2. Immunoglobulins
Circulating antibodies protect their
host by binding to and neutralizing
some protein toxins, by blocking the
attachment of some viruses and
bacteria to cells, by opsonizing
bacteria and by activating
complement.
Produced by Plasma Cells
GAMDE
3. Classes of Immunoglobulins
IgG
IgA
IgM
IgD
IgE
GAMDE 5 classes of Immunoglobulin
IG1= 66
IG2= 23
IG3=7
IG4=4
4. IgG
The major immunoglobulin in the blood, makes up 70% to 75% of the
total immunoglobulin pool.
The serum half-life of IgG is 23 days.
The only immunoglobulin capable of crossing the placenta and is thus
a major defense mechanism in the early part of an infant’s life.
Neutralize viruses and toxins, opsonize bacteria, and activate the
complement system.
5. IgG is an answer to
Autoimmune Disorders
Primary Immunodeficiency
8. Properties of IVIG
Pro-inflammatory
opsonic activity
fixation of complement
antibody dependent cytotoxicity
neutrophil chemiluminescence
phagocytosis
release of stored neutrophils
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
11. Humoral Immunity in NewBorns
Humoral immunity of the human newborn is provided primarily by maternal immunoglobulin G (IgG)
transferred transplacentally beginning at 8 to 10 weeks of gestation and accelerating during the last
trimester.
The lack of opsonic antibody is an important risk factor for susceptibility of newborns to infections
caused by many bacteria with polysaccharide capsules (eg, group B Streptococcus, Escherichia coli,
Haemophilus influenzae type b, Streptococcus pneumoniae) that cause serious bacterial infections in
newborns.
11Prof Ariyanto Harsono MD PhD SpA(K)
12. IgG in Preterm Infants
Premature infants, compared to full-term infants, have lower levels of IgG at birth that further
decreases during the first few weeks of life.
The relative deficiency of humoral immunity in premature newborns may contribute to the
inverse correlation of birth weight and rate of neonatal sepsis.
With an 86-fold increased rate of sepsis in newborns of birth weight 600 to 999 grams compared
to newborns of birth weight of more than 2500 grams.
Infants born prematurely are also at risk for nosocomial infections resulting from prolonged
hospitalization.
Prof Ariyanto Harsono MD PhD SpA(K) 12
13. Need for IVIG in Preterm Infants
The benefit of passive immunization by prophylactic administration of intravenous immune
globulin (IVIG) for prevention of bacterial infections has been established for patients with
primary a gammaglobulinemia and with symptomatic human immunodeficiency virus infection.
Routine administration of IVIG for other immunocompromised hosts has not consistently been
shown to clearly decrease the incidence of bacterial infections.
Therapeutic IVIG and monoclonal antibodies to gram negative bacteria have been studied as
adjunctive treatment for bacterial sepsis and shock but their effectiveness remains controversial.
13Prof Ariyanto Harsono MD PhD SpA(K)
15. Incidence of Thrombocytopenia
Neonatal alloimmune/ autoimmune
thrombocytopenia
o Incidence 1 per 1000
o First reports of IVIG in 1980s
o No RCTs
Immune-mediated thrombocytopenia
(Idiopathic thrombocytopenia - ITP)
o Extremely rare in newborns
o First reports of IVIG in 1981
o Subsequently effective in RCTs
o FDA approved
16. IVIG binds to the sensitised red cells.
IVIG Fc portion (fork handle) blocks the Fc receptor on
macrophages
IVIG upregulates inhibitory Fcγ RIIB receptors on macrophages.
This inhibits phagocytosis.
Possible mechanisms of IVIG in ITP
17. Guidelines for treatment of
Neonatal Autoimmune
Thrombocytopenia
Neonatal thrombocytopenia secondary to maternal
ITP may last for months and requires long-term
monitoring and occasionally a second dose of IVIg at
4 to 6 weeks after birth.
18.
19. Where there is delay in obtaining HPA-compatible
platelets, random donor platelet transfusions or
intravenous immunoglobulin (IVIG) can be used as
they often produce a significant platelet increment
in NAIT although the rise in platelet count after
IVIG may be delayed for at least 36 h
In some cases thrombocytopenia may persist for
up to 8–12 weeks. In such cases, IVIG usually
provides a better alternative to repeated platelet
transfusions.
23. IVIG IN HDN -AAP GUIDELINES
Indication: Hemolytic disease of newborn with significant
hyperbilirubinemia
Dose: 0.5-1gm/kg
Mode of administration: Infusion given over 2-4 hrs.
Monitoring: For adverse reactions
(Pediatrics 2004;114:297-316)
24. 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
25. 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).
26. 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.’
