CANADA IS ONE of the world s highest per

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1 Evidence-Based Guidelines on the Use of Intravenous Immune Globulin for Hematologic and Neurologic Conditions Paula Robinson, David Anderson, Melissa Brouwers, Thomas E. Feasby, and Heather Hume, on behalf of the IVIG Hematology and Neurology Expert Panels In Canada, intravenous immunoglobulin (IVIG) use has increased by 115% over the past 7 to 8 years. Given this increased usage, Canadian Blood Services and the National Advisory Committee on Blood and Blood Products for Canada identified the need to develop and disseminate evidencebased guidelines to facilitate appropriate IVIG use. As a result, guidelines for IVIG use in hematologic and neurologic conditions have been developed and are published in this supplement of Transfusion Medicine Reviews. This commentary provides a brief description of the process used to develop these guidelines and includes a summary of the recommendations for IVIG use in the various conditions evaluated. A 2007 Published by Elsevier Inc. CANADA IS ONE of the world s highest per capita users of intravenous immune globulin (IVIG), with its use increasing by 115% between and This expensive fractionated blood product consists of concentrated immunoglobulin, primarily IgG, derived from human plasma in pools of 3000 to more than donors. With a single infusion of 1 gm/kg for a 70-kg adult costing approximately $4000, IVIG now accounts for more than one third of Canadian Blood Services total budget for all fractionated and recombinant products or approximately one sixth of Canadian Blood Services entire budget. Although Health Canada has licensed specific IVIG preparations for the treatment of primary and secondary immunodeficiencies, allogenic bone marrow transplantation, chronic B-cell lymphocytic leukemia, pediatric HIV infection, and idiopathic thrombocytopenic purpura, IVIG is also being used to treat a growing number of boff-labelq indications. Much of the recent growth in IVIG use is believed to be due to this increasing boff-labelq usage. Given this escalating usage of IVIG, in 2004 Canadian Blood Services and the National Advisory Committee on Blood and Blood Products (an advisory group to the Canadian provincial and territorial Ministries of Health and Canadian Blood Services, composed of hospital-based transfusion medicine experts) identified the need to develop and disseminate evidence-based practice guidelines as a way to facilitate appropriate use of IVIG. Two separate panels of national experts were convened to develop evidence-based practice guidelines on the use of IVIG for 18 hematologic conditions and for 22 neurologic conditions. The panels mandates were to review the available evidence regarding the use of IVIG and formulate recommendations on IVIG use for each of the identified conditions in each area of expertise. This commentary provides a brief description of the process used to develop the guidelines and a summary of the recommendations for IVIG use in each of the clinical conditions evaluated. The primary sources used by the expert panels were recent evidence-based reviews, both published and unpublished. (For a complete set of references, refer to each document.) Recommendations for use of IVIG were developed based on interpretation of the available evidence and, where evidence was lacking, consensus of expert clinical opinion. Interpretation of the evidence involved recognition and discussion of factors influencing the decisionmaking process. Both expert panels evaluated the use of IVIG for a diverse range of conditions. The level of evidence required to recommend IVIG varied depending upon the condition. For rare diseases that have no effective alternative treatments, the threshold for recommendation of the use of IVIG was lower than for common diseases with established standard therapies. The level of evidence available to inform the recommendations for each condition was assessed Address reprint requests to Heather Hume, MD, FRCPC, Executive Medical Director, Transfusion Medicine, Canadian Blood Services, 1800 Alta Vista Drive, Ottawa, ON CANADA K1G 4J5. [email protected] /07/$ - see front matter n 2007 Published by Elsevier Inc. doi: /j.tmrv Transfusion Medicine Reviews, Vol 21, No 2, Suppl 1 (April), 2007: pp S3-S8 S3

