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 Childrens Hospital at
  Westmead
• NHMRC Clinical Trials Centre
• University of Sydney

3
because INIS will

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

4
(No Transcript)
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

7
(No Transcript)
8
IVIG for suspected infection in neonates Ohlsson
Lacy, Cochrane Library 2005
controls No IVIG treated IVIG Odds ratio
MORTALITY 24 38/ 161 15 23/ 157 0.63 (0.42 1.00)
DISABILITY ? ? ?
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
10
(No Transcript)
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 (lt96 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

15
(No Transcript)
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. (plt0.02)
• 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

21
(No Transcript)
22
Stoll et al JAMA 2004

• Neurodevelopmental and growth impairment among
  ELBW infants with neonatal infection
• 6093 infants lt 1000 g bwt assessed at 18 22
  months corrected for gestation

23
Neuro-developmental Impairment (NDI) in infected
versus uninfected infants
Category N () NDI (unadjusted) OR for NDI adjusted for 21 risk factors
uninfected 2161 (35) 29 -
Culture neg clinical infection 1538 (25) 43 1.3 (1.1-1.6)
Culture positive sepsis 1922 (32) 48 1.5 (1.2 1.7)
Sepsis and NEC 279 (5) 53 1.8 (1.4 2.5)
meningitis 193 (3) 48 1.6 (1.1 2.3)
24
Neuro-developmental impairment in infants with
different pathogens versus uninfected infants
Category N NDI (unadjusted) Adjusted OR for NDI relative to uninfected
uninfected 1976 29 -
CONS 853 44 1.3 (1.1 1.6)
Other Gm pos 256 48 1.7 (1.2 2.3)
Gram negative 185 45 1.8 (1.2 7.6)
Fungal 96 57 1.4 (0.9 2.2)
25
After adjustment for antenatal, perinatal and
postnatal factors

• Neonatal infection was associated with OFC lt 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 lt
  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

32
(No Transcript)
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.

35
(No Transcript)
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

38
(No Transcript)
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)?

40
(No Transcript)
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 lt 5 x 109/L, or CRP
  gt15 mg/L, or platelets lt 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 lt 30 weeks gestation to women
  with clinical chorioamnionitis vs infants born at
  lt 30 weeks gestation with no clinical
  chorioamnionitis vs infants born at 30 weeks.

45
Elevated maternal CRP

• infants born at lt 30 weeks gestation to women
  with elevated CRP (gt 80mg/l) vs infants born at lt
  30 weeks gestation with no elevated maternal CRP
  vs infants born at gt 30 weeks

46
Preterm birth and duration of membrane rupture

• Born at lt 37 weeks and membranes ruptured for lt
  24 hours, 24-48 hours or gt 48 hours vs born
  at gt 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

50
(No Transcript)
51
Validation of a parent report measure of
cognitive development in very preterm infants
Johnson et al. Dev Med Child Neurol 2004

• 64 two year olds who were lt 30 weeks gestation in
  UK follow up centres
• Assessed with the Mental Development Index of the
  Bayley II Scales and the modified Parent Report
  questionnaire
• Parent report score lt 49 predicted MDI lt 70 with
  81 sensitivity and 81 specifity

52

• Parent report will be used to assess cognitive
  outcome at 2 years corrected in all patients
• Alongside paediatrician assessment of general
  health and neurological status
• Bayley II scales will be performed in 600 ANZ
  infants, to validate Parent Report in ANZ

53
5

• INIS aims for a follow up rate
• as high as possible

54
Take home messages

• In the light of current evidence, collaborators
  are encouraged to recruit eligible infants still
  being treated with antibiotics for suspected or
  proven clinical sepsis and
• CONS
• Clinical chorioamnionitis (if still on
  antibiotics)
• Elevated maternal CRP (if still on antibiotics)
• Culture-negative clinical sepsis/ pneumonia if
  antibiotics are planned, or have been given, for
  5 or more days
• NB its prudent not to recruit infants who will
  be impossible to follow up at 2 years