3/29/2014 Update on Practical Aspects of Gammaglobulin in PID

3/29/2014
Update on Practical Aspects of
Gammaglobulin in PID
Jack Routes MD
Professor of Pediatrics and Medicine
Chief, Allergy and Clinical Immunology
Medical College of Wisconsin
Disclosures/Attestation
• Baxter Pharmaceuticals: PI initiated grant
• NIH
Learning Objectives
• To know the risk factors for the minor and serious
adverse effects of intravenous gammaglobulin
(IVIG).
• To be knowledgeable in the use of IVIG or
subcutaneous immunoglobulin (SCIG) in the
treatment of primary immunodeficiency disorders
(PIDD).
• To understand the advantages and disadvantages
of IVIG or SCIG in the treatment PIDD.
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Table Summary of Ig
Preparations in USA
http://primaryimmune.org/
treatment-information/immunoglobulin-products
FDA Indications: IVIG
• Treatment of primary immune deficiency disorders (PIDD)
• Treatment of ITP
• Prevention of coronary artery aneurysms in Kawasaki’s
Disease
• Chronic inflammatory demyelinating polyneuropathy
• Prevention of bacterial infections in patients with CLL
• Prevention of pneumonitis and GVHD following bone
marrow transplantation
• Kidney transplantation (ABO incompatible, high Ab
recipient)
• Reduction in bacterial infections in children with HIV-1
infection
Common Uses IVIG/SCIG
•
•
•
•
•
•
•
•
•
•
•
•
Primary immunodeficiency diseases (that result in defect in antibody
responses)
Secondary immunodeficiency conditions (with impaired antibody responses)
B-cell leukemia
Use of chemotherapy or radiotherapy
Autoimmune syndromes
Hematologic: ITP, autoimmune hemolytic anemia
Rheumatologic: RA, vasculitis, Kawasaki disease, uveitis, SLE
Endocrinologic: Autoimmune diabetes mellitus, Graves ophthalmopathy
Neurologic: Guillain-Barre´ syndrome, chronic inflammatory demyelinating
polyneuropathy, myasthenia gravis, dermatomyositis
Dermatologic: TEN, Steven-Johnson syndrome
Kidney transplantation (ABO incompatible, high Ab recipient)
Infectious diseases
– CMV
– Rotavirus
– Parvovirus B19
– HIV infection
JACI: 2010;125:S314-23
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Classification for PIDD using IVIG/SCIG
Category
B cells
IgG Content
IgG Quality
Examples
I
Absent/Dec
reased
Absent
Absent
Agammaglobulinemia
SCID
II
Present
Low
Low
Hyper IgM Syndrome (all forms)
CVID
III
Present
Normal
Low
NEMO
Specific Ab Deficiency
IV
Present
Low
Normal
Transient Hypogam. Infancy
adapted from: http://www.immunodeficiencysearch.com/ivig-replacement#!__ivig-replacement
Background Questions
• What is the optimal dose of antibody
replacement in XLA and CVID?
– Adjustment of dose based on trough levels?
– Adjustment of dose based on break-through
infections? (treat the patient not a level?)
• Does Ab replacement therapy prevent chronic
lung disease and sinus disease
Meta-analysis: IVIG/SCIG
• Meta-analysis SCIG (13 studies) or IVIG (17 studies):
major focus on relationship between serum IgG and
pneumonia
• For every increase in 100 mg/dl trough, 27% decrease in
incidence pneumonia
• Incidence pneumonia associated with level of 500 mg/dl
was 5 fold increased vs. 1000/mg/dl
• Increase 121 mg/dl trough for every increase of 100
mg/dl/month (IVIG); less (.89 mg/dl) for SCIG.
• Recent Canadian consensus document: recommended
trough level of at least 700mg/dl
Clin. Exp. Immunol. 169: 172–181, 2012 (SCIG) and Clin. Immunol. 137:21-30, 2010 (IVIG)
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Background
• Hypothesis: each patient requires individualized dose to
prevent infection
• Prospective study of 90 patients with CVID and 15
patients XLA over 22 years
• Single center
• Dose IgG (SCIG/IVIG) increased based on “break
through infections”
• Relationship between dose, trough IgG and infection free
intervals examined
J. Allergy Clin Immunol 125:1354-1360, 2010
Study Design
• Initial dose: 0.4 mg/kg or 0.6mg/kg/month (bronchiectasis,
BE)
• Increase dose IgG-0.15mg/kg/month
– 1 serious infection/yr- requires IV Abx
• (“Infection score 3”-serious infection)
– 3 moderate infections/year-requires oral Abx or
conjunctivitis.