2 S4 ROBINSON ET AL Table 1. Summary of Recommendations for the Use of IVIG in Patients With Hematologic Conditions Acquired hemophilia IVIG is not recommended for routine use in the treatment of acquired hemophilia. considered one option among adjunctive therapies, such as steroids, in urgent situations in this disorder. Acquired hypogammaglobulinemia (secondary to malignancy) Adult IVIG is recommended for infection prophylaxis in adults with malignant hematologic disorders associated with hypogammaglobulinemia or dysfunctional gammaglobulinemia and either (i) a recent episode of a life-threatening infection, which is reasonably thought to be caused by low levels of polyclonal immunoglobulins; or (ii) recurrent episodes of clinically significant infections (eg, pneumonia), which are reasonably thought to be caused by low levels of polyclonal immunoglobulins. considered one option for the treatment of acute lifethreatening infection in patients with malignant hematologic disorders associated with hypogammaglobulinemia or, more specifically, low levels of polyclonal immunoglobulins. The panel also recommends that health care providers consider the role of other contributing risks for infection (eg, neutropenia or chemotherapy-related mucositis) in determining the likely role of hypogammaglobulinemia in the development of the infectious process. Pediatric IVIG is not recommended for routine use in children with hematologic malignancies (with or without hypogammaglobulinemia). The panel recognizes 2 possible exceptions to this general recommendation: (i) For children with hematologic malignancies with acquired hypogammaglobulinemia and either a history of severe invasive infection or recurrent sinopulmonary infections, IVIG may be considered a treatment option according to the above recommendations for adult patients. (ii) Some multinational protocols for the treatment of hematologic malignancies (and/or hematopoietic stem cell transplantation) in childhood recommend routine use of IVIG for hypogammaglobulinemia, even in the absence of severe or recurrent infections. These recommendations are protocol specific and not necessarily consistent across protocols of similar intensity. Consequently, the panel suggests that IVIG may be administered to children registered on such clinical trials to comply with protocol recommendations. However, because the benefit of this approach has not been adequately studied and there is considerable uncertainty as to the efficacy of such an approach, the panel suggests that IVIG not be routinely used for nonregistered patients. Acquired red cell aplasia or pure red cell aplasia (PRCA) IVIG is not recommended as first line therapy for immunologic PRCA. Based on consensus by the expert panel, IVIG is a reasonable option for patients with immunologic PRCA who have failed other therapies (eg, prednisone or cyclosporin). Acquired red cell aplasia or pure red cell aplasia (continued) IVIG should be considered a first-line therapy for viral PRCA associated with parvovirus B19 in immunocompromised patients. Acquired von Willebrand disease (AvWD) IVIG is not recommended for routine use in the treatment of AvWD. considered one option among adjunctive therapies in the treatment of AvWD in urgent situations (eg, active bleeding or preoperatively). Aplastic anemia IVIG is not recommended for the treatment of aplastic anemia. Autoimmune hemolytic anemia (AIHA) IVIG is not recommended for routine use in either acute or chronic treatment of AIHA. considered among the options for treatment of severe lifethreatening AIHA. Autoimmune neutropenia IVIG is not recommended for routine treatment of autoimmune neutropenia. considered among the treatment options in rare circumstances of autoimmune neutropenia when the standard of care, G-CSF, fails. Fetal or neonatal alloimmune thrombocytopenia (F/NAIT) Treatment of F/NAIT before delivery IVIG is recommended as the standard first-line antenatal treatment of FAIT. Candidates for treatment include (i) Pregnant women with a previously affected pregnancy. Intravenous immunoglobulin should be initiated at a time in the pregnancy that corresponds to a gestational age in the present fetus that precedes by some weeks the time at which bleeding was thought to occur in the first pregnancy. (ii) Pregnant women with a familial history of F/NAIT or those found on screening to have platelet alloantibodies. Timing of IVIG treatment should be based on the severity of fetal thrombocytopenia determined by cordocentesis. Expert opinion suggests that treatment should be initiated around 20 wk and not later than 30 wk. Given the complexity of this disorder and its management, it is strongly recommended that treatment be under the direction of a high-risk obstetrical center with specialized expertise in the treatment of F/NAIT. Treatment of a newborn with F/NAIT In the opinion of the expert panel, the provision of antigennegative compatible platelets should be considered a firstline therapy and IVIG adjunctive. Given the lack of evidence to guide management in this rare disorder, it is strongly recommended that treatment of newborns with F/NAIT be under the direction of a center with specialized pediatric expertise in the treatment of this condition. Hematopoietic stem cell transplantation IVIG is not recommended for use after hematopoietic stem cell transplantation. The panel recognizes as a possible exception to this recommendation that some multinational protocols for (continued on next page)

