Intravenous immunoglobulin

 Properties
 Mode of action
 Indication
 FDA approved
 Off-label used
 Mode of administration
 Adverse effect

 Plasma fractionation (first step) by cold
ethanol/Cohn–Oncley modification (fraction II)
 98% IgG; > 90% monomeric IgG
 Traces of other Ig e.g., IgA , IgM, and serum proteins
 Addition of sugar, amino acids, or albumin stabilizes
IgG from aggregation
 Intact Fc receptor important for biological function
 Opsonization and phagocytosis
 Complement activation
 Antibody-dependent cytotoxicity
 Normal HL comparable to serum IgG
 Normal proportion of IgG subclasses
 Broad spectrum of Abs to bacterial and viral agents

Mark Ballow et al, clinical immunology clinical and practice , third edition.

 Donor selection
 Donor screening
 Donor plasma testing
 Viral antibody screen ( HBsAg, anti HCV, anti – HIV )
 Nucleic acid testing (NAT) : PCR ( HCV RNA,HBV DNA,HIV RNA, Parvovirus B19 DNA )
 Donor deferrala
 Mini-pool testing by NAT
 Viral inactivationb
 Depth filtration
 Column chromatography
 Caprylate precipitation
 Low pH incubation
 Solvent/detergent treatment
 Nanofiltration
 Pasteurization
 PEG precipitation

 a Plasma from donor is held for 6 months until donor returns for second
plasmapheresis donation.
b Not all products use same virus inactivation/removal steps. Each product uses 2–5
steps


( HCV )

Clinical Reviews in Allergy & Immunology Volume 29, 2005

Clinical Reviews in Allergy & Immunology Volume 29, 2005

 Anti-idiotypes against membrane-bound B-cell
receptors ( for proliferation )
 Fc-mediated inhibition of Ab production of B cells
 Anti-CD 5 Ab directed against subset of B cells
 Interference with differentiation of B cells (
neutralized BAFF )
 Inhibition of IL-6 production that is required for Ab
secretion by plasma cells
 Induction of apoptosis of B cells
 Neutralization of auto-Ab by anti-idiotypes (autoAb
directed against factor VIII, DNA, intrinsic
factor, thyroglobulin and ANCA )
 Increased catabolisms of Ab via intracellular FcRn

J Neurol (2006) 253 [Suppl 5]: V/18–V/24

 Binding of complement component C1
 Binding of complement component C3b ,C4b
 Binding of anaphylatoxins C3a and C5a
 Increased degradation of C3b
 Represent major mechanism in treatment of
dermatomyositis, ( include GBS )

J Neurol (2006) 253 [Suppl 5]: V/18–V/24

Transplantation • Volume 88, Number 1, July 15, 2009

 Affects differentiation,maturation and
functional status of DC (inhibition , in vitro)
 down-regulation of expression of co-
stimulatory molecules
 impairing ability of mature DC to produce IL-12
 Enhancing ability to produce Il-10
 inhibitionof auto- and alloreactive T-cell
activation and proliferation
 Modulates production of several cytokines
(including IL-1, -2, -3, -4, -5, -10, TNF-α, and
GM-CSF) and cytokine antagonists (IL-1RA) by
monocyte-macrophages and lymphocytes
Acta Derm Venereol 2007; 87: 206–218

 Ab against TCR- β-chain, CD4 and
CD8,Soluble CD4/CD8,HLA may inactivate
auto-reactive T cell by compete and
interrupt interaction with APCs
 Ab against HLA molecules, superantigens
 Ab against chemokine receptor CCR5
 Inhibition of maturation of DC with
consecutive
 inhibition of T cell activation and induced
apoptosis
 Increase expression of TGF-β, IL-10, Fox P3
and enhance property of Treg
J Neurol (2006) 253 [Suppl 5]: V/18–V/24

 Modulation of expression of adhesion
molecules like ICAM
 Antibodies against integrins
 Antibodies against RGD (Arg-Gly-Asp )motif
 Antibodies against CCR5

