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March 2020

Measles post exposure prophylaxis (PEP): IVIG versus other IG products. Which one should we use?

Authors: Dr. Juthaporn Cowan and Dr. Bill Cameron, Infectious Diseases, The Ottawa Hospital

Measles cases occur sporadically throughout Canada. Post exposure prophylactic (PEP) treatment with immunoglobulin (IG) offers protection to susceptible individuals if IG is given within an appropriate time frame. Due to changing knowledge of IG products and formulations, and changing recommendations, there has been some confusion regarding which IG products can and should be used.

Anti-measles antibody levels in IG products have been declining over the years, due to control of natural measles infection and declining re-exposure in the plasma donor pool. IG PEP is a passive immunization with the expectation that there is an adequate anti-measles antibody level in the IG products to ensure a protective trough level of neutralising antibody in recipient serum above 120 mIU (or 0.12 IU) /mL. It is reassuring that all IG preparations have to meet a regulatory standard requirement of anti-measles antibodies of 25 IU/mL minimum concentration, which is enough to deliver a trough titre well above the protective level.

GamaSTAN S/D, which is an intramuscular (IM) formulation, has long been recommended for measles and hepatitis A PEP. However, this product can only be given at a small volume not exceeding 15 mL. Provided that the recommended dosage is 0.5 mL/kg, an individual whose weight is greater than 30 kg may not get adequate protection due to the limited maximum dose. Intravenous formulation of IG such as Gammunex, IGIVnex, Gammagard, and Privigen can be given without a low maximum dosage, therefore, it can provide better seroprotection to individuals who weigh greater than 30 kg. For this reason, IVIG at 400 mg/kg is now recommended for use in measles outbreak or exposure situations. The downside of IVIG is a need for an active monitoring over several hours of infusion by trained personnel.  Currently, subcutaneous formulations such as Hizentra, Cuvitru or Cutaquig have not been evaluated for measles PEP.

Take home messages:

Both IM and IV formulations of IG products can be used for measles PEP
IMIG may not provide full protection to susceptible individuals who weigh greater than 30 kg
IVIG is preferred in susceptible individuals who weigh ³ 30 kg

References:

Tunis MC, Salvadori MI, Dubey V, Baclic O. Updated NACI recommendations for measles post-exposure prophylaxis. Can Commun Dis Rep 2018;44(9):226-30. https://doi.org/10.14745/ccdr.v44i09a07

Vandeberg P et al., Measles antibody trough levels after treatment with immunoglobulin products and predicted levels assuming lower measles antibody specifications.  TRANSFUSION Volume 58, p 3072, December 2018

High-dose intravenous immunoglobulin (IVIG) for treatment of heparin-induced thrombocytopenia (HIT)

Author: Theodore (Ted) E. Warkentin, MD

Professor, Dept. of Pathology and Molecular Medicine, and Dept of Medicine, McMaster University; Regional Director, Transfusion Medicine, Hamilton Regional Laboratory Medicine Program; Hematologist, Service of Clinical Hematologist, Hamilton General Hospital; Core Member, McMaster Centre for Transfusion Research, Hamilton, Ontario, Canada.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated prothrombotic drug reaction that is usually triggered by exposure to heparin, either unfractionated or low-molecular-weight. HIT pathogenesis is driven by antibodies that target a cationic platelet-derived protein, platelet factor 4 (PF4), when it forms multimolecular complexes with (polyanionic) heparin. The pathogenic antibodies, which are predominantly of immunoglobulin G (IgG) class, produce strong platelet activation by forming PF4/heparin/IgG immune complexes that cross-link platelet surface IgG Fc receptors. HIT is one of the most prothrombotic disorders in medicine: affected patients have approximately 15-fold greater risk of thrombosis than expected for the clinical situation. Moreover, patients often develop unusually severe thrombotic events (e.g., limb loss secondary to limb artery thrombosis or venous limb gangrene; thrombotic stroke; adrenal necrosis secondary to adrenal vein thrombosis).

HIT has traditionally been viewed as a disorder of heparin-dependent platelet-activating antibodies. However, there is growing recognition of an important subset of HIT—recently named autoimmune HIT (aHIT)—in which the patient’s HIT antibodies cause both heparin-dependent and heparin-independent platelet activation. Clinical correlates of aHIT antibodies include: delayed-onset HIT (thrombocytopenia that begins or worsens after stopping heparin); persisting (refractory) HIT (thrombocytopenia that continues for >1 week after stopping heparin); heparin “flush” HIT (HIT triggered by exposure to small amounts of heparin); and “spontaneous HIT syndrome” (a disorder clinically and serologically indistinguishable from HIT but where there is no plausible preceding exposure to heparin). Further, most patients with severe HIT (platelet count <20 × 109/L with overt disseminated intravascular coagulation; HIT with multiple venous and arterial thromboses) have associated aHIT antibodies.

