2. Introduction
• IVIG is a fraction purified from plasma.
• Principally contains IgG in a form that can be safely administered
intravenously.
• Prepared from pooled plasma from 3000-10,000 healthy donors.
• The large number of donors in the pool increases the number of
antibody activities in the preparation.
• Products prepared by different manufacturers have differing
contents of IgA, traces of other proteins and stabilizers.
• Product to product and lot to lot variation in specific antibody titers is
likely.
3.
4. Safety from blood-borne pathogens
• All products in U.S. are believed to be free from all
known pathogens.
• No products produced with the current safety measures
have ever been reported to have transmitted a blood
borne disease.
• However unknown agents may still be present.
• CDC guidelines;
– Caution is still warranted with the use of IVIG.
– IVIG should not be considered totally benign.
– Patients receiving IVIG should be monitored at regular intervals.
5. Adverse Reactions
• 5-20% IVIG infusions are associated with
adverse reaction.
• Majority are rate-related and mimic one or more
features of anaphylactoid reaction.
– Chills –Flushing –Tachycardia –Headache
– Chest tightness –Shortness of Breath
– Nausea/Vomiting.
• Most are non-life threatening; reduce rate or
temporarily pause the infusion.
6. Adverse Reactions
• True anaphylaxis can occur in completely IgA deficient
patients.
• Pre-formed IgE or IgG antibodies against IgA are
responsible for this reaction.
• Patients with partial IgA deficiency are not at risk.
• Treatement with pre-meds;
– Acetaminophen; 30 mins prior to infusion.
– Diphenhydramine
– Corticosteroids; PO or IV frequently used prophylactically.
7. Renal complications
• >100 cases of acute Kidney injury reported with IVIG infusion.
• >90% cases occurred with sucrose containing products.
• Pathogenesis believed to involve;
– Osmotic uptake of sucrose by tubular cells causing swelling and
obstruction of tubules.
– Increased blood viscosity and thus reduction in renal flow.
– Immune complex deposition.
• Clinical manifestations vary from asymptomatic rise in serum
creatinine to anuric renal failure.
• Spontaneous resolution typically occurs within four to eight days.
8. Renal complications
• Risk factors for this adverse reaction include;*
– Renal insufficiency
– Diabetes Mellitus.
– Dehydration.
– Age >65.
– Sepsis.
– Paraprotienemia.
– Concomitant use of nephrotoxic agents.
1. Avoid sucrose containing products in patients with pre-existing renal
disease.
2. Patients should be adequately hydrated.
3. Administration of IV fluids before IVIG infusion may be useful in preventing
renal complications.
*IVIG adverse effects and safe administartion
Orbach et al; Clinical Reviews in Allergy and Immunology, Vol 29, 2005
9. Thrombotic complications
• Multiple cases of serious thromboembolic events following IVIg therapy
have been reported.*
*IVIG adverse effects and safe administartion
Orbach et al; Clinical Reviews in Allergy and Immunology, Vol 29, 2005
• Majority of cases had risk factors for thromboembolism or received high
doses or high infusion rates.
• Precautionary statements have been published and can be found at
http://www.fda.gov/medwatch/safety/2002/safety02.htm#igiv.
• High concentrations of IgG can raise the viscosity of serum and whole
blood.*
• Local thrombosis at infusion site with extension to larger veins as well as
remote thromboembolic events may occur.*
• Transient ischemic attacks, transient angina pectoris, as well as stroke and
myocardial infarction have been reported.*
10. Thrombotic complications
• The use of schemes in which infusion rate is increased
“as tolerated” should be avoided.
• Should be used with caution in;
– Elderly patients.
– Patients with increased risk of hyperviscosity syndromes.
– Patients with increased risk of thromboembolic disease.
• When instituted 2g/kg should be given over 5 days (400
mg/kg/d) and not more than 50 mg/kg/hr, in no less than
8 hrs.*
*IVIG adverse effects and safe administartion
Orbach et al; Clinical Reviews in Allergy and Immunology, Vol 29, 2005
11. Hematologic complications
• Several cases of Coombs positive hemolytic anemia
have been reported after IVIG infusion.
• Episodes are invariably self-limited, although may
occasionally be severe.
• More significant hemolysis with reduced haptoglobin,
increased serum LDH and transient reticulocytosis may
occur following high dose infusions.
• Transient neutropenia have also been reported and is
not likely to increase the risk of infection.