J Neurol (2006) 253 [Suppl 5]: V/18–V/24

 bind to several distinct epitopes on extra
cellular portion of Fas and occurring anti-Fas
Ab ( activation or functional blockade of
death receptor depend on cell type
concerned )
 protect keratinocytes, target cell in TEN,
from apoptosis via blockade of Fas death
receptor
 capable of promoting apoptosis in some
lymphocytes and monocytes ,terminate
immune reaction
 inhibit TNFα-mediated cytotoxicity
J Neurol (2006) 253 [Suppl 5]: V/18–V/24

 Complement
 IVIg bind complement C1q, C3b and C4
 C3b degradation is faster
 Phagocytosis ( major mechanism of IVIg in ITP )
 Blockade of Fc receptors (saturation of Fc
receptors leads to decreased cellular
destruction)
 Induction of expression of inhibitory FcγIIB receptor
 Cytokines
 Inhibition of B cells
 Induction of cytokine secretion and NO production
 IgG metabolism
 Blockade of protective intracellular FcRn
J Neurol (2006) 253 [Suppl 5]: V/18–V/24

No. of FDA Disease state Indication
licensed
products
11 PID or PHID Rx of PID states or for increase of Ab levels in PID or for
replacement therapy of PID states in which severe
impairment of Ab-forming capacity
5 ITP rapid increase in plt.count is needed to prevent
bleeding, control bleeding, or both in ITP or to allow
patient with ITP to undergo surgery
3 Kawasaki prevention of coronary artery aneurysms
2 B-cell CLL prevention of bacterial infections in patients with
hypogammaglobulinemia, recurrent bacterial infections,
or both associated with B-cell CLL
1 HIV infection Pediatric HIV to decrease frequency of serious and
minor bacterial infections and frequency of
hospitalization and increase time free of serious
bacterial infection
1 BM BM transplant recipients ≥ 20 years of age to decrease
transplantation risk of septicemia and other infections, interstitial
pneumonia of infectious or idiopathic causes,
and acute GVHD in first 100 days after transplantation
J ALLERGY CLIN IMMUNOL APRIL 2006.

 Primary antibody deficiency disorder
 Acute phase of Kawasaki disease
 ITP AIHA

 GBS MG
 Pemphigus, Toxic epidermal necrolysis
 Hemaphagocytic lymphohistiocytosis (HLH)

 Categorization of evidence and basis of recommendation
 Ia From meta-analysis of randomized controlled studies
 Ib From at least 1 randomized controlled study
 IIa From at least 1 controlled trial without randomization
 IIb From at least 1 other type of quasiexperimental study
 III From nonexperimental descriptive studies,
eg.comparative, correlation, or case-control studies
 IV From expert committee reports or opinions or clinical
experience of respected authorities or both
 Strength of recommendation
 A Based on category I evidence
 B Based on category II evidence or extrapolated from category
I evidence
 C Based on category III evidence or extrapolated from
category I or II evidence
 D Based on category IV evidence or extrapolated from
category I, II, or III evidence

Benefit Disease Evidence Strength of
category recommendation

Definitely PID with absent B cells IIb B
beneficial
Primary immune defects with IIb B
hypogammaglobulinemia and impaired
Specific Ab production
Probably CLL with reduced IgG and history of Ib A
beneficial infections
Prevention of bacterial infection in HIV- Ib A
infected children

PID with normogammaglobulinemia and III C
impaired specific Ab production


Benefit Disease category
Evidence recommendation
Strength of
Definitely Graves ophthalmopathy Ib A
Definitely
beneficial PID with absent B cells IIb B
beneficial
Idiopathic thrombocytopenic purpura Ia A
Probably Specific Ab production
Dermatomyositis and polymyositis IIa B
Probably
beneficial CLL with reduced IgG and history of Ib A
Autoimmune uveitis IIa B
Prevention of bacterial infection in HIV- Ib A
infected children


 50 children with acute ITP
 26 observed with no therapy,12 IVIG, 12 MDMP
 % of patients whose platelet > 20 and > 50 x 109/L at
3 days after starting therapy significantly higher in
both IVIG and MDMP groups than in no therapy group
(p < .01),
 no significant difference at 10 and 30 days after
initiation between 3 groups (p > .05 in each
comparison)
 suggest :
 therapy not increase rate of recovery
 but shortens duration of thrombocytopenia in the first
days
 If extensive bleeding and decision is to treat, both IVIG
and MDMP are equally effective