28. Intravenous immunoglobulin for suspected or
subsequently proven infection in neonates
Lacy J, Ohlsson A. Arch Dis Child 1995;72:F151-5
Ohlsson A, Lacy J. Cochrane Library, January 1998
Ohlsson A, Lacy J. Cochrane Library, February 2001
Unpublished update September, 2003
29. Background
Nosocomial infections continue to be a significant cause of
morbidity and mortality among preterm and/or low birth weight
infants
Maternal transport of immunoglobulins to the fetus occurs mainly
after 32 weeks gestation
Endogenous synthesis does not begin until several months after
birth
30. Background
Administration of intravenous immunoglobulin provides IgG that can:
bind to cell surface receptors
provide opsonic activity
activate complement
promote antibody dependent cytotoxicity
improve neutrophilic chemoluminescence
31. IVIG has the potential of:
Preventing serious nosocomial infections
Altering the course of congenital or nosocomial infections
32. Study Details
Objective
To assess the effectiveness/safety of IVIG administration - compared to placebo or no intervention - to preterm (< 37 weeks
gestational age at birth) and/or low birth weight (< 2500 g) infants in preventing nosocomial infections
Results
When 10 studies (n = 3,975) were combined there was a statistically significant reduction in sepsis (one or more episodes)
When 16 studies (n = 4,986) were combined there was a statistically significant reduction in any serious infection (one or more
episodes)
There were no statistically significant differences for:
mortality from all causes
mortality from infection
NEC, BPD, IVH
length of hospital stay
no major adverse effects of IVIG were reported in any of the studies
a rise in serum IgG was noted in all studies that reported on this outcome
33. Main results
There were no statistically significant differences for:
mortality from all causes
mortality from infection
NEC, BPD, IVH
length of hospital stay
no major adverse effects of IVIG were reported in any of the studies
a rise in serum IgG was noted in all studies that reported on this outcome
34.
35. Attempts to explain across study
heterogeneity in a systematic review
of prophylactic administration of
intravenous immunoglobulin (IVIG) in
neonates
Beyene J, Shah V, Ohlsson A
36. Comparison: IVIG vs placebo/no treatment
Outcome: Any serious infection (RR)
37. Comparison: IVIG vs placebo/no treatment
Outcome: Any serious infection (RD)
40. Conclusions
Statistically significant in-between study heterogeneity was present
due to differences in control group event rates
IVIG administration results in a 3-4% reduction in sepsis and/or any
serious infection
Is not associated with reductions in other morbidities: NEC, IVH,
length of hospital stay or mortality
Prophylactic use of IVIG is not associated with any short term
serious side effects
41. Conclusions
The decision to use prophylactic IVIG will depend on the costs
and the values assigned to the clinical outcomes
There is no justification for further RCTs testing the efficacy of
previously studied IVIG preparations to reduce nosocomial
infections in preterm and/or LBW infants
The results of these meta-analyses should encourage basic
scientists and clinicians to pursue other avenues to prevent
nosocomial infections
42. Intravenous immunoglobulin for
suspected or subsequently
proven infection in neonates
Lacy J, Ohlsson A. Arch Dis Child 1995;72:F151-5
Ohlsson A, Lacy J. Cochrane Library, January 1998
Ohlsson A, Lacy J. Cochrane Library, February 2001
Unpublished update September, 2003
43. Objectives
To assess the effectiveness of intravenous immunoglobulin
(IVIG) to reduce mortality/morbidity caused by suspected
infection in newborn infants
In secondary analyses to assess the effectiveness of IVIG to
reduce mortality/morbidity in those neonates, who entered
into the studies with suspected infection and who later were
confirmed as being infected.
44. Main results
Six of 9 identified studies (n = 318) reported on the outcomes of all
randomized patients with clinically suspected infection
Mortality was not reduced (borderline statistical significance)
RR 0.63 (95% CI; 0.40, 1.00)
RD – 0.09 (95% CI; 0.00, - 0.17)
No statistically significant between study heterogeneity
45. Main results
Treatment with IVIG (seven trials,
n = 262) in cases of subsequently proved infection did result
in a statistically significant reduction in mortality
RR 0.55 (95% CI; 0.31, 0.98)
RD -0.09 (95% CI; - 0.01, - 0.18)
NNT 11 (95% CI; 6, 100)
There was no statistically significant between-study
heterogeneity
46.
47.
48.
49. Conclusions
The reduced mortality following treatment with IVIG for suspected sepsis and the imprecise
estimate of the effect size to prevent one death (NNT 11, 95% CI; 6, 100) justify further research
50. Conclusions
The role of IVIG preparations with high concentrations of antibodies to specific organisms should
be evaluated
If such trials are to be undertaken, the design should include long-term follow-up assessment
and cost-effectiveness evaluation
51. Conclusions
Researchers should be encouraged to undertake well-designed trials to confirm or refute the
effectiveness of IVIG to reduce adverse outcomes in neonates with suspected infection
