Intravenous immunoglobulin

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Intravenous immunoglobulin (IVIG) is a blood product administered intravenously. It contains the pooled, polyvalent, IgG antibodies extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months. It is mainly used as treatment in three major disease categories:

Trade names of IVIG include Flebogamma, Gamunex, Privigen and Gammagard.

IVIG use[edit]

IVIG is given as a plasma protein replacement therapy (IgG) for immune deficient patients who have decreased or abolished antibody production capabilities. In these immune deficient patients, IVIG is administered to maintain adequate antibody levels to prevent infections and confers a passive immunity. Treatment is given every 3–4 weeks. In the case of patients with autoimmune disease, IVIG is administered at a high dose (generally 1-2 grams IVIG per kg body weight) to attempt to decrease the severity of the autoimmune diseases such as dermatomyositis. Currently, IVIg is being increasingly used off-label in a number of pathological conditions; the increasing world-wide usage of IVIg may lead to shortages of this beneficial drug.

IVIG is useful in some acute infection cases such as pediatric HIV infection as well as autoimmune, such as Guillain–Barré syndrome.[1]

As asthma treatment[edit]

Asthma is a condition which can have many causes. In patients with both immune abnormalities and an infection causing asthma, the triggering infection could be eliminated with IVIG therapy.[2] However, most asthma patients have a normal immune system and their asthma is the result of lower airway inflammation which can be managed in the context of a healthy immune system.[2][3] Despite popularity of use, IVIG is not recommended for recurrent asthma infections unless the patient presents an impaired response to vaccine immunizations or natural infections.[2][3]

Mechanism of action[edit]

The precise mechanism by which IVIG suppresses harmful inflammation has not been definitively established but is believed to involve the inhibitory Fc receptor.[4][5] However, the actual primary target(s) of IVIG in autoimmune disease are still unclear. IVIG may work via a multi-step model where the injected IVIG first forms a type of immune complex in the patient.[6] Once these immune complexes are formed, they interact with activating Fc receptors on dendritic cells[7] which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state.

Additionally, the donor antibody may bind directly with the abnormal host antibody, stimulating its removal. Alternatively, the massive quantity of antibody may stimulate the host's complement system, leading to enhanced removal of all antibodies, including the harmful ones. IVIG also blocks the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis.

IVIG may also regulate the immune response by reacting with a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to autoreactivity and induction of tolerance to self.[8] Recent studies on T cell regulatory epitopes, Tregtiopes, might explain some of the tolergenic and regulatory effects of IVIG.[9]

A recent report stated that IVIG application to activated T cells leads to their decreased ability to engage microglia. As a result of IVIG treatment of T cells, the findings showed reduced levels of tumor necrosis factor-alpha and interleukin-10 in T cell-microglia co-culture. The results add to the understanding of how IVIG may affect inflammation of the central nervous system in autoimmune inflammatory diseases.[10]

IVIG notes[edit]

  • IVIG is an infusion of IgG antibodies only. Therefore, peripheral tissues that are defended mainly by IgA antibodies, such as the eyes, lungs, gut and urinary tract are not fully protected by the IVIG treatment.
  • X-linked agammaglobulinemia patients are immune to the most dangerous adverse effect, anaphylactic shock, as they do not have the antibodies to react against the treatment. Anaphylactic shock has a higher chance to occur in IgA deficient patients which do have other antibody types.
  • In case of recurring side effects, it is recommended to slow the pace of the IVIG administration and to reduce the dosage. It is also advisable to change IVIG brand, as some people react against a specific brand.
  • If the patient is diabetic, he should take into consideration the medium in which the antibodies are solubilized in the IVIG treatment, as some brand solubilize antibodies with high concentrated sugars (such as sucrose and maltose).
  • U.S. Food and Drug Administration (FDA) guidelines for IVIG state the product should be:
    • Prepared out of at least 1,000 different human donors.
    • All four IgG subgroups (1-4) should be present.
    • The IgG should maintain biological activity and lifetime of at least 21 days.
    • Does not contain samples which are HIV, hepatitis B, hepatitis C positive.
    • Screened and treated in a manner that destroys viruses.
  • IVIG is also considered a modulator of the immune system and was shown to be beneficial in treating numerous autoimmune diseases such as relapsing, myasthenia gravis, pemphigus, polymyositis (PM), dermatomyositis (DM), Wegener's granulomatosis (WG), Churg-Strauss syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) and more.
  • IVIG can be given to pregnant women.
  • IVIG is also used as a treatment for unexplained recurring miscarriages. The effectiveness of the therapy is controversial.
  • IVIG cost is stable but over $75/g. ($15,000 for a 100 kg (220 lbs) person at 2g/kg)

Dosage[edit]

Dosage of IVIG is dependent on indication.

