BC Transfusion Medicine Advisory Group

Immunoglobulin Related Reactions:

• Overview of IVIG Related Reactions

• IVIG Related Low-Severity Reactions

• IVIG Related Severe Reactions

• RhIG Related Hemolysis

Transfusion Reaction EducationModule 4

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Speaker

Dr. Doug Morrison

MD FRCPC

Medical Director,

Transfusion Medicine, FH

Disclosure:

Dr Morrison has received speaker honoraria from CSL Behring

and Octapharma.

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Contents of Module 4

• Goals and Objectives of the module

• Overview of IVIG related reactions

• IVIG-related low-severity infusion reactions/side effects

• IVIG-related severe reactions

• RhIG-related reactions

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Goal of Module 4

Goal:To review the signs, symptoms and management of the following immunoglobulin-related transfusion reactions:

•IVIG related low-severity infusion reactions/side effects

•IVIG related severe reactions

•RhIG related hemolytic reactions

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• recognize the signs and symptoms of immunoglobulin-related transfusion reactions

• recommend appropriate management and reporting for these reactions

• direct the laboratory investigation of immunoglobulin-related reactions

• correctly identify and report this reaction type

Objectives of Module 4

On completion of this module, you should be able to:

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Overview of IVIG Related

Reactions

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What constitutes a reportable reaction to IVIG?

• Difficult to define• High prevalence of undesirable symptoms

– Up to 65% of patients– 2-25% of infusions

• Rare events are easily characterized as severe transfusion reactions – Hemolytic Transfusion Reaction, Aseptic Meningitis,

Thromboembolism, Acute Renal Failure, TRALI & Anaphylaxis

• Others…less so….

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Incidence of Transfusion Reactions• Data from clinical trials for licensure

– Not standardized vis-à-vis definitions, data collection & reporting

– Limited size & lack of controls– e.g. a study of 50 subjects has statistical

power to detect only TR that occur with a true frequency of > 6%

– TR incidence per infusion 2 – 20%

• Post-market surveillance– Temporal association not necessarily causal– Under-reporting

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Clinical Trials – Gamunex 10% info from product monograph

PID 3 trials 200 pts• TR per infusion:• 1.7% increased

cough• 0.8% headache• 0.1 % fever• 0.8% pharygitis• 0.5% nausea• 0.5% urticaria

ITP, 2 trials 48 pts• Headache 50% of pts

– Mild 25%– Moderate 21%– Severe 4%

• Vomiting 13% of pts– Mild 10%– Moderate 2%

• Fever 10%• Rash 6% Back pain 6%• Asthenia 4% pruritis 4%• Arthralgia 4%• Dizziness 2%

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Clinical Trials: Gammagard Liquid in PID61 patients – 12 month study ( info from product monograph)

Sign/Symptom By Infusion By Patient

Headache 6.9% 36.1%

Fever 2.3% 21.3%

Fatigue 2.2% 16.4%

Vomiting 1.2% 14.8%

Chills 1.7% 13.1%

Infusion site rxn 1.0% 13.1%

Nausea 1.0% 9.8%

Dizziness 0.8% 8.2%

Pruritis 0.6% 6.5%

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Clinical Trials: Privigen – PID80 patients – 12 month study (info from product monograph)

Sign/Symptom By Infusion By Patient

Headache 8.7% 43.8%

Fever 1.1% 7.5%

Fatigue 2.8% 16.3%

Vomiting 1.3% 8.8%

Chills 1.4% 11.3%

Back pain 1.3% 10.0%

Nausea 2.1% 12.5%

Pain 1.3% 8.8%

Diarrhea 0.5% 6.3%

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Hughes et al. ICE study - IVIG in CIDP. Lancet Neurology 2008; 7 :136-44

