Immunoglobulin therapy

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 four major disease categories:

Primary Immune deficiencies such as X-linked agammaglobulinemia (XLA), Common variable immunodeficiency (CVID) and hypogammaglobulinemia.
Acquired compromised immunity conditions (secondary immune deficiencies) featuring low antibody levels.
Autoimmune diseases, e.g. immune thrombocytopenia, inflammatory diseases, Kawasaki disease, and Guillain-Barre Syndrome.
Acute infections.

There are numerous trade names of IVIG products, including Flebogamma, Gamunex, Privigen and Gammagard.

Medical use

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.^{[citation needed]}

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

Side effects

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:

headache
dermatitis - usually peeling of the skin of the palms and soles.
infection (such as HIV or viral hepatitis) by contaminated blood product; there is also an as yet unknown risk of contracting variant CJD (vCJD) however the process whereby the product is extracted shows that the contaminants are usually not present in the product.
pulmonary edema from fluid overload, due to the high colloid oncotic pressure of IVIG
allergic/anaphylactic reactions; for example, anaphylactic shock, especially in IgA deficient patients, who by definition can still produce IgG antibodies (IgA deficient patients are more likely to produce IgG against the IVIG administration than normal patients).
damage such as hepatitis caused directly by antibodies contained in the pooled IVIG.
acute kidney injury^[2]
venous thrombosis
aseptic meningitis
immune-mediated hemolytic reactions (high doses and/or continual dosing)

Interference with laboratory testing (blood typing)

false positive antibody screen
isohemagglutinins have been identified in IVIG solutions, which can alter the reverse type^[3]

Mechanism of action

The precise mechanism by which IVIG suppresses harmful inflammation is likely multifactorial. For example, it has been reported that IVIG can block Fas-mediated cell death.^[4]

Perhaps a more popular theory is that the immunosuppressive effects of IVIG are mediated through IgG's Fc glycosylation. By binding to receptors on antigen presenting cells, IVIG can increase the expression of the inhibitory Fc receptor, FcgRIIB, and shorten the half-life of auto-reactive antibodies.^[5]^[6]^[7] The ability of IVIG to suppress pathogenic immune responses by this mechanism is dependent on the presence of a sialylated glycan at position CH2-84.4 of IgG.^[5] Specifically, de-sialylated preparations of IVIG lose their therapeutic activity and the anti-inflammatory effects of IVIG can be recapitulated by administration of recombinant sialylated IgG1 Fc.^[5]

There are several other proposed mechanisms of action and the actual primary targets of IVIG in autoimmune disease are still being elucidated. Some believe that IVIG may work via a multi-step model where the injected IVIG first forms a type of immune complex in the patient.^[8] Once these immune complexes are formed, they can interact with Fc receptors on dendritic cells^[9] which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state.

Other proposed mechanisms include the possibility that donor antibodies may bind directly with the abnormal host antibodies, stimulating their removal; the possibility that IgG stimulates the host's complement system, leading to enhanced removal of all antibodies, including the harmful ones; and the ability of IVIG to block the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis. Indeed, it is becoming more clear that IVIG can bind to a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to auto reactivity and induction of tolerance to self.^[10]^[5]

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.^[11]

Canadian guidelines

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.^[12] IVIG is

Specifically recommended for routine use for^[12]

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^[12]

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^[12]

Contraindicated for^[12]

Heparin-induced thrombocytopenia

US rules

FDA-approved indications

Allogeneic bone marrow transplant
IgG deficiency
Chronic lymphocytic leukemia
Common variable immunodeficiency (CVID) a group of approximately 150 primary immunodeficiencies (PIDs), which have a common set of features (including hypogammaglobulinemia) but which have different underlying causes
Idiopathic thrombocytopenic purpura
Pediatric HIV
Primary immunodeficiencies
Kawasaki disease
Chronic inflammatory demyelinating polyneuropathy (CIDP). Only the "Gamunex" brand manufactured by Grifols is approved for CIDP (in 2008), under the U.S. Orphan Drug law provisions
Kidney transplant with a high antibody recipient or with an ABO incompatible donor

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 .^{[clarification needed]}

Off-label uses

In chronic lymphocytic leukemia and multiple myeloma, as well as various rare deficiencies of immunoglobulin synthesis (e.g. X-linked agammaglobulinemia, hypogammaglobulinemia), IVIG is administered to maintain adequate immunoglobulin levels to prevent infections.

References

^ Hughes, RA (Sep 23, 2003). "Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology" (PDF). Neurology. 61 (6): 736–40. doi:10.1212/WNL.61.6.736. PMID 14504313. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Daw, Z; Padmore, R; Neurath, D; Cober, N; Tokessy, M; Desjardins, D; Olberg, B; Tinmouth, A; Giulivi, A (August 2008). "Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis". Transfusion. 48 (8): 1598–601. PMID 18466176.
^ Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, Hunziker T, Saurat JH, Tschopp J, French LE (1998). "Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin". Science. 282 (5388): 490–3. doi:10.1126/science.282.5388.490. PMID 9774279.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c ^d Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun. 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMID 25578468.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ 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.
^ 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.
^ 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.
^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ 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.
^ 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.
^ ^a ^b ^c ^d ^e Anderson, D (April 2007). "Guidelines on the use of intravenous immune globulin for hematologic conditions" (PDF). Transfusion medicine reviews. 21 (2 Suppl 1): S9–56. doi:10.1016/j.tmrv.2007.01.001. PMID 17397769. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Gever, John. "IVIG Stops Alzheimer's in Its Tracks". MedPage Today. Retrieved 17 July 2012.
^ 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.
^ 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.
^ 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.
^ 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).
^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)