immunoglobulins for protection against systemic infection.The placental transfer of these protective antibodies, however, does not occur until week 32 of gestation and post-natally IgG levels decrease due to reduced production in newborns.The administration of intravenous immunoglobulin (IVIg) may improve immune function by providing IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemo luminescence.However, there remains an ongoing debate about the effi cacy of IVIg in the treatment of neonatal sepsis 13 .

IVIg prophylaxis and adjuvant therapy
The fi rst four studies published in 1981,1986,1988  and 1989 showed an increased risk of death in septic neonates given antibiotics but not treated with IVIg, compared to children given antibiotics plus IVIg, signifying the importance of IVIg as useful adjunctive therapy.The prophylactic role of IVIg was fi rst studied in 1986 and 1987, which showed a benefi t from the use of IVIg to prevent proven bacterial sepsis 14 .
Various small single center clinical trials in mainland China have shown benefi cial effects of use of IVIg in suspected or proven neonatal sepsis, especially premature infants [15][16][17] .On the contrary few recent trials have shown no effect of IVIg in prevention and treatment of neonatal sepsis in premature infants 18,19 .The effectiveness of IVIg preparations in the prevention or treatment of neonatal sepsis remained uncertain, due in part to studies that included relatively small or heterogeneous populations.Internationally there have been various studies with contradictory results.In 1994 fi rst large clinical trial was done.The National Institute of Child Health and Human Development Neonatal Research Network published the largest randomized clinical trial (n=2,416) assessing the role of IVIg in the reduction of premature neonatal sepsis.The prophylactic administration of IVIg in this study did not reduce the incidence of nosocomia l infections, morbidity and mortality in premature infants 20 .
In the past 10 years, many systematic reviews and clinical trial results were published.In 2004 a systematic review by Cochrane collaboration evaluated the relationship between IVIg therapy and all-cause mortality during hospitalization in premature and term infants.Combining the results of 7studies (n=262), treatment with IVIg in cases of culture-proven infection resulted in a reduction in all-cause mortality (RR 0.55; 95% CI 0.31, 0.98) 21 .The authors did not observe between-study heterogeneity; however, (especially in a setting when fewer than 20 studies are analyzed), and the studies were different in the variety of IVIg products, different dosing regimens, and patient populations.In 2006 a multicenter (20 sites), randomized, double blinded, placebo controlled study evaluated the safety and effi cacy of 2 infusions (14 days apart, dose = 1000 mg/Kg) of an anti-staphylococcal IVIg (Altastaph) in VLBW infants.The product was determined to be safe among the intervention group (n=104); however, when compared to placebo (n=102) no change was observed in the cumulative incidence of invasive staphylococcal infections 22 .
In 2007, another multicenter, randomized clinical study involving 95 sites in the US and Canada evaluated the effect of up to 4 infusions of INH-A21 (Veronate, dose = 750 mg/Kg dosed on days 1, 3, 8 and 15), an anti-staphylococcal IVIg (anti-clumping Factor A and anti-Ser-Asp dipeptide repeat G), on the prevention of Staphylococcal late-onset sepsis among 1,983 infants with birth weights <1,250 g who received at least one infusion of study drug or placebo (989 vs. 994, respectively).In this study, no difference was observed between treatment groups in frequency of Staphylococcus aureus infections, 5% for INH-A21 vs 6% for placebo 23 .Pagibaximab, an anti-staphylococcal monoclonal antibody (anti-lipoteichoic acid) administered in 3 doses (7 days apart, 60 to 90 mg/kg/dose), was evaluated in a randomized, placebo controlled phase II study in infants with birth weight <1,300 g (n= 88).A trend was observed in the reduction of Staphylococcal bloodstream infections; none of the subjects in the 90 mg/kg group had confi rmed staphylococcal sepsis compared to 20% and 13% in the 60 mg/kg and placebo groups, respectively (P<0.11) 24 .
In 2010, Khalid N.Haque did a pragmatic review of 14 studies published within 1970 to 2010.The primary and only outcome parameter measured for this study was the impact of immunoglobulin therapy on mortality from neonatal sepsis.Analysis of 14 studies revealed a reduction of 48% in all cause mortality associated with neonatal sepsis when IVIg was used as an adjunct to standard therapy (OR 0.52; 95% CI 0.40-0.67) 25.In the same year, Cochrane updated its previous review of intravenous immune globulin for infection in neonates with suspected or subsequently proven infection.It included 10 trials of variable quality undertaken in eight countries 26 .Mortality was reduced among patients with clinically suspected infection in 7 trials involving 378 infants (relative risk, 0.58; 95% CI, 0.38 to 0.89) and among patients with subsequently proven infection in 7 trials involving 262 patients (relative risk, 0.55; 95% CI, 0.31 to 0.98).Because of concerns about study quality, there was still insuffi cient evidence to support the routine administration of IVIg to prevent mortality in infants with suspected or subsequently proved neonatal infection.A large study of the effectiveness of IVIg in neonates with suspected infection had recently been completed.Results of the International Neonatal Immunotherapy Study (INIS trial) 27 , which enrolled 3,493 infants, were expected to establish the usefulness of IVIg for suspected infection in newborns.

Latest Clinical Evidence
In 2011, the outcome of multicenter clinical trial organized by International Neonatal Immunotherapy Study (INIS) Collaborative Group was published.The trial enrolled 3493 infants receiving antibiotics for suspected or proven serious infection in the multicenter clinical trial at 113 hospitals in nine countries and randomly assigned to receive two infusions of either polyvalent IgG immune globulin (at a dose of 500 mg per kilogram of body weight) or matching placebo 48 hours apart.The primary outcome was death or major disability at the age of 2 years.The multicenter trial by INIS collaborative group showed no signifi cant between-group difference in the rates of the primary outcome, which occurred in 686 of 1759 infants (39.0%) who received intravenous immune globulin and in 677 of 1734 infants (39.0%) who received placebo (relative risk, 1.00; 95% confi dence interval, 0.92 to 1.08).Similarly, there were no signifi cant differences in the rates of secondary outcomes, including the incidence of subsequent sepsis episodes.In follow-up of 2-year-old infants, there were no signifi cant differences in the rates of major or non major disability or of adverse events 27 .
In 2012, systematic review with meta-analysis by Andréia C. B. F. Franco et.al evaluated seven RCTs for the mortality rate, including 3,756 patients.The global effect of this outcome showed no statistically signifi cant difference between the groups 28 .

Conclusion
The development of IVIg has been a great achievement in medical history.But its use should be clinical evidence based.Latest evidence showed no signifi cant benefi ts of IVIg use in neonatal sepsis.For the developing countries like Nepal, where the constraint for use of IVIg is its cost and availability, this result should come as a relief.In addition, prevention of ineffective expensive treatment therapy can save millions of dollars.Studies on other adjuvant therapies such as colony stimulating factors, probiotics, glutamine supplementation and lactoferrin have been tested with mixed results.In future, further large randomized clinical trials should evaluate the effectiveness of other adjuvant or prophylactic therapies for suspected or proven neonatal sepsis which may result in signifi cant decrease in neonatal mortality and morbidity.