Pediatr Hematol Oncol 2002;19:219-25

 METHODS: In a 2:1-randomized study 23 children
 dexa (0.6 mg/kg /d for 4 days once monthly for 6 months, n = 15)
 IVIg (800 mg/kg iv once monthly for 6 months, n = 8)
 After 4 courses of treatment crossover offered to nonresponders
 total of 20 children received dexamethasone and 11 received IVIg
 RESULTS:
 1/ 8 IVIg and 2 / 15 dexamethasone CR
 2 / 15 dexamethasone partial response
 1/8 IVIg and 5 /15 dexamethasone discontinued treatment
 5 patients crossed over from IVIg to dexamethasone ( 1 CR)
 3 from dexamethasone to IVIg (none responded).
 5/ 20 dexamethasone complete or partial response
 1 / 11 IVIg patients CR
 Platelet 30,000 by day 3 were reached in 9 /12 (75%) dexamethasone
and all 8 IVIg
 CONCLUSIONS: Treatment with pulsed high-dose dexamethasone
is not always effective in children with chronic ITP, but it is worth
trying in severe symptomatic chronic childhood ITP
J Pediatr Hematol Oncol
2003;25: -

 compared IVIg with high-dose MP in adults with severe AITP
 assessed efficacy of subsequent oral steroids compared with placebo
 Primary outcome : number of days with platelet 50,000 within first 21
days
 METHODS:
 122 severe AITP (platelet count < or =20,000)
 randomisation A : receive either IVIg or high-dose MP on days 1-3 then
 randomisation B : receive either oral prednisone or placebo on days 4-21
 FINDINGS:
 number of days : 18 in IVIg ,14 in high-dose MP (p=0.02)
 Percentage of patients ,platelet 50,000 on days 2 and 5
 7% and 79%, respectively, in IVIg
 2% and 60%, respectively, in high-dose MP (p=0.04)
 Prednisone more effective than placebo for all short-term endpoints
 IVIg & prednisone platelet 50,000 for 18.5 days , high-dose MP and
prednisone for 17.5 days (p=0.005)
 INTERPRETATION: IVIg and oral prednisone seems more effective than
high-dose MP and oral prednisone in adults with severe AITP, although the
latter treatment is effective and well tolerated
Lancet 2002;359:23-9


Definitely
Definitely PID with absent B cells
GBS ,CIDP IIb
Ia B
A
beneficial
beneficial
MMN Ia A
Probably LEMS
Specific Ab production Ib A
beneficial
Probably CLL with reduced IgG and history of Ib A
MG Ib-IIa B
Prevention of bacterial infection in HIV-
-IgM antimyelin-associated glycoprotein Ib
Ib A
A
infected children
paraprotein–associated peripheral
neuropathy
-Stiff-man syndrome
PID with normogammaglobulinemia and III C


 multicenter trial
 METHODS: GBS < 2 weeks and unable to walk
independently
 assigned to receive 5 PE or 5 doses of ivig (0.4 g/ kg/day)
 outcome : improvement at 4 weeks of motor function
 RESULTS:
 150 patients treated
 strength had improved in 34 % treated with PE, 53% treated
with ivig (difference, 19 %; 3-34%; P = 0.024).
 median time to improvement = 41 days with PE and 27 days
with IVIg (P = 0.05)
 IVIg group significantly fewer complications and less need for
artificial ventilation.
 CONCLUSIONS: In acute GBS, treatment with ivig at least
as effective as plasma exchange and may be superior.

N Engl J Med 1992;326:1123-9.

 international, multicentre, randomised trial
 383 adult with GBS
 METHODS: 5PE (8-13 days), IVIg (0.4 g/kg/d for 5 days), or
PE course immediately followed by IVIg course
 inclusion criteria : severe disease and onset within 14
days. Patients were F/U for 48 weeks.
 FINDINGS:
 mean improvement 0.9 (SD 1.3) in 121 PE-group patients, 0.8
(1.3) in the 130 IVIg-group patients, and 1.1 (1.4) in 128
patients received both treatments
 no significant difference between any of treatment groups in
secondary outcome measures
 INTERPRETATION: In treatment of severe GBS during first 2
weeks after onset of neuropathic symptoms, PE and IVIg
had equivalent efficacy. The combination of PE with IVIg
did not confer a significant advantage.