3 IVIG CLINICAL GUIDELINES S5 Hematopoietic stem cell transplantation (continued) the treatment of hematologic malignancies and/or hematopoietic stem cell transplantation in childhood recommend routine use of IVIG for hypogammaglobulinemia. These recommendations are protocol specific and not necessarily consistent across protocols of similar intensity. Consequently, the panel suggests that IVIG may be administered to children registered on such clinical trials to comply with protocol recommendations. However, because the benefit of this approach has not been adequately studied and there is considerable uncertainty as to the efficacy of such an approach, the panel suggests that IVIG not be routinely used for nonregistered patients. Hemolytic disease of the newborn (HDN) IVIG is not recommended for use in the management of HDN without established hyperbilirubinemia. The panel recommends that IVIG be offered to patients with HDN as treatment for severe hyperbilirubinemia and endorses the recommendations outlined in the American Academy of Pediatrics (AAP) guideline on the management of hyperbilirubinemia. AAP recommendations (July 2004) state: In isoimmune hemolytic disease, administration of IVIG ( g/kg over 2 h) is recommended if the total serum bilirubin (TSB) is rising despite intensive phototherapy or the TSB level is within 2-3 mg/dl (34-51 lmol/l) of the exchange level. If necessary, this dose can be repeated in 12 h. Although the AAP recommendation states that a dose of IVIG may be given over 2 h, this may represent an infusion administration faster than that recommended by the manufacturer; this needs to be taken into consideration in treatment decisions. Hemolytic transfusion reaction IVIG is not recommended for either the prophylaxis or routine treatment of hemolytic transfusion reactions. considered as an option among supportive therapies for urgent situations in this disorder. Hemolytic transfusion reaction in sickle cell disease IVIG is not recommended for the routine treatment of non life-threatening delayed hemolytic transfusion reactions in patients with sickle cell disease. considered among the options for treatment of serious, lifethreatening, delayed hemolytic transfusion reactions in patients with sickle cell disease. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) IVIG is not recommended as first-line therapy for HUS or TTP in either the pediatric or adult population. considered one option among adjunctive therapies when first-line therapy has failed. Heparin-induced thrombocytopenia IVIG is contraindicated for treatment of heparin-induced thrombocytopenia. HIV-associated thrombocytopenia IVIG is recommended as a treatment option for HIV-associated thrombocytopenia when there is active bleeding or when platelet counts are less than /L. Idiopathic thrombocytopenic purpura (ITP) in children Pediatric ITP IVIG is recommended as one option for first-line therapy of acute ITP in children with platelet counts less than /L. IVIG is recommended as part of a multimodality approach (ie, in conjunction with platelet transfusions and bolus intravenous methylprednisolone) for treatment of children with ITP who have life-threatening bleeding. considered as one option for treatment of children with chronic ITP. Another related option (ie, a plasma derived immunoglobulin product) for Rh-positive nonsplenectomized children is anti-d, provided that there are no contraindications to the use of this product. Neonates of mothers with ITP The expert panel endorses the American Society of Hematology (ASH) guideline recommendations, which are bin newborns without evidence of intracranial hemorrhage, treatment with IVIG is appropriate if the infant s platelet count is b20000/ll ( /L). Newborns with platelet counts of /lL ( /L to /L) do not necessarily require IVIG treatment. Newborns with counts N50000/lL ( /L) should not be treated with IVIG or glucocorticoids.q Newborns with imaging evidence of intracranial hemorrhage should be treated with