International Neonatal Immunotherapy Study (INIS)

1. International Neonatal Immunotherapy Study (INIS)

2. Why is the INIS follow up study so important? William Tarnow-Mordi Westmead Hospital and Children’s Hospital at Westmead NHMRC Clinical Trials Centre University of Sydney

3. because INIS will • exemplify disability-free survival as a primary outcome measure in neonatal trials. • test common preconceptions on the importance of various pathogens and clinical presentations in neonatal sepsis. • Provide evidence on potential immuno-modulatory effects of IVIG • be the first large-scale use of a Parent Report of cognitive performance at 2 years, validated against the BSID II MDI. • aim for as high as possible follow up to maximise validity.

5. William Silverman (‘Fumer’) 1917-2004 Taught his students and friends • to consider the long term consequences of neonatal care, for patients and families • to cultivate a habit of lifelong (un) learning • ‘semper plangere’ (always complain) - and look for better evidence

6. 1 Disability-free survival as a primary outcome measure

8. IVIG for suspected infection in neonatesOhlsson Lacy, Cochrane Library 2005;

9. History of oxygen use in preterm neonates • early 1950s: unrestricted, high O2, subsequent huge increase in RLF (severe ROP) From: Wright K. Textbook of Ophthalmology 1997. Eds. Williams & Wilkins. Chapter 22

11. Cost of preventing Retrolental Fibroplasia?Cross K. Lancet 1973 • Each baby whose sight was saved by limiting oxygen may have cost • 16 hypoxic deaths and • many survivors with spastic diplegia • A large RCT should have evaluated not just ROP but mortality and long term morbidity

12. Early postnatal (<96 hr) corticosteroids for preventing chronic lung disease in preterm infants.Cochrane Review: Halliday, Ehrenkrantz, Doyle. • 7 RCTs with 991 infants • 69% increase in relative risk of cerebral palsy [1.69 (1.2 – 2.38)] • Re-illustrates risk of introducing an effective therapy (known to reduce chronic lung disease) without knowing its impact on disability-free survival

13. 2 Relative importance of specific pathogens and presentations

14. Two personal (un) learning points

16. (a) IVIG is not indicated in coagulase negative staphylococcus (CONS) sepsis because it has no impact on long term morbidity …

17. (b) IVIG is not indicated in Culture-negative clinical infection (clinical sepsis treated with antibiotics for 5 days or more, with no pathogen identified) because it is not associated with adverse long term outcome …

18. Association between cerebral palsy and coagulase-negative staphylococci.Mittendorf et al. Lancet 1999 • Cultured the space between the membranes after aseptic separation of amnion from chorion in 107 preterm infants in MagNET trial • 35% grew no organisms. 28% grew CONS • CONS isolated in 4/5 (80%) infants who later manifest CP vs 26/102 (25%) who did not. (p<0.02) • Remained significant after adjusting for birthweight, seizures, neonatal ventilation and presentation.

19. Mittendorf et al. Lancet 1999 • First report of a specific perinatal bacterium in association with CP. • Generates the hypotheses that • CONS may play a causal role in CP • mediated by virulence factors such as haemolysins, deoxyribonuclease, slime and adhesins

20. Cerebral Palsy after neonatal sepsis Murphy et al, BMJ 1997 Population-based case control study in 293 3-5 year olds born before 32 weeks gestation After adjusting for gestation, antenatal and intrapartum risk factors, odds ratio for CP after neonatal sepsis was 3.6 (2.5 – 9.3) • CONS was the single most common cause of neonatal sepsis in this cohort (25-50% of all pathogens) David Isaacs, unpublished data

22. Stoll et al JAMA 2004 • Neurodevelopmental and growth impairment among ELBW infants with neonatal infection • 6093 infants < 1000 g bwt assessed at 18 – 22 months corrected for gestation

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

24. Neuro-developmental impairment in infants with different pathogens versus uninfected infants

25. After adjustment for antenatal, perinatal and postnatal factors • Neonatal infection was associated with OFC < 10th centile at 36 weeks • Neonatal infection, including CONS and culture-negative sepis, was associated with increased neuro-developmental impairment and poor head growth at 18-22 months

26. The Stoll cohort study raises important questions • Is neonatal infection a cause of long term neuro-developmental impairment? • Is Coagulase negative staphylococcus the most common infective cause of NDI? • Can anti-inflammatory therapies, like IVIG, reduce, increase or leave disability unchanged after neonatal infection?