For primary immune dysfunction 100 to 400 mg/kg of body weight every 3 to 4 weeks is implemented. However that is just a starting dose. The dose needs to be adjusted on the needs of the patient. The therapeutic dose is the one that prevents serious infections and prevents the patient from getting more infections than the general population.

For neurological and autoimmune diseases 2 grams per kilogram of body weight is implemented for three to six months over a five day course once a month. Then maintenance therapy of 100 to 400 mg/kg of body weight every 3 to 4 weeks follows.

Canadian guidelines[edit]

National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services has developed an evidence-based practice guideline on the use of IVIG for hematologic conditions.[11] IVIG is

Specifically recommended for routine use for[11]
  • Acquired red cell aplasia
  • Acquired hypogammaglobulinemia (secondary to malignancy)
  • Fetal-neonatal alloimmune thrombocytopenia
  • Hemolytic disease of the newborn
  • HIV-associated thrombocytopenia
  • Idiopathic thrombocytopenic purpura; and
  • Posttransfusion purpura.
Not recommended for use, except under certain life-threatening circumstances[11]
  • 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
  • Viral-associated hemophagocytic syndrome
Not recommended for[11]
  • Aplastic anemia
  • Hematopoietic stem cell transplantation
Contraindicated for[11]
  • Heparin-induced thrombocytopenia

US rules[edit]

FDA-approved indications for IVIG[edit]

In 2004 the FDA approved the Cedars-Sinai IVIG Protocol which has been 90-95% successful in removing antibodies from the blood of kidney transplant recipients so that they can accept a living donor kidney from any healthy donor no matter blood type (ABO incompatible) or tissue match.

In Phase III testing in the US (as of December 2008)[edit]

Early experimental results in 2012 from a small clinical trial in humans have shown hints that IVIG may protect against the progression of Alzheimer's Disease.[12][13] Memory enhancing effects of IVIG have also been reported in an animal model, associated with a reduction in Aβ oligomers in the brain.[14]

According to experts at the Alzheimer's Association International Conference 2012 in Vancouver, the immune therapy called Gammagard is the first long-term treatment shown to halt the progression of Alzheimer's disease. [15] However, Gammagard failed a phase III clinical trial in 2013.[16]

Off-label uses[edit]

Complications and side effects[edit]

Although routine use of IVIG is common practice, sometimes for long term treatments, and is considered safe, complications of IVIG therapy are known and include:

References[edit]