combined glucocorticoid and IVIG therapy if the platelet count is b20000/ll ( /L). In this setting it is prudent to use glucocorticoids in combination with other treatment. Idiopathic thrombocytopenic purpura (ITP) in adults Adult acute ITP with bleeding Based on consensus by the expert panel, IVIG is strongly recommended as part of multimodality therapy for adults with acute ITP and major or life-threatening bleeding complications and/or clinically important mucocutaneous bleeding. Adult acute ITP with severe thrombocytopenia but no bleeding Based on consensus by the expert panel, IVIG is not recommended as first-line therapy alone for acute ITP with severe thrombocytopenia but no major bleeding or wet purpura, except for patients with contraindications to steroids. Adult ITP with no or slow response to adequate dose steroids considered as a possible adjunctive therapy for patients not responding or slowly responding to steroids. Adult chronic ITP postsplenectomy considered as a possible adjunctive therapy as a steroidsparing measure. Pregnancy-associated ITP When pregnancy-associated ITP requires treatment, as outlined in the ASH guidelines, IVIG is recommended as one option for first-line therapy, as are steroids. Clinical judgment should inform the decision. The expert panel endorses the treatment parameters outlined in the ASH recommendations. (continued on next page)

4 S6 ROBINSON ET AL Summary of ASH recommendations: Platelet counts greater than /L do not routinely need treatment and should not receive steroids or IVIG. Platelet counts between 30 and /L in first or second trimester also should not receive treatment. Treatment is required if platelet count is b /L at any time in the pregnancy or between 10 and /L in second or third trimester or if there is bleeding. Pregnant women who fail steroids and IVIG should be considered for splenectomy in the second trimester if platelet count is less than /L and there is bleeding. A platelet count of /L is sufficient for vaginal delivery or cesarean section. Intravenous immunoglobulin may be useful if very rapid elevation of platelet count is needed before delivery. These recommendations are based on clinical experience and expert consensus. Posttransfusion purpura (PTP) IVIG is recommended as the standard first-line therapy for PTP. Viral-associated hemophagocytic syndrome (VAHS) IVIG is not recommended for routine use in the treatment of VAHS. considered among the options for treatment of severe lifethreatening VAHS. using the system developed by Bob Phillips et al from the National Health Service (UK) Centre for Evidence-Based Medicine. (A detailed description of the classification system is given in the full guidelines document.) Using membership lists for appropriate professional organizations, we circulated drafts of the practice guidelines to hematologists and neurologists across Canada, and feedback was obtained via a questionnaire using a web-based survey tool. The results from this consultation process were then reviewed by the expert panels, and subsequent modifications to the guidelines were made where appropriate. The guidelines produced through this process include a brief clinical description plus a summary of the available evidence and the expert panel s interpretation and recommendations regarding use of IVIG for each of the conditions reviewed. HEMATOLOGIC CONDITIONS For most of the hematologic conditions reviewed by the hematology expert panel, routine use of IVIG was not recommended. Recommendations for routine use of IVIG (ie, clinical settings in which IVIG could be considered an appropriate therapeutic option) were made for the following Table 2. Summary of Recommendations for the Use of IVIG in Patients With Neurologic Conditions Neurologic conditions Acute disseminated encephalomyelitis (ADEM) IVIG is recommended as an option for treatment of monophasic ADEM when first-line therapy with high-dose corticosteroids fails or when there are contraindications to steroid use. considered as an option for treatment of relapsing ADEM to eliminate steroid dependency or for those patients who fail to respond, or have contraindications, to steroids. Adrenoleukodystrophy IVIG is not recommended for the treatment of adrenoleukodystrophy. Amyotrophic lateral sclerosis IVIG is not recommended for the treatment of amyotrophic lateral sclerosis. Autism IVIG is not recommended for the treatment of autism. Chronic inflammatory demyelinating polyneuropathy IVIG is recommended as an option for the short-term management of new-onset chronic inflammatory demyelinating polyneuropathy (CIDP) or CIDP