IVIG adverse effects and safe administartion
Orbach et al; Clinical Reviews in Allergy and Immunology, Vol 29, 2005
22. Indications for use.
• FDA approved for 6 conditions:
1. Idiopathic thrombocytopenic purpura.
2. Primary immunodeficiency states.
3. Secondary immunodeficiency in CLL.
4. Pediatric HIV infection.
5. Kawasaki syndrome.
6. Prevention of GVHD and infection in adults.
26. A controlled trial of high-dose intravenous immunoglobulin
infusions as treatment for dermatomyositis.
Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al.
NEJM 1993;329:1993–2000.
• A double blind, placebo controlled.
• 15 patients (18-55 years) biopsy-proven, treatment-resistant.
• Randomly assigned to receive IGIV (#8) or placebo (#7) every
month for 3 months, with option to cross over to alternative therapy
for 3 more months after a wash out period of 1 month.
• Continued to receive prednisone (mean dose 25mg/day),
unchanged for 3 months before and after therapy.
• No other immunosuppressants during that time.
27. A controlled trial of high-dose intravenous immunoglobulin
infusions as treatment for dermatomyositis.
Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al.
NEJM 1993;329:1993–2000.
• Histological and immunopathological improvement
sought in repeated muscle biopsies.
• Clinical response was gauged by assessing changes in:
– muscle strength (18 proximal muscle groups), using a modified
Medical Research Council (MRC) scale, a well-validated scale in
the treatment of neuromuscular disorders.
– neuromuscular symptom scores that provide a picture of the
daily living activities (20 activities).
– the rash, using photography with unchanged lighting conditions.
28.
29.
30.
31. A controlled trial of high-dose intravenous immunoglobulin
infusions as treatment for dermatomyositis.
Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al.
NEJM 1993;329:1993–2000.
32.
33.
34.
35. IVIG in Dermatomyositis
• IVIG is not recommended as monotherapy for
dermatomyositis.
• IVIG is recommended as an option, in combination with
other agents for treatment resistant (conventional
immunosuppressive therapies) patients.
• IVIG is recommended in combination with other agents,
as a steroid sparing option.
• IVIG may be considered in conjunction with other agents
for treatment of severe, life-threatening dermatomyositis.
Guidelines for use of IVIG for Neurologic conditions
Feasby et al; Transfusion medicine Reviews, Vol 21 No 2, Suppl 1 April 2007:
pp S57-S107
38. IVIg in Inclusion Body Myositis
• The available evidence shows some
improvement with IVIG, but no evidence of
sustained benefit.
• IVIG is not recommended for treatment of
IBM.
Guidelines for use of IVIG for Neurologic conditions
Feasby et al; Transfusion medicine Reviews, Vol 21 No 2, Suppl 1 April 2007:
pp S57-S107
41. IVIg in Polymyositis.
• IVIG may be considered among the
treatment options for polymyositis in
patients who fail to respond to first-line
therapies.
Guidelines for use of IVIG for Neurologic conditions
Feasby et al; Transfusion medicine Reviews, Vol 21 No 2, Suppl 1 April 2007:
pp S57-S107
43. A study of 20 SLE pts with IVIg clinical and serologic response
Levy Y, Sherer Y, Ahmed A, Langevitz P, George J, Schoenfeld Y et al
Lupus 1999;8;705
• 20 SLE patients were treated with high-dose (2 g/kg)
IVIg monthly, in a 5-d schedule.
• Each patient received between 1-8 treatment courses.
• They were evaluated for;
– Clinical response
– Systemic Lupus Activity Measure (SLAM) score before and after
IVIg
– levels of antinuclear antibody (ANA)
– dsDNA (double-stranded DNA)
– SS-A or SS-B, ENA (extractable nuclear antigens)
– C3 and C4 levels before and after the treatment, and before and
after each treatment course.
44. Clinical details of the patients included in the study prior to IVIg treatment
46. A study of 20 SLE pts with IVIg clinical and serologic response
Levy Y, Sherer Y, Ahmed A, Langevitz P, George J, Schoenfeld Y et al
Lupus 1999;8;705
• There was a tendency towards abnormal levels of
complement and Abs before IVIg courses among the
treatment responders compared with the non-responders.
• Similarly treatment responders tended to have
normalization of their abnormal levels more than the
non-responders.
• These differences were found statistically significant only
with respect to C4 and SS-A or SS-B levels before IVIg
courses.