  1. ^ Hughes, RA; Wijdicks, EF; Barohn, R; Benson, E; Cornblath, DR; Hahn, AF; Meythaler, JM; Miller, RG; Sladky, JT; Stevens, JC; Quality Standards Subcommittee of the American Academy of, Neurology (Sep 23, 2003). "Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology.". Neurology 61 (6): 736–40. doi:10.1212/WNL.61.6.736. PMID 14504313. 
  2. ^ a b c Primary Immunodeficiency Committee Of The American Academy Of Allergy; Orange, J.; Hossny, E.; Weiler, C.; Ballow, M.; Berger, M.; Bonilla, F.; Buckley, R.; Chinen, J.; El-Gamal, Y.; Mazer, B.; Nelson Jr, R. P.; Patel, D. D.; Secord, E.; Sorensen, R. U.; Wasserman, R. L.; Cunningham-Rundles, C. (2006). "Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology". Journal of Allergy and Clinical Immunology 117 (4): S525–S553. doi:10.1016/j.jaci.2006.01.015. PMID 16580469.  edit
  3. ^ a b American Academy of Allergy, Asthma, and Immunology. "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation (American Academy of Allergy, Asthma, and Immunology). Retrieved August 14, 2012. 
  4. ^ Gern JE (August 2002). "Antiinflammatory Activity of IVIG Mediated through the Inhibitory FC Receptor". Pediatrics 110 (2): 467–8. doi:10.1542/peds.110.2.S1.467-b. 
  5. ^ Nimmerjahn F, Ravetch JV (January 2007). "The antiinflammatory activity of IgG: the intravenous IgG paradox". J. Exp. Med. 204 (1): 11–5. doi:10.1084/jem.20061788. PMC 2118416. PMID 17227911. 
  6. ^ Clynes R (January 2005). "Immune complexes as therapy for autoimmunity". J. Clin. Invest. 115 (1): 25–7. doi:10.1172/JCI23994. PMC 539209. PMID 15630438. 
  7. ^ Siragam V, Crow AR, Brinc D, Song S, Freedman J, Lazarus AH (June 2006). "Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells". Nat. Med. 12 (6): 688–92. doi:10.1038/nm1416. PMID 16715090. 
  8. ^ Bayry J, Thirion M, Misra N, et al. (October 2003). "Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases". Neurol. Sci. 24 Suppl 4: S217–21. doi:10.1007/s10072-003-0081-7. PMID 14598046. 
  9. ^ De Groot, Anne; W. Martin; L. Cousens; F. Mingozzi (Oct 2013). "Tregitope Peptides: The Active Pharmaceutical Ingredient of IVIG?". Clinical and Developmental Immunology (Article ID 493138). 
  10. ^ Janke AD, Yong VW (April 2006). "Impact of IVIg on the interaction between activated T cells and microglia". Neurol. Res. 28 (3): 270–4. doi:10.1179/016164106X98143. PMID 16687052. 
  11. ^ a b c d e Anderson, D; Ali, K; Blanchette, V; Brouwers, M; Couban, S; Radmoor, P; Huebsch, L; Hume, H; McLeod, A; Meyer, R; Moltzan, C; Nahirniak, S; Nantel, S; Pineo, G; Rock, G (April 2007). "Guidelines on the use of intravenous immune globulin for hematologic conditions". Transfusion medicine reviews 21 (2 Suppl 1): S9–56. doi:10.1016/j.tmrv.2007.01.001. PMID 17397769. 
  12. ^ Andrew Pollack (July 17, 2012). "Small Trial Hints Drug Can Slow Alzheimer’s". New York Times. Retrieved 2012-07-19. 
  13. ^ "Experimental Alzheimer's drug Gammagard may stall memory decline, small study suggests". CBS News. 2012-07-17. Retrieved 2012-07-19. 
  14. ^ St-Amour I, Paré I, Tremblay C, Coulombe K, Bazin R, Calon F. (2014). "IVIg protects the 3xTg-AD mouse model of Alzheimer's disease from memory deficit and Abeta pathology.". J Neuroinflammation 11 (1): 54. doi:10.1186/1742-2094-11-54. PMID 24655894. 
  15. ^ "Most Popular E-mail Newsletter". USA Today. 2012-07-17. 
  16. ^ "Promising Alzheimer's drug Gammagard fails key study". CBS News. 7 May 2013. 
  17. ^ Gever, John. "IVIG Stops Alzheimer's in Its Tracks". MedPage Today. Retrieved 17 July 2012. 
  18. ^ Beales, IL (December 1998). "Gastrointestinal involvement in Behçet's syndrome". The American journal of gastroenterology 93 (12): 2633. doi:10.1111/j.1572-0241.1998.02633.x. PMID 9860455. 
  19. ^ Shutty, B; Garg, KJ; Swender, D; Chernin, L; Tcheurekdjian, H; Hostoffer, R (July 2012). "Optimal use of ivig in a patient with Behçet syndrome and common variable immunodeficiency". Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 109 (1): 84. doi:10.1016/j.anai.2012.05.014. PMID 22727170. 
  20. ^ Seider, N; Beiran, I; Scharf, J; Miller, B (November 2001). "Intravenous immunoglobulin therapy for resistant ocular Behçet's disease". The British journal of ophthalmology 85 (11): 1287–8. doi:10.1136/bjo.85.11.1287. PMC 1723778. PMID 11673289. 
  21. ^ Hernandez-Bautista, V; Yamazaki-Nakashimada, MA; Vazquez-García, R; Stamatelos-Albarrána, D; Carrasco-Daza, D; Rodríguez-Lozano, AL (December 2011). "Treatment of Kimura Disease With Intravenous Immunoglobulin". PEDIATRICS 128 (6). 
  22. ^ Laupland KB, Kirkpatrick AW, Delaney A (December 2007). "Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis". Crit. Care Med. 35 (12): 2686–92. doi:10.1097/01.CCM.0000295312.13466.1C. PMID 18074465. 
  23. ^ Aaron Graumann, MS-IV And Edward T. Zawada Jr, MD (March 2010). "Case Report: Acute Renal Failure After Administering Intravenous Immunoglobulin". Postgraduate Medicine. 122 (2): 142–147. doi:10.3810/pgm.2010.03.2131. PMID 20203465. 

Further reading[edit]