Role of intravenous immunoglobulin in suspected or proven neonatal sepsis

GAUTAM M K，JIANG Li

(1.School of Medicine，Southeast University，Nanjing 210009，China;2.Department of Pediatrics，Zhongda Hospital，Southeast University，Nanjing 210009，China)

1 Introduction

Neonatal sepsis is a clinical syndrome characterized by systemic signs of infection and accompanied by bacteremia in the first month of life［1］.Sepsis occurring in the first 72 hours of life is defined as early-onset sepsis(EOS)and that occurring beyond 72 hours as late-onset sepsis(LOS).Center for disease control and prevention(CDC)defines neonatal early onset sepsis as blood or cerebrospinal fluid culture proven infection occurring inthe newborn younger than7 days of age.Neonatal LOS sepsis is usually defined as a culture-proven systemic infection in an infant between 7 days and 3 months of age.For hospitalized VLBW infant，EOS is defined as cultureproven infection occurring at fewer than 72 hours of age［2］.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［3］.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［4］.The incidence of neonatal sepsis in India according to data of National Neonatal Perinatal Database(2002-2003)is 30/1000 live births［5］.Sepsis has been reported as cause of neonatal death in 20%-50%cases in community based studies.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 5 years of age［7］.Developing countries share 99%of neonatal deaths and almost 1 million of these deaths are attributable to infectious causes including neonatal sepsis，meningitis and pneumonia［6］.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［7-8］.Increase in incidence of neonatal sepsis is also attributed by increasing preterm delivery.Incidence in preterm infants has risen to 4/1000 live births.Despite considerable progress in hygiene，introduction of newer effective microbial agents and advanced techniques in early diagnosis and treatment，neonatal septicemia still remains one of the most important causes of mortality and morbidity in this age group［9-10］.

The high mortality and morbidity rates despite improved antibiotics and advancement in technology has let scientific search for other adjunctive therapies for neonatal sepsis.Neonates are considered immunocompromised in view of their relatively immature immune defense mechanisms;they have quantitative and qualitative deficiency in their humoral immunity.In addition，very preterm infants have reduced complement factors，opsonic activity，polymorphonuclear chemotaxis and are liable to exhaust their storage pools［11-12］.Barbara Stoll et al，［13］in a study of over 6，000 infants weighing 1，000 Grams or less have confirmed earlier studies［14-16］that VLBW/preterm infants who survive at least one episode of proven sepsis in the neonatal period have 30%-80%increased odds for neurodevelopmental impairment and a 30%-100%increase in odds for poor head growth(an indirect reflection of poor neurological development)at 18-22 months despite the use of powerful antibiotics.

2 Intravenous immunoglobulin

2.1 Clinical History

It has been more than 60 years since Ogden C.Bruton reported an 8-year-old boy with recurrent Streptococcus pneumonia bacteremia whose plasma contained little gamma globulin(immunoglobulin G，IgG).Bruton treated the boy's agammaglobulinemia with regular intramuscular(i.m.)injections of humanplasmaderived IgG.The treatment resulted in increased serum IgG levels and an impressive reduction in the number of serious bacterial infections experienced.Immunoglobulin preparations were first used therapeutically in the 1950s as imm-unoglobulin replacement therapy for primary immunodeficiency disorders.In recent years，IVIg has become an important treatment option in a number of clinical indications beyond primary immunodeficiency，including autoi-mmune and acute inflammatory conditions［17］.The offlabel prescribing has crossed over into almost every medical specialty including neonates.

Endogenous immunoglobulin synthesis does not begin until 24 weeks of life，thus 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 postnatally IgG levels decrease due to reduced production in newborns［18］.It seemed reasonable，therefore，to consider IgG replacement therapy in premature neonates.

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.Therefore，investigators have proposed the use of intravenous immunoglobulin(IVIg)to prevent and treat neonatal sepsis in this population.