• (“Infection score 2”-moderate infection)
J. Allergy Clin Immunol 125:1354-1360, 2010
Outcome Measurements
• Determined the dose/mean trough level to
prevent infection (to an acceptable rate) for a
period of one year
– Infection score <4.5
– Infection score <2.5
– Infection score =0
• 885 periods, 741 patient years
J. Allergy Clin Immunol 125:1354-1360, 2010
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Outcome Measurements (cont.,)
• Also analyzed patients on basis of:
– dx (XLA, CVID)
– Bronchiectasis (BE)
– Splenomegaly
– Clinical phenotype:
• No other disease, enteropathy, cytopenias,
polyclonal lymphoproliferation,
autoimmune, malignancy
J. Allergy Clin Immunol 125:1354-1360, 2010
Results
• Weak but statistically significant relationship between
dose or trough of IgG required to prevent infection at
ANY of the 3 infection scores
• Dose required to prevent infection was unique to the
individuals and influenced by secondary complications
• The presence of ANY disease related phenotype
required a higher dose of IgG to prevent infection
J. Allergy Clin Immunol 125:1354-1360, 2010
Results (cont.,)
• Compared to pts without bronchiectasis (BE),
pts. with BE required about a 2 fold higher
dose to maintain an equivalent trough IgG
• Infection scores in patients with and without
BE were similar
• Patients with splenomegaly also required a
higher dose to maintain equivalent trough
levels
J. Allergy Clin Immunol 125:1354-1360, 2010
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Summary
• The high degree of patient heterogeneity
contributes to distinct doses of Ig required to
prevent infection in CVID
• Certain conditions (splenomegaly, BE) require
higher doses to achieve similar troughs as
patients w/o these conditions
• When dosing IgG replacement, you treat the
patient not a level.
Study Background
• Multicenter prospective study of 224 patients
with CVID
• Define spectrum of illness at the clinical onset
and over follow-up (mean time: 11 years)
• Long term effects of immunoglobulin
treatment.
J. Clin. Immunol. 27: 308-316, 2007
Results
• Mean age at the time of diagnosis was 26.6
years.
• The mean age at the onset of symptoms was
16.9 years, implying a mean diagnostic delay
of 8.9 years.
• Morbidity due to CVID, including chronic lung
and sinus disease increased with time
despite Rx with IVIG
J. Clin. Immunol. 27: 308-316, 2007
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Chronic Lung Disease and Sinus Disease
Progress Despite Ab Replacement
Chronic Lung Disease
N=224 pts. (CVID)
Mean f/u 11 yrs.
Chronic Sinus Disease
J. Clin. Immunol. 27: 308-316, 2007
and J Clin Immunol. 31:315-22, 2011
At Dx
Development during F/u
Safety of IVIG Against
Infectious Agents
Viral Safety-Donor Restrictions
• HCV outbreak from IVIG (1984-USA) changed FDA
requirements for IVIG production
• Donors are not from large metro areas (note: each lot of
IVIG/SCIG pooled serum of at least 1,000 donors, some
preparations >10,000 donors)
• Not lived in Great Britain > 6mos 1986-present
• Careful H&P-not acutely ill, exclude known high risk groups
• Screened for HIV-1 p24 Ag, HBVAg, antibodies to HIV-1/2,
syphilis, HCV and PCR for HBV
• Units are not released for 6 months until donor has been
retested for above pathogens
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Safety Against Pathogens
• Heat Rx with stabilizers
• Detergent solubilization (enveloped viruses)
• Caprylic acid (enveloped viruses)
• Pepsin and low pH
• Deep filtration/nanofiltrations: deep filtration
common to all IVIG and thought to remove
prion proteins
Factors in IVIG Influencing
Adverse Events
• Sodium content
• Type and concentration of sugar
• Osmolarity and osmolality
• pH
• Volume Load
• IgA concentration
• Lyophilized vs. liquid?
• Dose: Immunomodulatory (2gm/kg/month) vs.