Sign/Symptom Patients Infusion Patients Infusion

Headache 32% 5.2% 8% 2.6%

Fever 13% 2.5% 0 0

↑ BP 9% 1.8% 4% 1.0%

Asthenia 8% 0.9% 3% 0.7%

Chills 8% 0.9% 3% 0.7%

Back pain 8% 0.9% 3% 0.7%

Rash 7% 1.2% 1% 0.2%

Arthralgia 7% 1.0% 1% 0.2%

Nausea 6% 0.8% 3% 0.5%

Gamunex n=113 Placebo n=95

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Recognition, management and reporting of IVIG infusion reactions is

unique, because of

– The frequency of undesirable symptoms– The usually mild/transient nature of reactions– The ability to ameliorate the symptoms with

reduced flow rate– The provisions for continuing the infusion with

symptomatic treatment

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IVIG RelatedLow-severity

InfusionReactions

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Low severity IVIG infusion reactions

• Relatively common and rarely serious• Usually mild, transient & rate related• Resembles a systemic inflammatory response:

– Headache, chills, fever, flushing, myalgia, malaise, tachycardia, nausea and vomiting

– Pro-inflammatory cytokines (Tumour Necrosis Factor)– Possibly related to IgG aggregates & dimers– Managed by decreasing infusion rate until symptoms

subside

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“Side Effects” of IVIGNursing Quick reference Guide & IVIG Infusion Guide

• mild transient signs & symptoms• common & rarely serious• resolve with reduced flow rate or medication• mild reactions that do not require D/C of infusion

or reporting to TMS/Lab

Refer to:• product insert• facility policies

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IVIG infusion reaction by severity

Severity SymptomsMild Headache, flushing, muscle aches, shivering, feeling

sick, itching, localized urticaria, anxiety, light-headedness, dizziness or irritability

Moderate Mild reactions becoming worse, fever, rigors, chest, back or abdominal pain, wheezing, non-localized urticaria or rash, vomiting.

Severe Moderate reactions persisting or becoming worse, tightness of the throat, severe headache and shaking, severe breathlessness or wheezing, severe dizziness or fainting, sensation of pressure in the chest or collapse.

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Report to TMS/LabSeverity Resolved by

slowing flow rate

Report to TMS/Lab

mild yes no

no yes

moderate not applicable yes

severe not applicable yes

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Low-severity Infusion Reactions

Cause • Infusion rate too fast• Osmotic changes due to large volume of product• IgG aggregates causing activation of biochemical

mediators, such as complement, TNF• Opsonization of pathogens • Complement activation

Onset • often occur during the infusion, as the rate is increased, however,

• it is not uncommon for symptoms (e.g. headache) to appear as late as 24-48 hours following the infusion.

Frequency • very common (up to 20% of infusions)

Pierce & Jain. Risks Associated with the use of IVIG. Trans Med Rev 2003; 17:241

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Low-severity Infusion Reactions Recommendations:

In-facility patients Mild signs and symptoms that respond to ongoing transfusion care do not need to be reported as transfusion reactions.

Departed out-patient Patients who have left the facility after IVIG infusion should report signs and symptoms to the TMS/lab.

Such reactions are not investigated by the laboratory, but the pathologist may choose to make recommendations for future transfusions.

Recommendations future transfusions:

Any of the following may be warranted:• Reduced infusion rate &/or dosage • Change of product or premedication

Distinguish between Headache & aseptic meningitis

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Safety profile of home infusion of IVIG in neuroimmunologic disorders

• 420 patients over 12 months (2009)• 334 neuroimmunologic disorders• 86 PID• 4076 infusions• Including Gammagard, Gamunex, Privigen• 30 ml/hr → 120 ml/hr

Souayah et al. J. Clin Neuromuscul Dis. 2011; 12 (4): S1-S10

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Souayah et al. 2011… Patients who experienced symptoms (vs other studies)

Sign/Symptom Souayah et al.