relapses. considered as an option in combination with other immunosuppressive therapy for the long-term management of CIDP. If IVIG is to be used in the long-term management of CIDP, the patient should be under the care of a qualified expert with specialized knowledge of CIDP, and a systematic approach should be taken to determine the minimal effective dose. Critical illness polyneuropathy IVIG is not recommended for the treatment of critical illness polyneuropathy. Dermatomyositis Based on consensus by the expert panel, pathologic confirmation by means of a skeletal muscle biopsy is required for the diagnosis of dermatomyositis. It is critical that the muscle specimen be procured, processed, and interpreted in a laboratory familiar with the correct handling of muscle biopsy specimens and that the final interpretation be made by an expert in neuromuscular pathology. Based on consensus by the expert panel, use of IVIG for the treatment of patients with dermatomyositis should be made in consultation with an expert in neuromuscular disease. IVIG is not recommended as monotherapy for dermatomyositis. IVIG is recommended as an option, in combination with other agents, for patients with dermatomyositis who have not adequately responded to other immunosuppressive therapies. IVIG is recommended, in combination with other agents, as a steroid-sparing option for patients with dermatomyositis. Diabetic neuropathy IVIG is not recommended for treatment of diabetic polyneuropathy, mononeuropathy, or proximal lower limb neuropathy. Based on consensus by the expert panel, IVIG use for patients with diabetes who have evidence of a CIDP phenotype should follow the recommendations outlined in the CIDP section of this guideline. (continued on next page)

5 IVIG CLINICAL GUIDELINES S7 Table 2 (continued) Neurologic conditions Table 2 (continued) Neurologic conditions Guillain-Barré syndrome (GBS) IVIG is recommended as a treatment option for GBS within 2 wk of symptom onset for (i) Patients with symptoms of grade 3 severity (able to walk with aid) or greater; or (ii) Patients with symptoms less than grade 3 severity whose symptoms are progressing. considered as a treatment option for patients who initially responded to IVIG and who are experiencing a relapse of symptoms. Based on consensus by the expert panel, the recommendations for use of IVIG for GBS also apply to patients with Miller- Fisher and other variants of GBS. Diagnosis of GBS variants should be made by a specialist with expertise in this area. Inclusion body myositis Based on consensus by the expert panel, pathologic confirmation by means of a skeletal muscle biopsy is required for the diagnosis of inclusion body myositis. It is critical that the muscle specimen be procured, processed, and interpreted in a laboratory familiar with the correct handling of muscle biopsy specimens and that the final interpretation be made by an expert in neuromuscular pathology. IVIG is not recommended for the treatment of inclusion body myositis. Intractable childhood epilepsy IVIG is not recommended for the treatment of intractable childhood epilepsy. Lambert-Eaton myasthenic syndrome IVIG is recommended as an option for treatment of Lambert- Eaton myasthenic syndrome. Objective evidence of clinical improvement is needed for sustained use of IVIG. Multifocal motor neuropathy IVIG is recommended as first-line treatment for multifocal motor neuropathy. Based on consensus by the expert panel, diagnosis of multifocal motor neuropathy should be made by a neuromuscular specialist because the diagnosis requires very specific electrodiagnostic expertise. Multiple sclerosis (MS) IVIG is recommended as an option for treatment of patients with relapsing-remitting MS who fail, decline, or are not able to take standard immunomodulatory drug therapies. For those patients with rapidly advancing relapsing-remitting MS, consideration should first be given to immunosuppression therapy. IVIG is not recommended for the treatment of primary or secondary progressive MS. Based on consensus by the expert panel, IVIG is not recommended for treatment of acute exacerbations of MS, except in patients with severe, refractory, optic neuritis who have had no recovery of vision after 3 months of standard steroid therapy or patients for whom corticosteroid therapy is contraindicated. considered as a treatment option for patients with relapsing-remitting MS who are pregnant or breast-feeding or in the immediate postpartum period for women whose exacerbation rate was high before pregnancy and who were on disease-modifying agents before pregnancy with plans to