William Tarnow-Mordi Professor of Neonatal Medicine University of Sydney

1. The Intravenous Immunoglobulins: Current and Future Role in the NICUCould IVIG be neuro-protective? William Tarnow-Mordi Professor of Neonatal Medicine University of Sydney Westmead Hospital and The Children’s Hospital at Westmead

2. OFF LABEL DISCLOSURE William Tarnow-Mordi has documented that his presentation involves comments or discussion of unapproved or off-label, experimental or investigational use of (a) polyclonal intravenous immunoglobulin (IVIG) (b) Veronate (anti-staphylococcal immunoglobulin)

3. DISCLOSURE STATEMENT Dr. William Tarnow-Mordi has documented that he has nothing else to disclose.

4. MISSION STATEMENT The primary aim of clinical studies in the newbornis to identify interventions that increase disability-free survival, employing the most reliable evidence from RCTs.

5. OUTLINE

6. Current role of IVIG (a) Immunomodulatory properties of IVIG (b) Thrombocytopenia (b) Haemolytic disease (c) Infection

7. Future potential role of IVIG Is IVIG neuro-protective in newborns with, or at risk of, infection?

8. Future role of IVIG • Do neonatal infections remote from the brain, including CONS, cause brain damage? • Are white matter damage and periventricular leukomalacia partly immune-mediated?

9. 3. Is multiple sclerosis (and its animal model) a model for PVL? 4. Can IVIG promote re-myelination in multiple sclerosis and other CNS inflammatory states? • Can we do trials big enough to test reliably if IVIG is neuro-protective in newborns with, or at risk of, infection?

10. Current role of IVIG (a) Immunomodulatory properties of IVIG (b) Thrombocytopenia (b) Haemolytic disease (c) Infection

13. Pro-inflammatory • opsonic activity • fixation of complement • antibody dependent cytotoxicity • neutrophil chemiluminescence • phagocytosis • release of stored neutrophils

14. “The phagocytes won’t eat the microbes unless the microbes are nicely buttered for them. Well, the patient manufactures the butter himself alright, but my discovery is that the manufacture of that butter, which I call OPSONIN, goes in the system by ups and down.There is at the bottom only one genuinely scientific treatment for all diseases, and that is to stimulate phagocytosis”. Dr RidgeonThe Doctor’s DilemmaG B Shaw 1909

15. Anti-inflammatory Down-regulation of inflammatory cytokines via • Fc receptor blockade, • provision of anti-idiotype antibodies • interference with activation of • T-cells • B-cells • the cytokine network • complement Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. Kazatchkine MD,. et al. N Engl J Med 2001

17. Current role of IVIG (a) Immunomodulatory properties of IVIG (b) Thrombocytopenia (b) Haemolytic disease (c) Infection

18. Neonatal alloimmune/ autoimmune thrombocytopenia • Incidence 1 per 1000 • First reports of IVIG in 1980s • No RCTs

19. Immune-mediated thrombocytopenia (Idiopathic thrombocytopenia - ITP) • Extremely rare in newborns • First reports of IVIG in 1981 • Subsequently effective in RCTs • FDA approved

20. Current role of IVIG (a) Immunomodulatory properties of IVIG (b) Thrombocytopenia (b) Haemolytic disease (c) Infection

21. IVIG for Rhesus disease and ABO incompatibility:Two systematic reviews of the same data 1. Alcock GS, Liley H. Cochrane Review 2002 2. Gottstein R, Cooke RW. Arch Dis Child Fetal Neonatal 2003 In 3 RCTs in 199 infants, IVIG led to • Fewer exchange transfusions • Relative Risk 0.28 (0.17 – 0.47) • Shorter phototherapy and hospital stay • No data on disability-free survival

22. Reduced need for exchange transfusion with IVIG vs standard treatment for haemolytic jaundice: Number needed to treat 2.7 (95% CI 2.0 to 3.8).

23. Similar results: differing conclusions Alcock GS, Liley H. Cochrane Review 2002 ‘Well designed studies are needed before routine use of IVIG can be recommended.’ Gottstein R, Cooke RWI. Arch Dis Child Fetal Neonatal 2003 ‘IVIG is an effective treatment.’

24. Mechanisms of action of IVIG in ITP and haemolytic jaundice • Similar mechanisms are postulated for effects of IVIG in both conditions. • They are incompletely understood.

25. Possible mechanisms of IVIG in ITP Plat Theory 1: IVIG (Fab portion – fork end) binds sensitised red cells. IVIG Fc portion (fork handle) blocks the Fc receptor on macrophages Macrophage Fehr et al, 1982

26. Possible mechanisms of IVIG in ITP Theory 2: IVIG upregulates inhibitory FcγRIIB receptors on macrophages. This inhibits phagocytosis. FcγRIII or IIA Plat Macrophage ? ↑ FcγRIIB expression Samuelsson et al, 2001

27. Current role of IVIG (a) Immunomodulatory properties of IVIG (b) Thrombocytopenia (b) Haemolytic disease (c) Infection

28. (c) Infection • Therapeutic IVIG • Prophylactic polyclonal IVIG • Prophylactic hyper-immune IVIG (Veronate) to prevent staphylococcal infection

29. Therapeutic IVIG Two Cochrane reviews • IVIG for treating sepsis and septic shock Alejandria MM, Lansang MA, Dans LF, Mantaring JBV. 2. Polyclonal IVIG for suspected or subsequently proven infection in neonates Ohlsson A, Lacy JB.