By Patient

Other Studies

By Patient

Headache 10.7%

1.1% of infusions

Fatigue, weakness, fever, chills, other infusion related

4.2% 15 – 62%

N/V/diarrhea 3.8% 3 – 24%

Infusion site rxn 2.1% 4 - 33%

Generalized rash 1.9% 6 – 14%

Aseptic Meningitis 0.2% 6.7%

Superficial Phlebitis 0.4%

ARF, VTE, HTR None reported

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Souayah et al. 2011…premedication

• 65.7% of patients received one or more of: – Acetaminophen (1g)– Diphenhydramine (60mg) – Dexamethasone (12 mg)

• 78% acetaminophen & diphenydramine• 5% dexamethasone monotherapy• Incidence of transfusion reactions lower in

premedicated group:– Neuroimmunologic 18.2% vs 29.3% p=0.02– PID 19.5% vs 22.2% p=0.76

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IVIG – related Severe

Reactions

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Signs & Symptoms of Severe IVIG Reactions

Acute Anaphylaxis facial and tongue swelling, chest tightness, airway edema, dyspnea, hypotension, shock, tachycardia, nausea/vomiting, widespread rash (>2/3 body).

TRALI Hypoxia with non-cardiogenic pulmonary edema +/- hypotension or fever, during or within six hours of infusion

Acute orDelayed

Hemolytic hemoglobinuria (red/brown urine), a fall of at least 10 g/L in hemoglobin (Hgb)

Delayed AsepticMeningitis

severe and incapacitating headache with nuchal rigidity, drowsiness, fever, lethargy, photophobia, painful eye movements, nausea/vomiting, deterioration of mental status

Thromboticevents

symptoms related to myocardial infarction, transient ischemic attacks, stroke, deep vein thrombosis

Acute Renal Insufficiency

Oliguria, anuria, edema, increasing serum creatinine, hypertension, back/flank pain, etc.

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Anaphylaxis in IgA Deficiency

• Patients with preformed IgE or IgG directed against IgA – rare!

• Acute onset, within minutes– facial and tongue swelling, chest tightness,

airway edema, dyspnea, hypotension, shock, tachycardia, nausea/vomiting, widespread rash (>2/3 body), anxiety, fever

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“Rate –related” anaphylactoid reactions

by comparison…• May include flushing, tachycardia, chest

tightness or dyspnea, nausea and/or vomiting, anxiety– Unlike true anaphylaxis, associated with ↑BP

• These reactions are not mediated by IgE• Usually occur midway through an infusion• May respond to slower infusion rates• May become less severe with subsequent

infusions of the same product

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Anaphylactoid reactions cont…

• Flushing is common & isolated urticaria may occur:

• ? Complement activation by IgG aggregates or newly formed immune complexes

• ? Presence of active kinins or kallikrein• ? Secretion of prostaglandins by monocytes

stimulated by IgG• ? Crosslinking of Fc receptors & cytokine

release

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Presentation • Anemia with spherocytes & biochemical evidence of hemolysis 1-10 days post IVIG

Pathogenesis • Positive DAT in nearly all patients• anti-A or anti-B recovered in eluate

Frequency • Uncommon but not rare

Risk factors • Non O blood group• High cumulative dose (>100g) IVIG

Reporting • Report reaction to TMS, PBCO, and Manufacturer

IVIG related hemolysis

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IVIG related hemolysis Suggested treatment and recommendations:

Acute HTR:

(<24 hr)

• Stop the transfusion. Do NOT restart.• Report the reaction to the TMS/lab.• IVIG is not returned to the TMS. • Confirm hemolysis: blood film, Hb, LD, bilirubin, haptoglobin• Maintain hydration, monitor creatinine• Rule out DIC• Consult medicine/nephrology• ABO, Rh, DAT, eluate vs A, B, and O screening cells, A1 typing

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IVIG related hemolysis Suggested treatment and recommendations:

Delayed HTR:

(>24 hr)

• Confirm hemolysis and initiate serologic investigations (ABO, Rh, DAT, eluate, etc.)• Notify attending physician• Maintain hydration, rule out DIC, follow Hb, creatinine, etc.• Reassess the need for IVIG therapy.• Consider change of dose and/or alternate manufacturer or infusion route.