Lancet 1997;

 RDBPC trial of IVIG treatment in MG
 Patients received IVIG 2 gm/kg at induction
and 1 gm/kg after 3 weeks vs. 5% albumin
placebo
 Primary measurement : change in
quantitative MG Score (QMG) at day 42
 15 patients (6 to IVIG; 9 to placebo)
 At day 42, no significant difference in
primary or secondary outcome measurements
between 2 groups.
 In subsequent 6-week open-label study of
IVIG, positive trends were observed.
Muscle Nerve 2002;26:549-52.

 87 MG exacerbation
 3 PE (n = 41), or IVIg (n = 46) 0.4 gm/kg /d further
allocated to 3 (n = 23) or 5 days (n = 23)
 main end point : myasthenic muscular score (MSS)
between randomization and day 15
 MSS similar in both groups (median value, +18 in PE
group and +15.5 in IVIg group, p = 0.65)
 Similar efficacy, although slightly reduced in the 5-
day group was observed with both i.v.Ig schedules
 tolerance of IVIg better than PE , 8 in PE group and 1
in IVIg group (p = 0.01)
 IVIg is alternative for treatment of MG crisis. small
sample sizes in our trial, however, could explain why
difference in efficacy was not observed
Ann Neurol

 12 patients with generalized moderate to severe MG
on immunosuppressive treatment for at least 12
months
 evaluated clinically using quantified MG clinical score
(QMGS) before and at F/U visits after each treatment
 1 week after treatments, patients received PE
showed significant improvement in QMGS compared
to baseline but some improvement after IVIG ,not
reach statistical significance
 4 weeks after both PE and IVIG ,significant
improvement in QMGS compared to baseline
 1 and 4 weeks after treatment, no significant
difference between 2 treatments was found
 Both treatments have clinically significant effect 4
weeks out in chronic MG, but improvement more
rapid onset after PE than IVIG.
Artif Organs, Vol. 25, No. 12, 2001

 retrospective multicenter chart review
 Compare efficacy and tolerance of (28/27)PE
and (26/24)IVIg in treatment of 54 episodes of
myasthenic crisis
 PE (compared with IVIg) was associated with
superior ventilatory status at 2 weeks (partial F =
6.2, p = 0.02) and 1 month functional outcome
(partial F = 4.5, p = 0.04)
 However, complication rate higher with PE
compared with IVIg (13 vs 5 episodes, p = 0.07).
 IVIg : BUN elevation (2),infections(2),CV instability (1)
 PE : Infections (6), CV instability (6), coagulopathy (1)

Neurology 1999;52:629-32


Definitely Kawasaki disease
PID with absent B cells Ia
IIb A
B
beneficial
CMV-induced pneumonitis in
Primary immune defects withsolid organ Ib
IIb A
B
transplants
Probably Neonatal sepsis Ia A
Probably
beneficial CLL with reduced IgG and history of Ib A
-Rotaviral enterocolitis Ib A
Preventioninfections in lymphoproliferative
-Bacterial of bacterial infection in HIV- Ib A
infected children
diseases
-Staphylococcal toxic shock III C
PID with normogammaglobulinemia and
-Enteroviral meningoencephalitis III C


 Study design:
 case-control study
 KD (n = 178; 89 matched pairs) diagnosed 1987 - 1999
 89 received IVIG at day 5 or earlier matched to patients diagnosed within 4
weeks and given IVIG at days 6 to 9 of fever
 Results:
 Patients treated on day 5 or less of fever shorter total fever duration (5.2 days
vs 8.0 days, P < .0001), longer fever after IVIG treatment (1.5 ± 1.9 days vs 0.8 ±
1.3 days, P = .008), and less coronary artery ectasia at 1 year after KD onset (4%
vs 16%, P = .02).
 Patients treated on day 5 or less of fever had higher levels of serum albumin and
ALT , lower platelet count than control during acute phase.
 Conclusions: Early treatment of KD resulted in less coronary ectasia at 1
year after KD onset but not associated with quicker resolution of fever,
increased number of treatment failures, increased need for adjunctive
therapy, LOS, development of coronary artery lesions.
 IVIG on or before 5 days of fever resulted in better coronary outcomes
and decreased total length of time of clinical symptoms.

