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Transfusion Reaction Education Module 4

Immunoglobulin Related Reactions: Overview of IVIG Related Reactions IVIG Related Low-Severity Reactions IVIG Related Severe Reactions RhIG Related Hemolysis. Transfusion Reaction Education Module 4. Speaker. Dr. Doug Morrison MD FRCPC Medical Director, Transfusion Medicine, FH

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Transfusion Reaction Education Module 4

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  1. Immunoglobulin Related Reactions: Overview of IVIG Related Reactions IVIG Related Low-Severity Reactions IVIG Related Severe Reactions RhIG Related Hemolysis Transfusion Reaction EducationModule 4

  2. Speaker Dr. Doug Morrison MD FRCPC Medical Director, Transfusion Medicine, FH Disclosure: Dr Morrison has received speaker honoraria from CSL Behring and Octapharma.

  3. 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

  4. 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

  5. Objectives of Module 4 On completion of this module, you should be able to: • 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

  6. Overview of IVIG RelatedReactions

  7. 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….

  8. 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

  9. 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%

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

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

  12. Hughes et al. ICE study - IVIG in CIDP. Lancet Neurology 2008; 7 :136-44 Gamunex n=113 Placebo n=95

  13. 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

  14. IVIG RelatedLow-severity InfusionReactions

  15. 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

  16. “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

  17. IVIG infusion reaction by severity

  18. Report to TMS/Lab

  19. Low-severity Infusion Reactions Pierce & Jain. Risks Associated with the use of IVIG. Trans Med Rev 2003; 17:241

  20. Low-severityInfusion Reactions Recommendations:

  21. 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

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

  23. 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

  24. IVIG – related SevereReactions

  25. Signs & Symptoms of Severe IVIG Reactions

  26. 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

  27. “Rate –related” anaphylactoid reactionsby 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

  28. 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

  29. IVIG related hemolysis

  30. IVIG related hemolysis Suggested treatment and recommendations:

  31. IVIG related hemolysis Suggested treatment and recommendations:

  32. IVIG Hemolysis Pharmacovigilance GroupCBS CL 2009 - 02(1of2)

  33. IVIG Hemolysis Pharmacovigilance Group CBS CL 2009 - 02(2of2)

  34. IVIG-related AsepticMeningitis

  35. IVIG-related AsepticMeningitis

  36. IVIG-related Aseptic MeningitisSuggested treatment and recommendations:

  37. IVIG-related Thrombosisreports to Health Canada Oct 1997 – July 2007Canadian 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

  38. 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.”

  39. 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

  40. 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

  41. 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

  42. IVIG related TRALI

  43. RhIg-relatedIntravascularHemolysis

  44. 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

  45. 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)

  46. RhIG associated IVH…cont • A decrease in Hb can be expected • 50 mg/kg dose: average decrease of 17 g/L • 25-40 mg/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

  47. RhIg – when to report hemolysis

  48. M4-01 Immunoglobulin Related Reactions Key Points

  49. 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

  50. Course Contributors – Advisory Panel

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