Active Monitoring

•Advisory Letter to physicians•CBC, retic, LD, bili & DAT 3-7d post IVIG

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Variable DefinitionOnset within 10 days of IVIG administration

Laboratorysigns

drop in hemoglobin of ≥10 g/L positive DAT AND at least 2 of the following:

- increased reticulocyte count- increased LD level- low haptoglobin level- unconjugated hyperbilirubinemia- hemoglobinemia- hemoglobinuria- presence of significant spherocytosis

IVIG Hemolysis Pharmacovigilance Group CBS CL 2009 - 02 (1 of 2)

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Variable Definition

Exclusioncriteria

history or examination consistent with an alternate cause of anemia, including:

o blood loss, other drug-induced hemolysis, o anemia associated with chemotherapy, o hemolysis associated with an underlying disease

negative DAT absence of other inclusion criteria, in

particular evidence of hemolysis

IVIG Hemolysis Pharmacovigilance Group CBS CL 2009 - 02 (2 of 2)

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IVIG-related Aseptic Meningitis

Risk factors • high-dose IVIG therapy• history of previous migraines • total dose infusion time of < 24 hours

Onset • generally 24 to 48 hours post-therapy• symptoms usually resolve within 3 to 5 days

Frequency • rare

Pathogenesis • Meningeal irritation by IgG

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IVIG-related Aseptic Meningitis

CSF examination

results

• is sterile• has an elevated protein and shows a

pleocytosis ± eosinophilia.

Investigation • Patient samples are not required.

Results of reaction

• meningeal signs and symptoms usually resolve within 3 – 5 days

Reporting • Report reaction to TMS, PBCO, and Manufacturer

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IVIG-related Aseptic MeningitisSuggested treatment and recommendations:

Suggested treatment and recommendations

• Symptoms may be reduced by:– pre-medication with an analgesic or a non-steroidal anti-inflammatory and antihistamine– slowing the rate of administration– Pre & post-infusion hydration

• Suggest reassessment of the need for IVIG

• If necessary, recommend a lower dose and /or a slower rate of infusion.

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IVIG-related Thrombosis reports to Health Canada Oct 1997 – July 2007

Canadian Adverse Reaction Newsletter, January 2008

• 10 strokes, 6 DVT, 4 MI, 2 PE & 1 TIA suspected of being associated with IVIG– 9 of 10 strokes during or within 24 hrs of infusion

– 3 of 4 MI’s occurred during infusion

• 2 patients with PID

• 17 patients receiving “off-label” immunomodulatory Rx

• Gammagard S/D, Gamunex, IVnex & Gamimune N

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IVIG-related Thrombosis Manufacturer warnings

• Post market surveillance

• 2002, Baxter - Gammagard S/D

• 2011, CSL Behring – Vivaglobin– 19 TE episodes reported internationally– “reports that certain IVIG products have higher

levels of procoagulant activity that could predispose patients to thrombosis.”

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IVIG-related

Thrombosis

Rare, possibly multifactorial, due to:

• Increased serum viscosity

• Trace amounts of activated clotting factors (?Xa)

• Susceptible patients:– Elderly, low CO, immobility, paralysis, Hx of

MI, CVA, carotid stenosis obesity, monoclonal gammopathy, dehydration, diuretics, IgG >18 g/L

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IVIG-related Acute Renal Failure

• 88 reports to FDA mid 1980’s & 1990’s– 79 involved IVIG with sucrose stabilizer

– 7 involved glucose or maltose

• >50% of patients Rx for ITP (high dose)• <5% of patients Rx for PID• Osmotic nephrosis with histologic evidence of

swelling/vacuolation of proximal tubular cells• FDA warning persists on product monographs

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IVIG-related Acute Renal Failure…

• Increased risk in patients with:– Preexisting renal disease– Age > 65 years– Volume depletion– Sepsis– Paraproteinemia– Concomitant use of nephrotoxic drugs

• No products now use sucrose as stabilizer

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Presentation • Acute hypoxemia and non-cardiogenic pulmonary edema (ALI) during or within 6 hours of infusion