J Pediatr 2002;140:450-5

 METHODS :
 multicenter, randomized, controlled trial
 549 acute KD receive gamma globulin ( single infusion 2 g /kg over 10 hours or
daily infusions of 400 mg /kg for 4 days
 Both groups received aspirin (100 mg/kg/d through 14th day , then 3 to 5 mg
/kg/d)
 RESULTS:
 Relative prevalence of coronary abnormalities, with 4-day regimen, as
compared with single-infusion regimen
 1.94 (1.01 - 3.71) 2 weeks after enrollment
 1.84 ( 0.89 - 3.82) 7 weeks after enrollment
 single-infusion regimen lower mean temp. while hospitalized (day 2, P
<0.001; day 3, P = 0.004), shorter mean duration of fever (P = 0.028).
inflammation marker moved more rapidly toward normal. Lower IgG
levels on day 4 associated with higher prevalence of coronary lesions (P
= 0.005) and with greater degree of systemic inflammation
 2 groups similar incidence of AEs (including new or worsening CHF in 9
children), occurred in 2.7 % of children overall. All AEs were transient.
 CONCLUSIONS. In acute KD, single large dose of IVIg more effective than
conventional regimen of 4 smaller daily doses and is equally safe.

.
N Engl J Med 1991;324:1633-9

 METHODS. All published studies in all languages from 1967 – 1993
 children in studies received: (1) ASA alone, (2) low IVIG (< or = 1 g/kg)
and ASA, (3) high IVIG (> 1 g/kg) and ASA, (4) single IVIG (> 1 g/kg) and
ASA, (5) high IVIG and low ASA (< or = 80 mg/kg), or (6) high IVIG and high
ASA (> 80 mg/kg)
 RESULTS
 proportion of CAA at 30 and 60 days were:
 ASA group, 30 days, 22.8% ; 60 days, 17.1%
 low-IVIG group, 30 days, 17.3% ; 60 days, 11.1%
 high-IVIG group, 30 days, 10.3% ; 60 days, 4.4%
 single-IVIG group, 30 days, 2.3% ; 60 days, 2.4%
 high-IVIG-low-ASA group, 30 days, 13% ; 60 days, 4.8%
 high-IVIG-high-ASA group, 30 days, 9.1% ; 60 days, 4%
 CONCLUSION: incidence of CAA both at 30 and 60 days
 significantly lower in low-IVIG than in ASA
 Lower in high-IVIG than in low-IVIG groups
 lower in single-IVIG than in high-IVIG group, but this was noted at 30 days and
not at 60 days
 no statistically significant difference in incidence of CAA both at 30 and 60 days
between high-IVIG-low-ASA and high-IVIG-high-ASA groups.

Pediatrics 1995;96: -

 OBJECTIVES: evaluate effectiveness of IVIG in treating, and preventing cardiac
consequences, of KD in children.
 SEARCH STRATEGY: Electronic searches (last searched April 2003)
 SELECTION CRITERIA: RCT of IVIg to treat KD were eligible for inclusion.
 DATA COLLECTION AND ANALYSIS:
 16 trial met all inclusion criteria
 MAIN RESULTS:
 meta-analysis of IVIG versus placebo
 show significant decrease in new CAAs in favour of IVIG, at 30 days RR = 0.74 (0.61 -
0.90) No statistically significant difference was found thereafter
 subgroup analysis
 significant reduction of new CAAs in children receiving IVIG RR = 0.67 (0.46 - 1.00)
 trend towards benefit from IVIG at 60 days (p=0.06)
 meta-analysis of 400 mg/kg/day for 5 days vs 2 g/kg in single dose
 statistically significant reduction in CAAs at 30 days RR (95%) = 4.47 (1.55 to 12.86)
 significant reduction in duration of fever with higher dose
 no statistically significant difference between different preparations of IVIG &
adverse effects in any group.
 CONCLUSIONS: KD should be treated with IVIG (2 gm/kg single dose) within 10 days
of onset of symptoms