Replacement (0.4-0.6 gm/kg/month)
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Typical Infusion Rates IVIG
• Children < 6yo: 0.5mg/kg/hr increase by 0.5
mg/kg/hr every 15min up to MAX of 3mg/kg/hr
• Older Children/Adults: 0.5mg/kg/hr increase by
0.5-1 mg/kg/hr every 15min up to MAX of
4mg/kg/hr
IgG Preparations: SCIG vs IVIG
• Aggregated Igs likely responsible for many
minor adverse events (AE)
• Newer preparations IVIG markedly reduced
aggregated Igs
• Subcutaneous only Ig (SCIG) preparations
SHOULD NOT be given IV (Hizentra in US)
• Currently Gammagard Liquid, Gamunex-C,
Gammaked for SCIG and IV routes
• IVIG preparations appear to be safe given via
sc route (not FDA approved)
AE to IVIG
• Most commonly occur during initiation of IVIG
• Recent bacterial infection increased AE
• Depending on IVIG used, some start with
lower concentration IVIG (5%) with first dose
• Low infusion rates initial dose (0.5mg/kg/min1.0 mg/kg/min increase 15’-30’ to maximum
of 2.5 mg/kg/min)
• Healthy older children/adults may tolerate
higher infusion rates with later infusions
(4mg/kg/min)
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Common AE to IVIG
• Most AE infusion rate related
• Headache (most common), anxiety
• Fever and/or chills, flushing
• Tachycardia and/or palpitations
• Chest tightness/pain, shortness of
breath/bronchospasm
• Nausea, abdominal pain
• Back pain, myalgias, arthralgias
• Mild hypotension
Adverse Events IVIG: Children
• Prospective study of 348 infusions in 58 children
• Headache most common AE
• Delayed AE more common than immediate AE
Arch. Dis. Child. 2006;91;651-6
Treatment of Mild Adverse Events
• For immediate reaction: stop infusion, give an
antihistamine and NSAID or acetaminophen
• Resume infusion in 15’-20’ at slower rate
• Consider pretreatment if problem persists:
antihistamines, NSAI and corticosteroids
• Make sure patient well hydrated before infusion
• Recommend non-sedating anti-histamines if adult
and driving (not Benadryl!)
• Consider alternative brand of IVIG or SCIT if
problem persists
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Adverse Reactions IVIGAseptic Meningitis
• More common with immunomodulatory doses
of IVIG (2 gm/kg)
• Prior hx migraine risk factor
• Sxns usually develop within 24h of infusion
• Nuchal rigidity, headache, photophobia--fever uncommon
• CSF: increased IgG/pleocytosis
Adverse Reactions :
Possibly Related to IgA in IVIG
• Most AE do not appear to be related to IgA content in
IVIG
• IgG or IgE Abs in patient directed against IgA in IVIG
• Immunologic mechanisms
– Anaphylactic: IgE Abs to IgA
– Serum sickness like illness
• Systemic reactions with administration of IVIG or
within 72 hrs—most occur in adults.
• Predisposed patients: Specific antibody deficiency
with IgA deficiency (< 10mg/dl), ? CVID patients with
absent IgA
• Most (all?) CVID patients with absent IgA cannot
make specific IgE
• Consider substituting low IgA product or SCIG
( JACI 129:628-634, 2011)
Severe Adverse Reactions IVIGCardiovascular system
• Thromboembolic: Deep vein thrombosis,
pulmonary embolism, stroke, central retinal
vein occlusion
• Myocardial ischemia/infarction
• Stroke
• Pulmonary edema
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Severe Adverse Events (SAE) IVIG:
Cardiovascular system
• Etiology unclear-likely increased viscosity of
blood
• IVIG risk factors
– High osmolarity or high salt concentration
– Lypholized product?
• FDA states insufficient data to clearly implicate
lyophilized products
– High infusion rate
– Immunomodulatory doses of IVIG
SAE Patient Risk Factors:
Cardiovascular System
• Dehydration
• Renal disease
• Diabetes
• Pre-existing cardiovascular disease
• Advanced age
• Prior thromboembolic events
• Patient immobilization
AE: IVIG-Renal AE
• Varied from mild azotemia to acute renal failure, osmotic
nephrosis and death
• Patient risk factors:
– Age (mean 60.5 yrs)
– Pre-existing renal disease
– Diabetes mellitus
– Dehydration
– Sepsis
– Other nephrotoxic drugs
• IVIG risk factors:
– 90% occurred with sucrose-containing IVIG!!!!!