Pathogenesis • Anti-granulocyte antibodies in IVIG

Frequency • Rare case reports

Risk factors • unknown

Reporting • Report reaction to TMS, PBCO, and Manufacturer

Canadian Adverse Rxn Newsletter October 2008; 18(4):3

IVIG related TRALI

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RhIg-relatedIntravascular

Hemolysis

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RhIG-related Intravascular Hemolysis

• Cangene warning letters re IVH in 2000, 2006 & 2010

• Post-market surveillance 1995-2009– 180 serious events worldwide (11 Canadian)– 58 definite & 59 probable

• 17 fatalities

• Sequelae are RF, DIC

• Frail, elderly patients cope poorly with IVH

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RhIg – Treatment of ITP in Rh

Positive Patient – Cangene • Contraindicated in patients with leukemia,

lymphoma, active HCV, EBV, CMV, age > 65 yrs with co-morbidities, hemolysis, positive DAT

Suggest:

• Inform physician (2010 warning letter)

• Pre-infusion DAT & baseline CBC, retic

• Monitor patient for 8 hours

• Instruct patient re S/S (eg red/brown urine)

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RhIG associated IVH…cont

• A decrease in Hb can be expected– 50 g/kg dose: average decrease of 17 g/L

– 25-40 g/kg dose: average decrease of 8 g/L

• Although uncommon, IVH is not rare– 1/1000 infusions (personal communication)

• 2005, FDA - 6 reports of DIC associated with acute IVH, 5 fatalities

• Clinically compromising anemia, rbc transfusion, renal insufficiency or DIC

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RhIg – when to report hemolysisIf the post-transfusion Hb drop from pre-transfusion baseline is

Then:

>20% OR

Clinically significant anemia requiring red cell transfusionOR

DIC or renal failure

• Pathologist determines if investigation is required.

• Sample collection may be required. • Examinations should include DAT

and an eluate if the DAT is positive (to prove anti-D is the cause of the hemolysis).

≤ 20% • No lab investigation is required. • Report will be sent to technical

supervisor for review.

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Reactions

Key Points

Related

Immunoglobulin

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Immunoglobulin ReactionsKey Points

• Low-severity infusion reactions are– Common & usually rate related

– Unique amongst transfusion reactions regarding management and reporting

• Reporting is recommended for:– Moderate or severe infusion reactions

– Low severity infusion reactions which are unresponsive to slowing of infusion rate

– All high severity reactions

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Course Contributors – Advisory Panel

Thanks to: Health Authority Advisory Group

Dr. Kate Chipperfield VCH TMAG

Dr. Jason Doyle IH TMAG

Dr. Doug Morrison FH TMAG

Dr. Louis Wadsworth PHSA TMAG

Maureen Wyatt IH TRG

Donna Miller VIHA NRG

Shelley Feenstra VCH NRG

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AcknowledgementsSincere appreciation is due to the clinical, technical and pathologist representatives of the BC Health Authorities who contributed their knowledge, expertise, time or materials to the development of these modules.

Development and secretariat support is provided by the BC Provincial Blood Coordinating Office (PBCO).

Funding for the support of transfusion reaction surveillance in BC is provided by the Public Health Agency of Canada (PHAC).

Included are members of:• BC Transfusion Medicine Advisory Group (TMAG)• BC Transfusion Transmitted Injuries Surveillance System

Working Group (BC TTISS WG) • Technical Resource Group (TRG)• Nursing Resource Group (NRG)

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Questions?

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Upcoming Live Webinars

Date / Time Topic Speaker

December 1, 2011

12:00 to 1:00pm

Transfusion Reaction Reporting and Surveillance

Dr. Louis Wadsworth MB FRCP(C)

FRCPath, Clinical Professor,

Department of Pathology, UBC

December 15, 2011

12:00 to 1:00pm

Transfusion Reaction Annual Data

Reports and Case Studies

Dr. Kate Chipperfield MD FRCPC

Regional Medical Leader, Blood

Transfusion Medicine, VCH

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Next Steps

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