Immunoglobulin therapy
Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin) to treat several health conditions.[13][14] These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy, Kawasaki disease, certain cases of HIV/AIDS and measles, Guillain–Barré syndrome, and certain other infections when a more specific immunoglobulin is not available.[13] Depending on the formulation it can be given by injection into muscle, a vein, or under the skin.[13] The effects last a few weeks.[14]
Clinical data
Flebogamma, Gammagard, Hizentra, others
normal human immunoglobulin (HNIG), human normal immunoglobulin (HNIG)
- AU: Exempt[1]
- none
Common side effects include pain at the site of injection, muscle pain, and allergic reactions.[13] Other severe side effects include kidney problems, anaphylaxis, blood clots, and red blood cell breakdown.[13] Use is not recommended in people with some types of IgA deficiency.[13] Use appears to be relatively safe during pregnancy.[13] Human immunoglobulin is made from human blood plasma.[13] It contains antibodies against many viruses.[14]
Human immunoglobulin therapy first occurred in the 1930s and a formulation for injection into a vein was approved for medical use in the United States in 1981.[15] It is on the World Health Organization's List of Essential Medicines.[16][17] Each formulation of the product is somewhat different.[14] A number of specific immunoglobulin formulations are also available including for hepatitis B, rabies, tetanus, varicella infection, and Rh positive blood exposure.[14]
Side effects[edit]
Although immunoglobulin is frequently used for long periods of time and is generally considered safe, immunoglobulin therapy can have severe adverse effects, both localized and systemic. Subcutaneous administration of immunoglobulin is associated with a lower risk of both systemic and localized risk when compared to intravenous administration (hyaluronidase-assisted subcutaneous administration is associated with a greater frequency of adverse effects than traditional subcutaneous administration but still a lower frequency of adverse effects when compared to intravenous administration). Patients who are receiving immunoglobulin and experience adverse events are sometimes recommended to take acetaminophen and diphenhydramine before their infusions to reduce the rate of adverse effects. Additional premedication may be required in some instances (especially when first getting accustomed to a new dosage), prednisone or another oral steroid.
Local side effects of immunoglobulin infusions most frequently include an injection site reaction (reddening of the skin around the injection site), itching, rash, and hives.[39] Less serious systemic side effects to immunoglobulin infusions include an increased heart rate, hyper or hypotension, an increased body temperature, diarrhea, nausea, abdominal pain, vomiting, arthralgia or myalgia, dizziness, headache, fatigue, fever, and pain.[39]
Serious side effects of immunoglobulin infusions include chest discomfort or pain, myocardial infarction, tachycardia, hyponatremia, hemolysis, hemolytic anemia, thrombosis, hepatitis, anaphylaxis, backache, aseptic meningitis, acute kidney injury, hypokalemic nephropathy, pulmonary embolism, and transfusion related acute lung injury.[39] There is also a small chance that even given the precautions taken in preparing immunoglobulin preparations, an immunoglobulin infusion may pass a virus to its recipient.[39] Some immunoglobulin solutions also contain isohemagglutinins, which in rare circumstances can cause hemolysis by the isohemagglutinins triggering phagocytosis.[40]
IVIG has long been known to induce a decrease in peripheral blood neutrophil count, or neutropenia in neonates,[41] and in patients with Idiopathic Thrombocytopenic Purpura, resolving spontaneously and without complications within 48 h.[42] Possible pathomechanisms include apoptosis/cell death due to antineutrophil antibodies with or without neutrophil migration into a storage pool outside the blood circulation.[43]
Immunoglobulin therapy interferes with the ability of the body to produce a normal immune response to an attenuated live-virus vaccine (like MMR) for up to a year,[39] can result in falsely elevated blood glucose levels,[39] and can interfere with many of the IgG-based assays often used to diagnose a patient with a particular infection.[44]
Routes of administration[edit]
1950s – intramuscular[edit]
After immunoglobulin therapy's discovery in 1952, weekly intramuscular injections of immunoglobulin (IMIg) were the norm until intravenous formulations (IVIg) began to be introduced in the 1980s.[45] During the mid and late 1950s, one-time IMIg injections were a common public health response to outbreaks of polio before the widespread availability of vaccines. Intramuscular injections were extremely poorly tolerated due to their extreme pain and poor efficacy – rarely could intramuscular injections alone raise plasma immunoglobulin levels enough to make a clinically meaningful difference.[45]
1980s – intravenous[edit]
Intravenous formulations began to be approved in the 1980s, which represented a significant improvement over intramuscular injections, as they allowed for a sufficient amount of immunoglobulin to be injected to reach clinical efficacy, although they still had a fairly high rate of adverse effects (though the addition of stabilizing agents reduced this further).[45]
1990s – subcutaneous[edit]