27. Limitations of an observational study in birthweight defined cohort • The uninfected group had more SGA babies (24%) than the other groups (14%, 14%, 13%, 16%) (p < 0.01) • Do SGA babies fare better (less infection, less NDI) than AGA babies of similar weight, even after adjustment for gestation? • Could this be a competing explanation for the association between infection and NDI?

28. Given the totality of evidence linking neonatal and perinatal sepsis with NDI (including gestation-based studies), whether neonatal infection contributes to NDI remains a major, unanswered question • RCTs like INIS are the only way to resolve the uncertainty reliably. If IVIG reduces NDI and/ or disability this would be good evidence that neonatal infection is causative.

29. 3 Potential immuno-modulatory effects of IVIG

30. Pro inflammatory properties of IVIG Promoting • opsonic activity, • fixation of complement, • antibody dependent cytotoxicity, • neutrophil chemiluminescence, • phagocytosis and • release of stored neutrophils.

31. Anti-inflammatory properties of IVIG 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 and complement Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. Kazatchkine MD,. et al. N Engl J Med 2001

33. Immunomodulatory effects of IVIG in cerebral inflammatory and auto-immune conditions • Systematic Reviews of RCTs support use of IVIG in • Chronic Inflammatory De-myelinating Polyneuropathy (CDIP) • Guillain-Barre syndrome • Idiopathic Thrombocytopenia • Kawasaki disease • Multiple Sclerosis

34. In Kawasaki disease, although we do not fully understand the mechanism of immune damage following infection, RCTs have shown that IVIG is an important anti-inflammatory therapy. It is now a standard of care. • INIS provides an opportunity to demonstrate whether IVIG is effective in neonatal sepsis. If so, it will stimulate more intensive research into mechanisms.

36. 91 patients within 6 weeks of the first event suggestive of multiple sclerosis • Randomly assigned to 2 g/ kg IVIG or placebo • Then 0.4 g/ kg every 6 weeks for a year

37. IVIG more than halved the risk of developing definite MS within one year • Relative risk 0.36 (0.15 – 0.88) • Fewer and smaller cerebral lesions on MRI

39. Duggan et al, Lancet 2001 • 36% of babies born before 30 weeks gestation had MRI cerebral lesions on scans done at a median 2 days after birth • The risk of cerebral lesions increased after • raised maternal CRP • preterm rupture of membranes • Could postnatal IVIG benefit pre-existing cerebral inflammation (as in adult MS)?

41. Primary Research Question Does intravenous immunoglobulin (IVIG) reduce the primary outcome of mortality or major disability at two years corrected for gestation in babies receiving antimicrobial therapy for a suspected or proven serious infection? * includes anti-virals or anti-fungals as appropriate

42. Selected subgroup analyses

43. Clinical severity at presentation from data recorded at trial entry • High severity • Looks seriously ill or inactive AND has low or high temperature, or prolonged capillary return, or is ventilated, or FiO2/ SpO2 consistent with high mortality risk • Moderate severity • None of the above, but WCC < 5 x 109/L, or CRP >15 mg/L, or platelets < 50 x 109/L, or pathogens in blood or sterile site, or pneumonia, or CSF suggests bacterial meningitis • Low severity • None of the above

44. Maternal chorioamnionitis • infants born at < 30 weeks gestation to women with clinical chorioamnionitis vs infants born at < 30 weeks gestation with no clinical chorioamnionitis vs infants born at = 30 weeks.

45. Elevated maternal CRP infants born at < 30 weeks gestation to women with elevated CRP (> 80mg/l) vs infants born at < 30 weeks gestation with no elevated maternal CRP vs infants born at > 30 weeks

46. Preterm birth and duration of membrane rupture Born at < 37 weeks and membranes ruptured for < 24 hours, 24-48 hours or > 48 hours vs born at > 37 weeks.

47. Early onset infection • (non contaminant organisms isolated from culture sent before 48 hours) a) group B streptococcal disease b) other pathogens c) indeterminate aetiology

48. Late onset infection • (non contaminant organisms isolated from culture sent after 48 hours) a) gram positive organisms except Staphylococcus epidermidis b) staphylococcus epidermidis c) other pathogens d) clinical sepsis with no organism grown

49. Parent Report of cognitive performance at 2 years