1. 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 Education Module 4

2. 2011 -11 - 17 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. 2011 -11 - 17 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. 2011 -11 - 17 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. 2011 -11 - 17 5 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:

6. 2011 -11 - 17 6 Overview of IVIG Related Reactions

7. 2011 -11 - 17 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. 2011 -11 - 17 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. 2011 -11 - 17 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. 2011 -11 - 17 10 Clinical Trials: Gammagard Liquid in PID 61 patients – 12 month study ( info from product monograph) Sign/SymptomBy InfusionBy Patient Headache6.9%36.1% Fever2.3%21.3% Fatigue2.2%16.4% Vomiting1.2%14.8% Chills1.7%13.1% Infusion site rxn1.0%13.1% Nausea1.0%9.8% Dizziness0.8%8.2% Pruritis0.6%6.5%

11. 2011 -11 - 17 11 Clinical Trials: Privigen – PID 80 patients – 12 month study (info from product monograph) Sign/SymptomBy InfusionBy Patient Headache8.7%43.8% Fever1.1%7.5% Fatigue2.8%16.3% Vomiting1.3%8.8% Chills1.4%11.3% Back pain1.3%10.0% Nausea2.1%12.5% Pain1.3%8.8% Diarrhea0.5%6.3%

12. 2011 -11 - 17 12 Hughes et al. ICE study - IVIG in CIDP. Lancet Neurology 2008; 7 :136-44 Sign/SymptomPatientsInfusionPatientsInfusion Headache32%5.2%8%2.6% Fever13%2.5%00 ↑ BP9%1.8%4%1.0% Asthenia8%0.9%3%0.7% Chills8%0.9%3%0.7% Back pain8%0.9%3%0.7% Rash7%1.2%1%0.2% Arthralgia7%1.0%1%0.2% Nausea6%0.8%3%0.5% Gamunex n=113Placebo n=95

13. 2011 -11 - 17 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. 2011 -11 - 17 14 IVIG Related Low-severity Infusion Reactions

15. 2011 -11 - 17 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. 2011 -11 - 17 16 “Side Effects” of IVIG Nursing 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. 2011 -11 - 17 17 IVIG infusion reaction by severity SeveritySymptoms MildHeadache, flushing, muscle aches, shivering, feeling sick, itching, localized urticaria, anxiety, light- headedness, dizziness or irritability ModerateMild reactions becoming worse, fever, rigors, chest, back or abdominal pain, wheezing, non-localized urticaria or rash, vomiting. SevereModerate 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.

18. 2011 -11 - 17 18 Report to TMS/Lab SeverityResolved by slowing flow rate Report to TMS/Lab mildyesno yes moderatenot applicableyes severenot applicableyes

19. 2011 -11 - 17 19 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

20. 2011 -11 - 17 20 Low-severity Infusion Reactions Recommendations: In-facility patientsMild signs and symptoms that respond to ongoing transfusion care do not need to be reported as transfusion reactions. Departed out-patientPatients 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 betweenHeadache & aseptic meningitis

21. 2011 -11 - 17 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. 2011 -11 - 17 22 Souayah et al. 2011… Patients who experienced symptoms (vs other studies) Sign/SymptomSouayah et al. By Patient Other Studies By Patient Headache10.7% 1.1% of infusions Fatigue, weakness, fever, chills, other infusion related 4.2%15 – 62% N/V/diarrhea3.8%3 – 24% Infusion site rxn2.1%4 - 33% Generalized rash1.9%6 – 14% Aseptic Meningitis0.2%6.7% Superficial Phlebitis0.4% ARF, VTE, HTRNone reported

23. 2011 -11 - 17 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. 2011 -11 - 17 24 IVIG – related Severe Reactions

25. 2011 -11 - 17 25 Signs & Symptoms of Severe IVIG Reactions AcuteAnaphylaxisfacial and tongue swelling, chest tightness, airway edema, dyspnea, hypotension, shock, tachycardia, nausea/vomiting, widespread rash (>2/3 body). TRALIHypoxia with non-cardiogenic pulmonary edema +/- hypotension or fever, during or within six hours of infusion Acute or Delayed Hemolytichemoglobinuria (red/brown urine), a fall of at least 10 g/L in hemoglobin (Hgb) DelayedAseptic Meningitis severe and incapacitating headache with nuchal rigidity, drowsiness, fever, lethargy, photophobia, painful eye movements, nausea/vomiting, deterioration of mental status Thrombotic events 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.