47. A study of 20 SLE pts with IVIg clinical and serologic response
Levy Y, Sherer Y, Ahmed A, Langevitz P, George J, Schoenfeld Y et al
Lupus 1999;8;705
• A beneficial clinical response following IVIg treatment
was noted in 17 out of 20 patients (85%).
• Few clinical manifestations responded more to
treatment:
– arthritis,
– fever,
– thrombocytopenia,
– neuropsychiatric lupus.
• In 9 patients evaluated before and after IVIg, mean
SLAM score decreased from 19.3+/-4.7 to 4+/-2.9
(P<0.0001).
48. Mean dose 29.7 mg/day before IVIg
Mean dose 13.8 mg/day after IVIg
Mean SLAM 19.3 before IVIg
Mean SLAM 4 after IVIg.
52. 14 Lupus pts;
Proliferative
glomerulonephritis
Induction therapy
Cyclophosphamide
+
Prednisone
5 pts
•IVIg (0.4 g/kg) monthly x 18 mths
9 pts
cyclophosphamide every 2 mths x 6 mths
then every 3 mths x 1 yr
53. no differences in kidney function, proteinuria, or
nephritis between the two treatment groups.
54. IVIg in Lupus.
• Not recommended as 1st line therapy.
• Can be considered in management of
Lupus;
– In severe life or organ-threatening
manifestations (cerebritis, nephritis*), when
conventional immunosuppression is either
unresponsive or contraindicated.
– Life threatening cytopenias such as
thrombocytopenia not responsive to steroids.
*Use non sucrose containing formulation
56. IVIg in APS
• Use of IVIg in APS (mostly hematological manifestations)
is found as case reports.*
*Sherer, Y., Levy, Y., and Shoenfeld, Y. (2000), Rheumatology 39, 421–426.
57. DAH with APA
• Diffuse alveolar hemorrhage (DAH) due to pulmonary
capillaritis in the setting of high titer APA.
• No evidence of acute thrombosis as a cause of DAH.
• A case series (4 pts) and literature review (1965-2003) of
total 17 pts.
58. DAH with APA
• All patients had a rapid clinical improvement to high dose
corticosteroids.
• Recurrence was noted with subsequent tapering of
steroids requiring alternative forms of
immunosuppression including; cyclophosphamide,
cyclosporine or MMF.
• In case of failure of conventional immunosuppression
IVIg was used (3 cases) with stabilization of recurrent
disease.
59. IVIg in CAPS
Catastrophic Antiphospholipid Syndrome: Where Do We Stand?
Doruk Erkan, Ricard Cervera, and Ronald A. Asherson
ARTHRITIS & RHEUMATISM
Vol. 48, No. 12, December 2003, pp 3320–3327
60.
61. APA in Pregnancy
• Pregnant women with APS are at increased risk for
– Maternal thrombosis
– Fetal loss after 10 weeks of gestation
– Uteroplacental insufficiency
– Intrauterine growth restriction
– Preeclampsia
• Most reports about the use of IVIg in APS have focused
on the obstetric complications (mainly recurrent
abortions).
62. A multicenter, placebo-controlled pilot
study of intravenous immune globulin
treatment of antiphospholipid syndrome*
during pregnancy.
The Pregnancy Loss Study Group.
Am J Obstetrics & Gynecology
2000 Jan;182(1 Pt 1):122-7.
* All pts met criteria for APS according to Sapporo criteria.
63. All patients (n=16)treated with
Low dose Aspirin
+
Heparin
1g/kg IVIg q month
(n=7)
until 36 weeks’ gestation
Placebo
(n=9)
until 36 weeks’ gestation
Baseline Characteristics
64. Results
• No pregnancy losses were observed in the 2 groups.
• Some non-significant differences were observed.
65. Randomized Study of Subcutaneous
Low Molecular Weight Heparin Plus Aspirin
Versus Intravenous Immunoglobulin in the
Treatment of Recurrent Fetal Loss
Associated With Antiphospholipid Antibodies
Giovanni Triolo, Angelo Ferrante, Francesco Ciccia, Antonina
Accardo-Palumbo, Antonino Perino, Antonio Castelli,
Antonio Giarratano, and Giuseppe Licata
ARTHRITIS & RHEUMATISM
Vol. 48, No. 3, March 2003, pp 728–731
66. 40 pregnant pts
with recurrent abortion (at least 3 occurrences)
and repeatedly positive tests for aCL or LA
IVIg Group
(n=21)
LMWH +
Low dose ASA
Group
(n=19)
ASA stopped at
34 week,
LMWH stopped at
37 week
Stopped at
31week
gestation
67. Major outcomes of pregnancy in the study groups
Treatment with LMW heparin plus low-dose aspirin should be considered
as the standard therapy for recurrent pregnancy loss due to aPL.
