The Journal of Pediatrics
Volume 148, Issue 1 , Pages 7-8, January 2006

Lessons from Kawasaki Disease: All Brands of IVIG are not Equal

  • E. Richard Stiehm, MD

      Affiliations

    • Corresponding Author InformationReprint requests: E. Richard Stiehm, MD, UCLA Department of Pediatrics, Division of Immunology/Allergy/Rheumatology, Mattel Children's Hospital at UCLA, 22-387 MDCC, Los Angeles, CA 90095.

UCLA Department of Pediatrics, Division of Immunology/Allergy/Rheumatology, Mattel Children's Hospital at UCLA, Los Angeles, CA 90095

See related article, p 38.

Article Outline

IVIG, Intravenous immune globulin, KD, Kawasaki disease

 

Every pediatrician knows that the treatment of children with Kawasaki disease (KD) requires the use of aspirin and high-dose intravenous immune globulin (IVIG). This therapy will rapidly improve the clinical course and reduce the risk of development of life-threatening coronary artery aneurysms. Yet up to 10% of patients are refractory or only partially responsive to this regimen so that additional IVIG retreatment, steroids, or other drugs must be added.1 The article in this month's Journal2 suggests that the brand of IVIG must also be considered.

Tsai et al2 from Taipai, Taiwan, used 4 brands of IVIG in the treatment of 437 children with KD. They were used sequentially (because of product availability), and their efficacy was assessed by the prevalence of coronary artery aneurysms at convalescence and the persistence of fever necessitating IVIG retreatment. All patients received IVIG at 2 g/kg plus standard aspirin therapy.

One IVIG brand (Intraglobin, Biotest Pharma) was associated with a higher rate of nonresponsiveness (12 of 93 cases [13%]) and coronary artery aneurysms (10%), including 3 fatal cases. Another brand (Venoglobin; Alpha Therapeutics) also had a high rate of nonresponsiveness (11%) and a 4% prevalence of aneurysms, significantly higher than in the 253 patients treated with 2 other brands, Gamimune N (Bayer) and CBSF Human Immunoglobulin (Scottish National Blood Transfusion Service). They had a combined 2.8% rate of nonresponsiveness and a 1.2% rate of coronary artery aneurysms.

The study has a few weaknesses, notably that the brand of IVIG was not allocated randomly, nor were different brands given at the same time period. In addition, side effects were not reported. Nevertheless, it emphasizes an important point: certain IVIGs may be clinically inferior to others in the treatment of specific disorders.

Tsai et al2 attribute the inferior response of the 2 brands of IVIG to the fact that the methods used in their manufacture (propiolactone for Intraglobulin, plasmin for Venoglobulin-S) affect the structure or function of the Fc (constant) portion of the Y-shaped immunoglobulin G (IgG) molecule. Many important properties are contained in the Fc portion of the molecule, including complement binding, regulation of IgG metabolism, transplacental passage, and binding to the Fc receptor of immune cells, thus inhibiting cytotoxicity.3 Indeed, therapeutic monoclonal antibodies are constructed with a human Fc segment to “humanize” their biologic properties.

Several studies have established that enzymes (pepsin and plasmin) or chemicals (acid, propiolactone) used to reduce the likelihood of reactions to IVIG or inactivate viruses can affect the biologic activity of the Fc portion of IVIG, without interfering with antibody activity.4, 5, 6

In KD, both the IVIG antibody activity and the non-antibody Fc activity are of probable therapeutic benefit. IVIG contains a spectrum of antibodies to putative microbial antigens (eg, Staphylococcal superantigens), cytokines, cytokine receptors, and endothelial antigens.7, 8 These antibodies, given early in the course of KD, inhibit microbial damage, dampen the cytokine storm, and prevent endothelial damage.

After inflammation is established in KD, the non-antibody Fc activity assumes paramount importance. High-dose IVIG inhibits monocyte/macrophage cytokine synthesis (notably the proinflammatory tumor necrosis factor-α and the pyrogen interleukin -1) blocks cytotoxic reactions and inhibits complement activation.9, 10, 11 Thus an IVIG without an intact Fc will be a less effective immunomodulator and antiinflammatory agent.

These non-antibody effects of IVIG are very important inasmuch as up to 75% of the IVIG is used for its immunomodulatory effects in neurologic disease (eg, Guillain-Barré syndrome), hematologic disease (eg, immune thrombocytopenic purpura), and cutaneous disease (eg, bullous pemphigoid).

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What are other Considerations in IVIG Brand Selection? 

