Intravenous immunoglobulin

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:
 * Immune deficiencies such as X-linked agammaglobulinemia, hypogammaglobulinemia (primary immune deficiencies), and acquired compromised immunity conditions (secondary immune deficiencies) featuring low antibody levels.
 * Autoimmune diseases, e.g. immune thrombocytopenia, and inflammatory diseases, e.g. Kawasaki disease.
 * Acute infections.

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

IVIG 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.

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

As asthma treatment
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. 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. 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.

Mechanism of action
The precise mechanism by which IVIG suppresses harmful inflammation has not been definitively established but is believed to involve the inhibitory Fc receptor. 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. Once these immune complexes are formed, they interact with activating Fc receptors on dendritic cells 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. Recent studies on T cell regulatory epitopes, Tregtiopes, might explain some of the tolergenic and regulatory effects of IVIG.

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.

IVIG notes

 * 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
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
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. IVIG is
 * Specifically recommended for routine use for
 * 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
 * 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
 * Aplastic anemia
 * Hematopoietic stem cell transplantation
 * Contraindicated for
 * Heparin-induced thrombocytopenia

FDA-approved indications for IVIG
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.
 * Allogeneic bone marrow transplant
 * 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 Talecris 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 Phase III testing in the US (as of December 2008)

 * Alzheimer's Disease

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.

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. However, Gammagard failed a phase III clinical trial in 2013.

Off-label uses

 * Adult HIV
 * Alzheimer's disease
 * Autism
 * Behçet's disease
 * Capillary leak syndrome
 * Chronic fatigue syndrome
 * Clostridium difficile colitis
 * Dermatomyositis and polymyositis
 * Graves' ophthalmopathy
 * Guillain-Barré syndrome
 * Kimura disease
 * Muscular dystrophy
 * Inclusion body myositis
 * Infertility
 * Lambert-Eaton syndrome
 * Lennox-Gastaut
 * Lupus erythematosus
 * Multifocal motor neuropathy
 * Multiple sclerosis
 * Myasthenia gravis
 * Neonatal alloimmune thrombocytopenia
 * Parvovirus B19
 * Pemphigus
 * Post-transfusion purpura
 * Renal transplant rejection
 * Spontaneous abortion/miscarriage
 * Sjogren's Syndrome
 * Stiff person syndrome
 * Susac's syndrome
 * Opsoclonus myoclonus
 * Severe sepsis and septic shock in critically ill adults
 * Toxic epidermal necrolysis


 * 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.

Complications and 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
 * venous thrombosis
 * aseptic meningitis