30. 1. IVIG for treating sepsis and septic shockAlejandria MM, Lansang MA, Dans LF, Mantaring JBV. Polyclonal IVIG reduces mortality in all age groups combined n=492 Relative Risk 0.64 (0.64 – 0.80) p = 0.00009

31. 1. IVIG for treating sepsis and septic shockAlejandria MM, Lansang MA, Dans LF, Mantaring JBV.

32. 1. IVIG for treating sepsis and septic shockAlejandria MM, Lansang MA, Dans LF, Mantaring JBV. • No mortality reduction with anti-cytokine or monoclonal IVIG • Anti-cytokine IVIG (4 RCTs, n =4,318) • RR=0.93; 95% CI 0.86 to 1.01); NS • Monoclonal IVIG (5 RCTs, n= 2,826) • RR=0.97; (95% CI 0.88 to 1.07); NS

33. 2. Polyclonal IVIG for suspected or subsequently proven infection in neonatesOhlsson A, Lacy JB. Cochrane Review 2004 mortality reduced in suspected infection, but with borderline statistical significance n = 318; Relative Risk 0.63 (95% CI; 0.40 - 1.00); p = 0.05 mortality reduced in subsequently proved infection, but with wide confidence interval n = 262; Relative Risk 0.55 (95% CI 0.31, 0.98); p = 0.04

34. 2. Polyclonal IVIG for suspected or subsequently proven infection in neonatesOhlsson A, Lacy JB. Cochrane Review 2004 • Insufficient evidence for routine IVIG.Well-designed trials to assess long term disability and cost effectiveness are needed. • One such trial is the International Neonatal Immunotherapy Study.

35. (c) Infection • Therapeutic IVIG • Prophylactic polyclonal IVIG • Prophylactic hyper-immune IVIG (Veronate) to prevent staphylococcal infection

36. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants Ohlsson A, Lacy JB. Cochrane Review 2004. • 16 RCTs of IVIG versus placebo or no intervention • ~ 5,000 infants < 37 weeks gestation or <2500 g • 3-4% reduction in sepsis or serious infection

37. Cumulative meta-analysis: IVIG vs Placebo or No Treatment Relative Risk 0.82 (95% CI 0.74-0.92) Risk Difference 0.04 (95% CI 0.02, 0.06)

38. Polyclonal IVIG prophylaxis • Reduces infection by 3-4% • statistically significant • marginal clinical significance • No reductions in mortality, or • NEC, IVH • hospital stay • No short term serious side effects • Inconclusive on disability-free survival

39. Conclusions • No further RCTs of standard IVIG to prevent infections • Basic scientists and clinicians should pursue other avenues

40. (c) Infection • Therapeutic IVIG • Prophylactic polyclonal IVIG • Prophylactic hyper-immune IVIG (Veronate) to prevent staphylococcal infection

41. Veronatedata courtesy of Dr Seth Hetherington • Intravenous Immune globulin • Donors selected for high titers to: • Clumping factor A – S. aureus • Serine-aspartate repeat G protein – S. epidermidis • Antibodies block attachment of bacteria to fibrinogen

42. Prophylactic hyperimmune anti-staphylococcal IVIG (Veronate): 2017 infants Bwt 500- 1250 g Blood Stream Infection           Control          Veronaten = 989n = 994 Staph aureus      5%                  6%Probable CONS      16%                15%Definitive CONS   9%                  11%Any Infection 35% 35% Mortality            7%                  6%

43. Veronate No difference was statistically significant Including these data may not alter the result of the meta-analysis of prophylactic trials: ~ 3-4% reduction in sepsis with prophylactic IVIG Too early for data on disability-free survival

44. Current use of IVIG in the NICU • Based on promising, but incomplete, evidence of effectiveness in • Thrombocytopenia • Haemolytic jaundice • Neonatal sepsis with no evidence of its long-term effects.

45. Future role of IVIG • Do neonatal infections remote from the brain, including CONS, cause brain damage? • Are white matter damage and periventricular leukomalacia partly immune-mediated?

47. Leviton, Gillies, Neff, Yaney 1976 White matter damage, or perinatal telencephalic leuco-encephalopathy (PTL), was more common after gram negative septicaemia. ‘It is hypothesized that endotoxin from bacteria adversely affects developing white matter…’

48. Stoll et al (JAMA) 2004

49. Stoll, Hansen, Adams-Chapman, Fanaroff, Hintz, Vohr, Higgins, for the NICHD Neonatal Research Network, JAMA 2004 • 6093 infants < 1000 g bwt assessed at 18 – 22 months corrected for gestation

50. Neuro-developmental Impairment (NDI) in infected versus uninfected infants