Treatment of HIT has traditionally focused on timely discontinuation of heparin plus initiation of an alternative non-heparin anticoagulant, such as a factor Xa inhibitor (danaparoid, fondaparinux, rivaroxaban, apixaban) or a direct thrombin inhibitor (argatroban, bivalirudin, dabigatran). A novel and increasingly utilized treatment adjunct is administration of high-dose intravenous immunoglobulin (IVIG), most often dosed as 2 g/kg (usually given as 1g/kg over 2 consecutive days). The biological rationale is dose-dependent inhibition by IVIG of HIT antibody-induced platelet activation through platelet Fc receptor blockade. A recent narrative review (Warkentin TE. Exp Rev Hematol 2019;12:685-698) of 36 HIT patients treated with high-dose IVIG concluded that most patients developed rapid platelet count recovery, without a prothrombotic signal.

Given that HIT is highly prothrombotic and that IVIG itself can trigger thrombotic events, the apparent low frequency of thrombosis in IVIG-treated HIT patients is consistent with the hypothesis that high-dose IVIG helps to rapidly deescalate HIT hypercoagulability, thus reducing subsequent risk of thrombosis and related sequelae. Moreover, in vitro data indicate that high-dose IVIG is especially effective at inhibiting heparin-independent platelet activation by HIT antibodies, suggesting that this novel treatment should be considered in patients whose clinical picture suggests an aHIT syndrome.

Ontario Transfusion Quality Improvement Plan Outline Red Blood Cell Utilization Results at Cornwall Community Hospital

Author: Patty Hebert, Eastern Ontario Regional Laboratory Association (EORLA), Interim Laboratory Manager, Queensway-Carleton Hospital

In 2018, Cornwall Community Hospital (CCH) initiated an improvement plan for RBC utilization.  A baseline retrospective audit of RBC utilization was performed using the Ontario Transfusion Quality Improvement Plan (OTQIP) Guidance Document for Institutional Implementation. The data from the audit was used to compare how the current hospital transfusion practices aligned with the recommended Choosing Wisely Recommendations and to assess any inappropriate transfusions.

Fifty consecutive transfusion orders were audited during the months of February and March 2018. Surgical patients, outpatient transfusion clinics, and any bleeding patients were excluded from the audit. A total of 91 RBC units were transfused to the 50 patients. Forty-three of fifty or 86% had a pre-transfusion hemoglobin of less than 80 g/L and 15 or 30% out of these total transfusions were single unit transfusions.  Forty-six RBCs or 51% of these units transfused could have potentially been saved. The transfusion target of 80% for patients with a pre-transfusion hemoglobin of less than 80 g/L was being met but the target of 80% being single unit transfusions was not. The data highlighted the need to improve on single unit transfusions.

Another retrospective audit of 50 consecutive transfusion orders during February and March 2019 was performed following the same criteria.  A total of 86 RBC units were transfused to the 50 patients. Forty-seven of fifty (94%) had a pre-transfusion hemoglobin of less than 80 g/L and 18/50 or 36% were single unit transfusions.

Dr Scharf, Chief of Staff at CCH initiated a Quality Improvement Plan (QIP) in 2019 for CCH using the Choosing Wisely Recommendations to reduce unnecessary patient testing, treatment and procedures to ultimately improve patient care. The QIP included the recommended transfusion medicine guidelines for transfusing single units and for transfusing patients with a pre-transfusion hemoglobin less than 80 g/L. A goal of a 10% increase in single unit transfusions per year was set until reaching the target of 80%. In order to improve the rate of single unit transfusions, it was agreed with Dr Scharf to screen all RBC transfusion orders received in the Transfusion Medicine department for multiple unit requests. Dr. Giulivi, EORLA Hematopathologist for CCH, guided and aided the transfusion lab MLTs with the screening process. The screening excluded bleeding patients, outpatient clinics and surgical units. Mohammed Sheheen, CIO of CCH, would also be implementing changes in the LIS to reflect the Choosing Wisely Recommendations for transfusions, to aid physicians when placing a transfusion order.

The physicians at CCH were informed by Dr. Scharf about the transfusion QIP project and the screening began on the 1st of June 2019.  A mini audit to track progress was performed for RBC transfusions during September 2019.  Thirty-one of 37 (31/37) or 84% of the transfusions were single unit transfusions, exceeding the expectations and the target. A further audit will be performed for 50 transfusion orders in February and March 2020 to determine if the improvement to the use of single unit RBC transfusions has been sustained.