68. IVIg in APS
• Not recommended as a standard therapy.
• No role for IVIg in obstetric complications of APS found
in randomized controlled trials.
• IVIg can be considered in special circumstances in APS;
– Marked APS-associated thrombocytopenia (similar to ITP)
– 2nd line therapy in life threatening cases of CAPS
– Subset of pts with Pulmonary capillaritis leading to DAH and
unresponsive to conventional immunosuppressive agents.
70. IVIg for the treatment of Kawasaki disease in children
Oates-Whitehead, R. M., Baumer, J. H., Haines, L.,et al. (2003),
Cochrane Database Syst Rev 4, CD004000
• Meta-analysis of 16 randomized controlled trials of IVIg
in Kawasaki disease.
• Showed a significant decrease in new coronary artery
abnormalities (CAAs) in favor of IVIG, at 30 days
[RR = 0.74, 95% CI 0.61 to 0.90].
• 400 mg/kg/day x 5 days vs. 2 gm/kg in a single dose
showed statistically significant reduction in CAAs at 30
days [RR = 4.47, 95% CI 1.55 to 12.86].
• Significant reduction in duration of fever with the higher
dose
Children fulfilling the diagnostic criteria for Kawasaki disease should be
treated with IVIG (2 gm/kg single dose) within 10 days of onset of symptoms.
71. Prevalence of coronary artery abnormalities in Kawasaki disease is highly
dependant on gamma globulin dose but independent of salicylate dose.
Terai,M, Shulman,ST
Journal of Pediatrics 1997; 131:888
• Meta-analysis of 6 randomized controlled studies.(1629 pts)
Treatment
CA abnormalities
Modality
30 days
CA abnormalities
> 60 days
Aspirin alone 26 % 18 %
IVIg(<1g/kg)+ ASA 18% 14%
IVIg(1-1.2g/kg)+ ASA 16% 10%
IVIg(1.6g/kg)+ ASA 9% 6%
IVIg(2g/kg)+ ASA 4% 4%
2 gm/kg IVGG combined with at least 30 to 50 mg/kg per day aspirin
provides maximum protection against development of coronary abnormalities
after KD.
72. IVIg for relapses of systemic vasculitides associated with ANCA: Results
of a multicenter, prospective, open-label study of twenty-two patients
Martinez V, Chen P, Pagnoux C.; French Vasculitis Study Group
Arthritis Rheum. 2008;58(1):308-17
• 19 WG and 3 MPA pts who had relapsed after
their initial treatment were enrolled.
• Pts were maintained on same regimen with
which they had relapsed and IVIg was added.
• Pts received 0.5mg/kg/day x 4 days of IVIg (total
2gm) every month for total 6 months.
• Pts followed for 24 months.
73. By month 9
Complete remission in 13 of the 22 patients (59.1% [95% confidence interval 0.39-
0.79])
Partial remission in 1 patient (4.5%)
74. IVIg for relapses of systemic vasculitides associated with ANCA: Results
of a multicenter, prospective, open-label study of twenty-two patients
Martinez V, Chen P, Pagnoux C.; French Vasculitis Study Group
Arthritis Rheum. 2008;58(1):308-17
• 8 pts were still in remission at 24 months.
• Median oral prednisone dosage at study
inclusion was 20 mg/day (range 5-500).
• Median oral prednisone dosage at follow-up;
– 15 mg/day (range 0-30) by week 4.
– 8 mg/day (range 0-12) by month 9.
– 3.25mg/day (range 0-10) by month 24.
75. IVIg for ANCA-associated systemic vasculitis (AAV) with persistent
disease activity
Jayne, D.R.W., Chapel,H., Adu,D., et al.
QJ Med 2000; 93:433-439.
• Randomized, placebo controlled trial.
• 34 pts with persistent active AAV despite previous
immunosuppression therapy.
• 17 pts randomized to receive 0.4mg/kg/day x 5 days IVIg (single
course) and 17 to receive placebo.
• Intention was to keep current immunosuppressive drugs unchanged.
• Pts were followed for 12 months.
76. • Vasculitic activity was monitored by Birmingham vasculitis activity
score (BVAS), CRP and ANCA levels.