2.2 Clinical Indications

Currently，the approved indications for intravenous immunoglobulin are:primary immunodeficiencies，secondary immunodeficiencies(multiple myeloma or chronic lymphoid leukemia)，Kawasaki syndrome，immune thrombocytopenic purpura，Guillain Barré syndrome，and graft versushost disease following bone marrow transplantation and repeat infections in HIV children.On the other hand，there are numerous"offlabel"indications of immunoglobulin，which represent 20%-60%of all clinical applications of this drug［19］.However，there remains an ongoing debate about the efficacy of IVIg in the treatment of neonatal sepsis.

3 IVIg prophylaxis and adjuvant therapy

3.1 Clinical research evidences

The first four studies published in 1981，1986，1988，1989 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 first studied in 1986 and 1987，which showed a benefit from the use of IVIg to prevent proven bacterial sepsis［20］.Since then various small and large scale researches have been going on to justify the use of IVIg in neonatal sepsis.Various small single center clinical trials in mainland China have shown beneficial effects of use of IVIg in suspected or proven neonatal sepsis，especially premature infants［21-23］.On the contrary few recent trials have shown little or no effect of IVIg in prevention and treatment of neonatal sepsis in premature infants［24-25］.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 popula-tions.Internationally there have been various studies with contradictory results.

In 1994 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 nosocomial infections，morbidity and mortality in premature infa-nts［26］.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 allcause 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 allcause mortality(RR 0.55;95%CI 0.31-0.98)［27］.In 2006 a multicenter(20 sites)，randomized，double blinded，placebo controlled study evaluated the safety and efficacy of 2 infusions(14 days apart，dose=1 000mg/Kg)of an antistaphylococcal 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［28］.

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－1dosed on days 1，3，8 and 15)，an antistaphylococcal IVIg(anti-clumping Factor A and anti-Ser-Asp dipeptide repeat G)，on the prevention of Staphylococcal lateonset 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 versus 6%for placebo［29］.

Pagibaximab，an anti-staphylococcal monoclonal antibody(anti-lipoteichoic acid)administered in 3 doses(7 days apart，60 to 90 mg·kg－1dose)，was evaluated in a randomized，placebo controlled phaseⅡ 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－1group had confirmed staphylococcal sepsis compared to 20%and 13%in the 60 mg·kg－1and placebo groups，respectively(P ＜ 0.11)［30］.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)［31］.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.Mortality was reduced among patients with clinically suspected infection in 7 trials involving 378 infants(RR 0.58;95%CI 0.38-0.89)and among patients with subsequently proven infection in 7 trials involving 262 patients(RR 0.55;95% CI 0.31 to 0.98)［32］.Because of concerns about study quality，the-re was still insufficient 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)，which enrolled 3，493 infants，were expected to establish the usefulness of IVIg for suspected infection in newborns.

3.2 Latest Clinical Research Evidence

In 2011，the outcome of multicenter clinical trial organized by International Neonatal Immunotherapy Study(INIS)Collaborative Group was published.The trial enrolled 3，493 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 significant between-group difference in the rates of the primary outcome，which occurred in 686 of 1，759 infants(39.0%)who received intravenous immune globulin and in 677 of 1，734 infants(39.0%)who received placebo(RR 1.00;95%CI 0.92-1.08).Similarly，there were no significant 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 significant differences in the rates of major or non major disability or of adverse events［33］.

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 significant difference between the groups［34］.

4 Conclusion

The development of IVIg has been a great achievement in history of medicine.But its use should be clinical evidence based.Although many previous reviews including Cochrane review of 10 trials in 378 infants showed that IVIg was associated with a statistically significant reduction in mortality，the INIS trial clearly showed that IVIg did not achieve the moderate improvements in death or major disability in term or preterm neonates.In the meta-analysis by Franco et al.，which included the INIS trail results，the earlier apparent reduction in mortality observed in Cochrane review disappeared.So，after many years of contradictory suggestions，current evidence indicates IVIg has no place in the treatment of neonatal infection whether prophylactic or therapeutic.Especially for the developing countries like Nepal and others in Southeast Asia，where the constraint for use of IVIg is its cost and availability，this result should come as a relief.In addition，caution in use of ineffective expensive treatment therapy can save millions of dollars globally.Studies on other adjuvant therapies such as colony stimulating factors，pathogen specific protective antibodies，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 significant decrease in neonatal mortality and morbidity.

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