Cochrane Database Syst Rev 2003

indication Evidence recommendation
category
Probably TEN IIa B
beneficial
Might provide Autoimmune III C
benefit blistering disease
Severe Vasculitides III D
and ANCA
Severe form of SLE III D

J ALLERGY CLIN IMMUNOL APRIL 2006

( Ib ,A )
(IIIb ,C)
(III-IV,C-D)
ANCA (Ia,B)
LN ( III)

Eur J Dermatol 2009 ; 19 (1) : 90-98


Definitely PID with absent B cells IIb B
Definitely
beneficial Sc therapy can reduce occurrence of IIa B
beneficial systemic AEs in selected patients
Maintenance of IgG trough levels >500 in IIb B
hypogammaglobulinemic
Probably CLL with reduces infectious consequences
patients reduced IgG and history of Ib A
Expert monitoring of patients receiving IV D
IGIV infusions to facilitate
management of AEs


Probably Providing home-based IGIV therapy for low IIa B
beneficial risk patients for AEs can improve patient
Definitely QOLwith absent B cells
PID IIb B
beneficial Use of low IgA content IGIV product for III C
IgA-deficient pts having IgG–anti-IgA Ab
-Product changes might improve AE IV D
profiles
-Premedication can improve mild AEs
Probably CLL with reduced IgGIGIV products to
-Matching particular and history of Ib A
specific patient characteristics to reduce
AEs
-Stopping infusion or slowing infusion rate
to facilitate management of AEs


 Starting dose : 400–600 mg/kg every 4 weeks
 trough level > 500 mg/dl or serum IgG level 300 mg/dl over baseline
 Higher trough levels (> 800 mg/dl) may be necessary to prevent chronic
pulmonary changes and enteroviral meningoencephalitis
 Depend on IgG catabolism and/or control over infections, may have to
decrease infusion interval to every 2–3 weeks
 may take ≥3 months to achieve steady state after change in dose
 Monitor serum BUN, Cr, and LFT every 6–12 months
 Keep log of dose, manufacturer, lot number, and reactions for each
infusion
 For patients with rate-related adverse SEs consider pretreatment with:
 Acetaminophen
 Diphenhydramine
 NSAIDs
 Corticosteroids
 Consider subcutaneous IVIg in patients with frequent adverse reactions


Product pH after IgA content ( μg/ml ) Stabilizer or Indication§
reconstitution added regulator
Carimune NF 6.6 720 Sucrose PI , ITP
Carimune NF 6.6 720 Sucrose PI ,ITP
Flebogamma 5-6 50 D-sorbitol PI ,ITP
Gamimune N 10% 4.25 Traces Glycine PI,ITP,BMT,HIV
Gammagard 5% S/D 6.8 2.2 2% Glucose PI,ITP,CLL,KD
Gammaraas 4 <70 sorbitol PI,ITP,CLL,KD
Gammagard liquid 4.6-5.1 37 Glycine PI
Gammar-P 6.8 25 Sucrose PI
Gamunex 4-4.5 46 Glycine PI
Iveegam EN 6.4-7.2 10 Glucose PI,KD
Octagam 5.1 100 Maltose PI
Panglobulin NF 6.6 720 Sucrose PI,ITP
Polygam S/D 6.8 2.2 Glucose PI,ITP,CLL,KD


Brand concentration price
Flebogamma 2.5g/50 cc 7,123 B
5g/100 cc 14,185 B
10g/200 cc 27,721 B
gammaraas 2.5g/50 cc 5,226 B
5g/100 cc 11,831 B

 Premedication
 sometimes but not always required
 Paracetamol and antihistamines can be useful
 Rarely may require corticosteroids
 Infusion

Starship Children’s Health Clinical Guideline

 Infused rate 0.01-0.02ml/kg/min for first 30
mins. ( BW 50kg,30-60 cc/hrs.)
 If not any discomfort rate may be increased
up to 0.04 ml/kg/mins.( BW 50kg,120cc/hrs.)
 If tolerated , rate may be higher
 If adverse effects occur rate should be
reduced or interrupted until symptoms
subside
 infusion may be resumed at rate which is
tolerated by patient