The side effects of different IVIG preparations vary considerably. For example, Rosenfeld et al12 treated 90 patients with KD with 2 brands of IVIG and found a 20% incidence of non-life-threatening side effects with 1 brand and a 2% incidence with another. Experienced clinicians recognize that some brands are tolerated better than others, and all are tolerated better if given slowly with premedication, usually acetaminophen and diphenhydramine. Thus patients needing repeated treatments who do well with 1 brand should, if feasible, continue with that brand.

Serious side effects are associated with certain brands. More than 100 cases of acute kidney failure after IVIG have been recognized, usually associated with a product containing high concentrations of sucrose.13 More than 50 thrombotic events have also been reported, usually associated with a high-dose hyperosmolar product that increases blood viscosity.14

These complications can be minimized by product selection, slowing the rate of infusion and avoiding high IVIG dose (>0.5 gm/kg/d) in patients at high risk. Patients at high risk include those over 50 years, those with preexisting kidney or cardiovascular disease, and those with obesity or immobility. Aseptic meningitis, another a well-recognized complication of high-dose IVIG, is not clearly associated with a particular formulation but occurs more commonly in patients with a history of migraine headaches.15

Finally, there is variability of the cost and availability of different brands of IVIG. Our pharmacy spends more on IVIG than almost any other pharmaceutical, in spite of a committee that must approve its use. Sometimes spot shortages occur, and the pharmacy must then pay a premium price. A supply is always kept on reserve for patients with KD.

In summary, IVIG is a valuable but expensive therapeutic agent, and the clinician must be aware of brand differences, potential side effects, high cost, and limited availability.

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References 

  1. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis, treatment and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114:1708–1733
  2. Tsai M-H, Huang Y-C, Yen M-H, Li C-C, Chiu C-H, Lin P-Y, et al. Clinical responses of patients with Kawasaki to different brands of intravenous immunoglobulin. J Pediatrics. 2006;148:38–43
  3. Stiehm ER. The B-lymphocyte system: Clinical immunology. In:  Stiehm ER,  Ochs HR,  Winkelstein JA editor. Immunologic disorders in infants and children. 4th ed.. Philadelphia: Elsevier/Saunders; 2004;p. 85–108
  4. Nielsen H. Immunoglobulin preparations for intravenous administration. A review of their biologic activities and comparison of various preparation methods. Allergy. 1994;49:59–73
  5. Skvaril F, Gardi A. Differences among available immunoglobulin preparations for intravenous use. Pediatr Infect Dis J. 1988;7(Suppl):S43–S48
  6. Jungi TW, Santer M, Lerch PG, Barandun S. Effect of various treatments of gamma-globulin (IgG) for achieving intravenous tolerance of the capacity to interact with human monocyte Fc receptors. Vox Sang. 1986;51:18–26
  7. Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens. J Clin Invest. 1993;91:602–607
  8. Takahashi M. The endothelium in Kawasaki disease: the next frontier. J Pediatr. 1988;133:177–179
  9. Iwata M, Shimozato T, Tokiwa H, Tsubura E. Antipyretic activity of a human immunoglobulin preparation for intravenous use in an experimental model of fever in rabbits. Infect Immunity. 1987;55:547–554
  10. Ichiyama T, Ueno Y, Hasegawa M, Niimi A, Matsubara T, Furukawa S. Intravenous immunoglobulin inhibits NF- kappa B activation and affects Fc-gamma receptor expression in monocytes/macrophages. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:428–433
  11. Finberg RW, Newburger JW, Mikati MA, Heller AH, Burns JC. Effect of high doses of intravenously administered immune globulin on natural cell activity in peripheral blood. J Pediatr. 1992;120:376–380
  12. Rosenfeld EA, Shulman ST, Corydon KE, Mason W, Takahashi M, Kuroda C. Comparative safety and efficacy of two immune globulin products in Kawasaki disease. J Pediatr. 1995;126:1000–1003
  13. Shah S, Vervan M. Use of IV immune globulin and occurrence of associated acute renal failure and thrombosis. Am J Health-Syst Pharm. 2005;62:720–725
  14. Paran D, Herishanu Y, Elkayam O, Shopin L, Ben-Ami R. Venous and arterial thrombosis following administration of intravenous immunoglobulins. Blood Coagul Fibrinolysis. 2005;16:313–318
  15. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med. 1994;121:259–262

PII: S0022-3476(05)00901-7

doi:10.1016/j.jpeds.2005.09.019

The Journal of Pediatrics
Volume 148, Issue 1 , Pages 7-8, January 2006

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