recommence therapy following birth or breast-feeding. Multiple sclerosis (MS) (continued) considered as a treatment option for patients with Marburg disease, given the life-threatening nature of this disease. Myasthenia gravis Adult and juvenile myasthenia gravis IVIG is recommended as a treatment option for patients with severe exacerbations of myasthenia gravis or myasthenic crises. considered as an option to stabilize patients with myasthenia gravis before surgery. IVIG is not recommended as maintenance therapy for patients with chronic myasthenia gravis. Neonatal myasthenia gravis considered among the treatment options for neonates severely affected with myasthenia gravis. Opsoclonus-myoclonus considered as an option for treatment of opsoclonus-myoclonus. Paraproteinemic neuropathy (IgM variant) IVIG is not recommended for the treatment of IgM paraproteinemic neuropathy. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) IVIG is recommended as an option for treatment of patients with PANDAS. Based on consensus by the expert panel, diagnosis of PANDAS requires expert consultation. POEMS syndrome IVIG is not recommended for the treatment of POEMS syndrome. Polymyositis Based on consensus by the expert panel, pathologic confirmation by means of a skeletal muscle biopsy is required for the diagnosis of polymyositis. It is critical that the muscle specimen be procured, processed, and interpreted in a laboratory familiar with the correct handling of muscle biopsy specimens and that the final interpretation be made by an expert in neuromuscular pathology. considered among the treatment options for patients with polymyositis who fail to respond to first-line therapies (eg, steroids). Rasmussen encephalitis IVIG may be an option as a short-term temporizing measure for patients with Rasmussen encephalitis. IVIG is not recommended for long-term therapy for Rasmussen encephalitis because surgical treatment is the current standard of care. Stiff person syndrome IVIG is recommended as an option for treatment of stiff person syndrome, if GABAergic medications fail or for patients who have contraindications to GABAergic medications. Abbreviations: G-CSF, granulocyte colony-stimulating factor; PANDAS, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes.

6 S8 ROBINSON ET AL 7 hematologic conditions: acquired red cell aplasia, acquired hypogammaglobulinemia (secondary to malignancy), fetal-neonatal alloimmune thrombocytopenia, hemolytic disease of the newborn, HIVassociated thrombocytopenia, idiopathic thrombocytopenic purpura, posttransfusion purpura. Intravenous immunoglobulin was not recommended for use, except under certain urgent or lifethreatening circumstances, for 8 conditions, namely, acquired hemophilia, acquired von Willebrand disease, autoimmune hemolytic anemia, autoimmune neutropenia, hemolytic transfusion reaction, hemolytic transfusion reaction associated with sickle cell disease, hemolytic uremic syndrome/ thrombotic thrombocytopenic purpura, and viralassociated hemophagocytic syndrome. Intravenous immunoglobulin was not recommended for aplastic anemia and hematopoietic stem cell transplantation. Intravenous immunoglobulin was considered to be contraindicated for heparin-induced thrombocytopenia. Table 1 provides a summary of the recommendations for the clinical use of IVIG for hematologic conditions. For a complete discussion of the panel s recommendations, including recommended dose and duration of IVIG therapy, please refer to the specific condition of interest in the accompanying guideline article in this issue of Transfusion Medicine Reviews. NEUROLOGIC CONDITIONS Of the 22 neurologic conditions reviewed by the neurology expert panel, specific recommendations for use of IVIG were made for 14 conditions, including acute disseminated encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, diabetic neuropathy, Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), polymyositis, Rasmussen encephalitis, and stiff person syndrome. Intravenous immunoglobulin was not recommended for the following 8 neurologic conditions: adrenoleukodystrophy, amyotrophic lateral sclerosis, autism, critical illness polyneuropathy, inclusion body myositis, intractable childhood epilepsy, paraproteinemic neuropathy (IgM variant), and POEMS syndrome. Table 2 provides a summary of the recommendations for the clinical use of IVIG for neurologic conditions. Please consult the complete guideline for a complete discussion of the panel s recommendations, including information on recommended dose and duration of IVIG therapy in this issue of Transfusion Medicine Reviews.