 No comparative data among different brands
 salt and sugar content, osmolality, total volume
infused, rate of infusion, concentration, and
total dose of IVIG infused appear to be
associated to side-effects
 usually transient and selflimited, often arise
during first hours of infusion,but can occur up to
72 h following infusion
 Rate-related
 Chills, Headache, Back pain, Myalgia, Malaise,
fatigue, Fever, Pruritus, Rash, Nausea, vomiting,
Tachycardia, Chest pain or tightness, Dyspnea,
Hypotension/hypertension

 possible consequences of low-level
aggregation of IgG, immune complex
formation and complement activation or, in
certain cases, to sugar content of IVIG
product
 Overcome by reducing rate of infusion,
administering corticosteroids,
antihistamines, NSAIDs, and/or
acetaminophen before beginning infusion


 Severe headaches
 Aseptic meningitis :
 may occur after first 24–72 h of high-dose IVIG
treatment, last for up to a week
 particularly in migraine
 dose-related (rarely seen following replacement doses)


 Azotemia
 Acute renal failure
 proximal tubular dysfunction
 reversible in almost all cases
 most cases ,transient increase Cr, recover completely
within days or weeks after end of IVIG treatment
 osmotic pressure caused by stabilizing agent
 Risk factors : male , age 65 years, pre-existing renal
disease, DM, high BP, hypovolemia, obesity, high
infusion rate
 Prevention : low IVIG concentrations (5% ), low
osmotic load (glycine ), infusion rates should be slow
 70- 90% of the renal SE associated with sucrose-
containing IVIG

 Thrombosis/cerebral infarction
 Rare ( incidence 0.6% )
 Risk factors : prior Hx of stroke, carotid artery
stenosis, chronic HT, high blood viscosity states
 Pulmonary embolism,DVT
 More rarely
 Risk factor :Hx of prior thrombosis, immobilization ,
hyperviscosity state
 Myocardial infarction
 risk factor :HT, DM, CAD,Hyperviscosity
 Posterior leukoencephalopathy syndrome


 especiallyin patients with low IgA levels
 current improvement in IVIG quality, the
incidence of problems with anti-IgA Ab is less
problematic than previously, and their
presence does not preclude use of such IVIG
preparations


 Cardiac rhythm abnormalities
 Coagulopathy
 Hemolysis – alloantibodies to blood type A/B
 Cryoglobulinemia
 Neutropenia ( transient ,D4-5 )
 Decrease lymphocyte counts, particular CD4
 Alopecia
 Uveitis
 Noninfectious hepatitis


 Mode of action of IVIg
 Functional blockade of Fc receptors
 Auto-Ab neutralization and inhibition of auto-Ab
production
 Complement inhibition
 Modulation of cytokine and cytokine antagonist
production
 Activation or functional blockade of death receptor
Fas (CD95)
 Modulation of dendritic cell properties
 Increased expression and signalling through inhibitory
Fc-receptor, Fc gamma RIIB
 Enhancing steroid sensitivity ( enhancement
glucocorticoid receptor-binding affinity )

 FDA-approved indication for IVIg
 primary or secondary
hypogammaglobulinaemias
 paediatric HIV infection
 chronic B-cell lymphocytic leukaemia
 bone marrow transplantation
 ITP
 Kawasaki disease

 Administration
 before initiating therapy with IVIG
 check LFT, renal function,CBC and viral hepatitis screen
 measure Ig levels to exclude IgA deficiency, high titres of
RF ,and cryoglobulinaemia
 On the day of infusion
 monitored (BP HR, temp.) before infusion, every 15 min
,
for first hour of infusion, and every 30 min for rest of
infusion
 Initial IVIG infusions are usually initiated at slow rate,
if tolerated, then increased every 15 min, and then
progressively accelerated in absence of SE
 After 2–3 successful infusions, initial rates are often
accelerated

 Dose
 Replacement therapy : 400-600 mg/kg
 Immunomodulatory indication : 2g/kg
 Drug interaction
 No drug interaction
 Not adminisitered at the same time as
attenuated lived vaccines (MMR)

Intravenous immunoglobulin

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Editor's Notes