Off-label Uses Of Intravenous Immunoglobulin(IVIG) In Paediatric Practice And A Meta-analysis Of IVIG For Treatment Of Neonatal Sepsis

Part I Off-label uses of intravenous immunoglobulin (IVIG) in paediatric practicePreparation of intravenous immunoglobulin(IVIG),the major component of which is immunoglobulin G, is a concentrate isolated from pooled plasma that has been donated by healthy people.It was initially used to treat primary immunodeficient. Nowadays, a rapid expansion of IVIG indications has been observed in other medical specialties,including neurology, haematology, rheumatology, oncology-haematology as well as dermatology. Beside those approved indications, the increase in IVIG use is partially attributed to off-label (or unlabelled) indications.These indications are based on data from empirical,uncontrolled case studies but short of supportive evidence from randomized controlled trials or systematic reviews. Given its high cost, inherent scarcity and potential risk as a blood product, rationalized IVIG utilization has become a focus of research. This study is aimed to access off-label usess of IVIG in a regional children’s hospital. Physician records for inpatients treated with IVIG during a1-year period were retrospectively reviewed. Indications are classified into two main groups, approved and off-label. Evidence-based clinical guidelines,including "AAAAI guideline (2006),"Clinical guidelines for immunoglobulin use(2nd Edition)", and "Criteria for the clinical use of intravenous immunoglobulin in Australia(2008), were applied to evaluate the rationality of off-label usess.The benefit of off-label uses were defined as following five categories,"definitely beneficial","probably beneficial","might provide benefit","unlikely to be beneficial or evidence of no benefit","insufficient or lack of evidence". In this study,24.1%of all IVIG administrations were for approved indications,whereas Off-label uses accounted for75.9%, among which13cases(0.7%) were for indications of " definitely beneficial",80(4.2%) for" probably beneficial",533(28.1%) for" might provide benefit ",477(25.1%) for" unlikely to be beneficial or evidence of no benefit", and794(41.9%) for "insufficient or lack of evidence".This result demonstrated that the majority of inpatient paediatric use of IVIG were for off-label uses. Patients with certain off-label uses benefited from IVIG therapy, which had been acknowledged by strong evidences and accepted by clinical practice.However, a greater number of other off-label uses called for high-quality clinical trial research and evidence. Part II A Meta-analysis of IVIG for treatment of neonatal sepsisNeonatal sepsis, the systemic inflammatory response syndrome induced by severe infection of various pathogens such as bacterium, virus or fungus, claims a major cause of neonatal mortality and morbidity. In addition of antibiotics which has been administered universally, ancillary therapy is indicated to improve the prognosis. In light of the shortage of maternal immunoglobulin (IgG) in neonates especially the preterm, it is theoretically beneficial to enhance their immunity by exogenous IgG replacement. Therefore,neonatal sepsis has become an indication of intravenous immunoglobulin (IVIG) in clinical practice whereas the efficacy of this hypothetic treatment remains unclear and controversial. The objective of the second part of this study is to evaluate the effect and safty of IVIG on neonatal sepsis.Data collection were conducted by searching The Cochrane Library(CDSR and CENTRAL), PUBMED, EMBASE and CBM.Studies or trails that met the inclusion criteria were accessed for quality and then analysed using RevMan5.1software from The Cochrane Library. Statistical analyses of inpatient mortality (IM), length of hospital stay(LHS) and incidence of adverse drug reactions (ADRs) were performed.A total of11randomized controlled trails (n=4012) reported in foreign languages were included in this systematic review. Neither IM nor LHS of neonates who received IVIG treatment was statistically different from the control’s(placebo/no intervention)[RR0.93,CI(0.81,1.07)], and there was no significant difference in ADRs in between [RD0.00(-0.01,0.01)]. After excluding studies with high risk of bias,sensitivity analysis showed that mortality of neonates, the major indicator of clinical outcome, did not change subsequently[RRO.97; CI(0.84,1.12)].Further comparison of subgroups in patients and IVIG preparations was carried out in order to eliminate potential impact of bias on the conclusions. Results showed that IM in patients with clinically proven sepsis was reduced following IVIG administration compared to placebo or no intervention control[RR0.49; CI(0.28,0.88)], but held no difference of statistical significance between group of suspected infection and control[RR0.96,CI(0.83,1.11)].Patients given IVIGAM preparation benefited more than controls who received placebo or no intervention[RR0.38; CI(0.18,0.82)], whereas such pattern was not observed in patients given standard IVIG preparation [RR0.97,CI(0.84,1.12)]. Statistical tests also failed to prove heterogeneity between preterm subgroup and term subgroup(which accounted for the majority of cases), and IM of both these subgroups did not statistically differ from that of the controls [RR0.94,CI(0.82,1.08)][RR0.75,CI(0.39,1.47)].In summary, the effectiveness of IVIG in improving the outcome of neonatal sepsis has not been validated by the studies included in this systematic review. The incidence of adverse drug reactions also remained unaffected following IVIG administration. Though data of this systematic review showed that the short-term mortality were reduced using IVIGAM preparation and IVIG could lower the mortality in patients with proven sepsis, larger, well-designed randomized controlled trials are still expected to establish the therapeutic effect of IVIGAM for sepsis in newborns and IVIG for neonates with proven sepsis because of concerns about the study quality and underlying bias.