• Reduction in BVAS >50% after 3 months was defined as treatment
response.
77. IVIg in Vasculitis.
• IVIg is 1st line therapy in management of acute Kawasaki
disease (single dose 2g/kg over 8-12 hrs). [Grade 1A*]
• IVIg may be used in pts with ANCA-associated vasculitis;
[Grade 1B/2B*]
– refractory (not responsive sufficiently to pred/cyclophosphamide)
disease.
– Pts with leukopenia or opportunistic infection and persistent
disease activity to bridge time until further immunosuppression is
reintroduced.
• Little or no evidence for IVIg use in other vasculitides.
[Grade 4C*]
*Intravenous Immunoglobulin Therapy in Vasculitis; Aries PM, Hellmich B, Gross WL
Clinical Reviews in Allergy & Immunology Volume 29, 2005
79. Introduction
• Passive immunization with immunoglobulin fraction of pooled normal
human sera used in the 1950s had a dramatic impact on the
frequency of sepsis in patients lacking immune globulins.
• Doses were limited by IM route of administration.
• Intravenous preparations of immune globulin became available in
1960s.
• These preparations contained protein aggregates that caused
anaphylactoid reactions.
• Today, large scale production of IVIG is carried out using pooled
plasma from thousands of donors.
80. Introduction
• Different manufacturers use various
combinations of precipitation,
chromatography and/or purification steps
to obtain a final preparation that consists
of >95% IgG.
81. WHO minimum standards for IVIG
manufacturing
• Should be extracted from a pool of at least 1000
individual donors.
• Should contain as little IgA as possible.
• Should be modified biochemically as little as
possible and possess opsonizing and
complement-fixing activities.
• Should be free from accumulating preservative
or stabilizers.
82. Safety from blood-borne pathogens
• Meticulous donor screening and selection is done.
• The individual blood units are tested for known viruses
by antigen and nucleic acid testing.
• Also tested for elevated liver enzymes (window period)
• Donated units that pass the tests are held back
(quarantine) until subsequent donation from same donor
is obtained and tests negative.
• The previous donation can then be pooled after nucleic
acid testing is repeated and is negative.
83. Headache
• Headache is most common adverse event reported with
IVIG infusion.
• Most resolve within 24 hrs .
• Some can be delayed in onset by 24-48 hrs.
• Induction of Migraine more likely in patients with prior
history.
• Severe headache with other features of meningeal
irritation/inflammation can be seen with high doses of
IVIG.
84. Hematologic complications
• Incidents far less frequent in the last
decade since efforts have been made to
lower the titers of RBC antibodies in IVIG
preparations.
IVIG adverse effects and safe administartion
Orbach et al; Clinical Reviews in Allergy and Immunology, Vol 29, 2005
85. Mechanisms of Action
• Most “natural antibodies” in healthy people and
hence in the immune globulin pool are
autoantibodies.
• Autoantigens stimulate autoreactive B cells to
produce natural autoantibodies (mostly IgG
class).
• Natural autoantibodies are more polyreactive
than immune antibodies (can bind to various
antigens).
86. Immune regulation.
• Natural antibodies of
immune globulin are
capable of interacting
with idiotypes.
• The formation of idiotype-idiotype
dimers may
account for some clinical
effects of immune
globulin.
87. Six-Month IVIG Utilization by Indication
Indication Total = 243
Category I 13 (5.3%)
Neonatal alloimmune thrombocytopenia (NAIT) 0
X-linked agammaglobulinemia (XLA) 0
Parvovirus infection with blast crisis 3
Other primary immune deficiency disorders presenting with a life-threatening infection, subject to the approval of either Dr. Gilsdorf or Dr.
McMorris
0
Severe combined immunodeficiency syndrome (SCID) 3
Kawasaki Disease 7
Category II 102 (42.0%)
Guillain Barre Syndrome (acute) 5
Chronic inflammatory demyelinating polyneuropathy (CIDP) 9
Multifocal motor neuropathy (MMN) 1
Myasthenia Gravis 4
BMT with prolonged hypogammaglobulinemia 83
Post-plasmaphoresis in pediatric patients due to IgG deficiency 0
Category III 60 (24.7%)
Common variable immune deficiency (CVID) 14
Immune thrombocytopenia 29a
CLL with hypogammaglobulinemia 3
Polymyositis and Dermatomyositis 12
Primary immunodeficiency diseases (other than SCID) 2b
Category IV 1 (0.4%)
Vasculitides 1