26. 2011 -11 - 17 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. 2011 -11 - 17 27 “ 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

28. 2011 -11 - 17 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. 2011 -11 - 17 29 PresentationAnemia with spherocytes & biochemical evidence of hemolysis 1-10 days post IVIG PathogenesisPositive DAT in nearly all patients anti-A or anti-B recovered in eluate FrequencyUncommon but not rare Risk factorsNon O blood group High cumulative dose (>100g) IVIG ReportingReport reaction to TMS, PBCO, and Manufacturer IVIG related hemolysis

30. 2011 -11 - 17 30 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

31. 2011 -11 - 17 31 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

32. 2011 -11 - 17 32 VariableDefinition Onsetwithin 10 days of IVIG administration Laboratory signs  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)

33. 2011 -11 - 17 33 VariableDefinition Exclusion criteria  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)

34. 2011 -11 - 17 34 IVIG-related Aseptic Meningitis Risk factorshigh-dose IVIG therapy history of previous migraines total dose infusion time of < 24 hours Onsetgenerally 24 to 48 hours post-therapy symptoms usually resolve within 3 to 5 days Frequencyrare PathogenesisMeningeal irritation by IgG

35. 2011 -11 - 17 35 IVIG-related Aseptic Meningitis CSF examination results is sterile has an elevated protein and shows a pleocytosis ± eosinophilia. InvestigationPatient samples are not required. Results of reaction meningeal signs and symptoms usually resolve within 3 – 5 days ReportingReport reaction to TMS, PBCO, and Manufacturer

36. 2011 -11 - 17 36 IVIG-related Aseptic Meningitis Suggested 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.

37. 2011 -11 - 17 37 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

38. 2011 -11 - 17 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. 2011 -11 - 17 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. 2011 -11 - 17 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. 2011 -11 - 17 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. 2011 -11 - 17 42 PresentationAcute hypoxemia and non-cardiogenic pulmonary edema (ALI) during or within 6 hours of infusion PathogenesisAnti-granulocyte antibodies in IVIG FrequencyRare case reports Risk factorsunknown ReportingReport reaction to TMS, PBCO, and Manufacturer Canadian Adverse Rxn Newsletter October 2008; 18(4):3 IVIG related TRALI

43. 2011 -11 - 17 43 RhIg-related Intravascular Hemolysis

44. 2011 -11 - 17 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. 2011 -11 - 17 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. 2011 -11 - 17 46 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

47. 2011 -11 - 17 47 RhIg – when to report hemolysis If the post-transfusion Hb drop from pre-transfusion baseline is Then: >20% OR Clinically significant anemia requiring red cell transfusion OR 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.

48. 2011 -11 - 17 48M4-01 Reactions Key Points Related Immunoglobulin

49. 2011 -11 - 17 49 Immunoglobulin Reactions Key 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. 2011 -11 - 17 50 Course Contributors – Advisory Panel Thanks to:Health AuthorityAdvisory Group Dr. Kate ChipperfieldVCHTMAG Dr. Jason DoyleIHTMAG Dr. Doug MorrisonFHTMAG Dr. Louis WadsworthPHSATMAG Maureen WyattIHTRG Donna MillerVIHANRG Shelley FeenstraVCHNRG

51. 2011 -11 - 17 51 Acknowledgements Sincere 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)

52. 2011 -11 - 17 52 Questions?

53. 2011 -11 - 17 53 Upcoming Live Webinars Date / TimeTopicSpeaker 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

54. 2011 -11 - 17 54 Next Steps Visit LearningHub - LearningHub LinkLearningHub Link https://edreg.cw.bc.ca/phsaedcalendar/Home.aspx Note: –Need LearningHub Username and Password –Confirm your email with LearningHub if not done Complete: –Participant Evaluation –Quiz (Closes midnight November 18, 2011)