– High osmolarity IVIG also risk factor
– Most received immunomodulatory doses of IVIG
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SAE: IVIG-Renal Mechanism
• IVIG acute renal failure usually occurs within 1 week of
IVIG
• Oliguric > non-oliguric renal failure
• 30% require short-term hemodialysis
• Majority return to normal renal function within 2 weeks.
• Acute Renal Failure Bx: Vacuolization and swelling of
proximal tubules consistent with osmotic nephrosis
• Sucrose is not metabolized by the kidney and accumulate
at tubular epithelium leading to accumulation, osmotic
damage/nephrosis
Summary: SAE and IVIG
• High Risk Patients: Extremes of age, preexisting heart or renal disease, diabetes,
dehydration
• Dose of IVIG (Immunomodulatory dose at
greater risk)
• Avoid high salt, high osmolarity, sucrose
containing IVIG in these patients
Advantages SCIG vs. IVIG
• Decreased systemic side effects
• Possible reduction AE due to anti-IgA Abs
• More consistent levels of IgG in blood-no IgG
“trough” levels
• IV access is not needed
• Easier and likely safer administration at home
• Improved quality of life
• Some believe safer in patients with or prone to
develop renal disease (acute protein load), heart
disease or other risk factors
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Contraindications SCIG
• Severe thrombocytopenia
• Bleeding disorder
• Anticoagulant therapy
• Diffuse severe skin disease (severe
eczema)
• Limited subcutaneous tissue
Disadvantages SCIG vs. IVIG
• Local side effects (swelling, erythema, itching) at
the site of infusion is common
• Poor choice in child/adult that is needle phobic
• Increased long-term exposure to needles
• Assuring patient compliance (home
administration)
• Need for pump to deliver Ig
SCIG-PK
• Dose absorbed and redistributed slowly
• The amount of IgG administered over time is
generally equivalent
• FDA mandated AUC equivalency for Vivaglobin
requiring 1.37X dose of IVIG (trough IVIG: 768
mg/dl; trough SCIG 1040 mg/dl)
• Mean half life 40.6 days
• Approximately 6 months of therapy is needed to
achieve a steady state
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Serum Levels IgG: IVIG vs. SCIG
A.
B.
IVIG
SCIG
SCIG: Establishing the Regimen
• Establish dose: if new patient (400-600
mg/kg/month); if on IVIG some use same dose
while others correct for AUC (1.37X IVIG dose)
• Patient preferences
– Number infusions per week (generally
1x/week)
– Volume per infusion
– Number of sites per infusion (simultaneous
sites or rotate sites)
– Volume per site
– Total time per infusion
SCIG: Infusion Rate & Volume/Site
• FDA Trial: limits 20 ml/hr and 15 ml/site
(published 20-35 ml/site)
• Berger reports mean 0.176 ml/site/hr average
infusion (12 ml/hr-70 Kg adult; 3.5 ml/hr-20-kg
child)
• Larger volumes may be given over longer period
of time
• Trend is for faster infusion, some patients “push”
SCIG and do not use pump
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SCIG: Local Reactions
Infusion-site Reactions (%)
• Swelling at site
of infusion most
common side
effect
• Mild rarely
requires
discontinuation
• Decreases with
time
Immunol Allergy Clin N Am 28 (2008) 779–802
SCIG: Where to Administer
• Careful instructions to patients with clinic
administration until competent and sure no
serious AE (first 2-4 infusions)
• Anterior abdominal wall to flanks (most frequent),
anterior or inner thighs, backs of arms
• Guideline: site ok if can “pinch and inch”
• Most important: draw back syringe BEFORE
administering Ig
• Reminder: the FDA approved forms of SCIG
cannot be used for IVIG
SCIG: Safety and Efficacy
• Several studies indicate similar efficacy to
IVIG
• Appears to have less systemic side effects
than IVIG
• Several studies suggest better QOL on
SCIG vs IVIG
• Alternative therapy in patients who desire
home therapy or have serious systemic AE
with IVIG
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Brand Name: Which is Better?
Immunol Allergy Clin N Am 28 (2008) 765–778
• No convincing studies that one brand of IVIG is better
at reducing infection than another
Further Reading
• Immunology Clinics of NA, Nov. 2008: Entire November
issue devoted to replacement Ig
• JACI 117: S525-553, 2006: Evidence based review by
AAAAI
• Concise Review. Bringing immunoglobulin knowledge up
to date: how should we treat today? Clin Exp Immunol
166:16-25, 2011.
• Concensus review on use of IVIG. Clin Immunol
135:255-263, 2011.
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