The first description of a subcutaneous route of administration for immunoglobulin therapy dates back to 1980,[46] but for many years subcutaneous administration was considered to be a secondary choice, only to be considered when peripheral venous access was no longer possible or tolerable.[45]
During the late 1980s and early 1990s, it became obvious that for at least a subset of patients the systemic adverse events associated with intravenous therapy were still not easily tolerable, and more doctors began to experiment with subcutaneous immunoglobulin administration, culminating in an ad hoc clinical trial in Sweden of 3000 subcutaneous injections administered to 25 adults (most of whom had previously experienced systemic adverse effects with IMIg or IVIg), where no infusion in the ad hoc trial resulted in a severe systemic adverse reaction, and most subcutaneous injections were able to be administered in non-hospital settings, allowing for considerably more freedom for the people involved.[45]
In the later 1990s, large-scale trials began in Europe to test the feasibility of subcutaneous immunoglobulin administration, although it was not until 2006 that the first subcutaneous-specific preparation of immunoglobulin was approved by a major regulatory agency (Vivaglobin, which was voluntarily discontinued in 2011).[45][47] A number of other brand names of subcutaneous immunoglobulin have since been approved, although some small-scale studies have indicated that a particular cohort of patients with common variable immunodeficiency (CVID) may develop intolerable side effects with subcutaneous immunoglobulin (SCIg) that they do not with intravenous immunoglobulin (IVIg).[45]
Although intravenous was the preferred route for immunoglobulin therapy for many years, in 2006, the US Food and Drug Administration (FDA) approved the first preparation of immunoglobulin that was designed exclusively for subcutaneous use.[45]
Mechanism of action[edit]
The precise mechanism by which immunoglobulin therapy suppresses harmful inflammation is likely multifactorial.[48] For example, it has been reported that immunoglobulin therapy can block Fas-mediated cell death.[49]
Perhaps a more popular theory is that the immunosuppressive effects of immunoglobulin therapy 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.[50][51][52] The ability of immunoglobulin therapy to suppress pathogenic immune responses by this mechanism is dependent on the presence of a sialylated glycan at position CH2-84.4 of IgG.[50] Specifically, de-sialylated preparations of immunoglobulin lose their therapeutic activity and the anti-inflammatory effects of IVIG can be recapitulated by administration of recombinant sialylated IgG1 Fc.[50]
Sialylated-Fc-dependent mechanism was not reproduced in other experimental models suggesting that this mechanism is functional under a particular disease or experimental settings.[53][54][55][56] On the other hand, several other mechanisms of action and the actual primary targets of immunoglobulin therapy have been reported. In particular, F(ab')2-dependent action of immunoglobulin to inhibit activation of human dendritic cells,[57] induction of autophagy,[58] induction of COX-2-dependent PGE-2 in human dendritic cells leading to expansion of regulatory T cells,[59] inhibition of pathogenic Th17 responses,[60] and induction of human basophil activation and IL-4 induction via anti-IgE autoantibodies.[61][62] Some believe that immunoglobulin therapy may work via a multi-step model where the injected immunoglobulin first forms a type of immune complex in the patient.[63] Once these immune complexes are formed, they can interact with Fc receptors on dendritic cells,[64] 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 immunoglobulin 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 immunoglobulin can bind to a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to autoreactivity and induction of tolerance to self.[50][65]
A report stated that immunoglobulin application to activated T cells leads to their decreased ability to engage microglia. As a result of immunoglobulin 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 immunoglobulin may affect inflammation of the central nervous system in autoimmune inflammatory diseases.[66]
Hyperimmune globulin[edit]
Hyperimmune globulins are a class of immunoglobulins prepared in a similar way as for normal human immunoglobulin, except that the donor has high titers of antibody against a specific organism or antigen in their plasma. Some agents against which hyperimmune globulins are available include hepatitis B, rabies, tetanus toxin, varicella-zoster, etc. Administration of hyperimmune globulin provides "passive" immunity to the patient against an agent. This is in contrast to vaccines that provide "active" immunity. However, vaccines take much longer to achieve that purpose while hyperimmune globulin provides instant "passive" short-lived immunity. Hyperimmune globulin may have serious side effects, thus usage is taken very seriously.
Hyperimmune serum and plasma contain high amounts of an antibody, as a consequence of disease convalescence[67] or of repeated immunization.[68] Hyperimmune plasma is used in veterinary medicine,[69] and hyperimmune plasma derivatives are used to treat snakebite.[70] It has been hypothesized that hyperimmune serum may be an effective therapy for persons infected with the Ebola virus.[71]
Society and culture[edit]
Brand names[edit]
As biologicals, various brand names of immunoglobulin products are not necessarily interchangeable, and care must be exercised when changing between them.[73] Brand names of intravenous immunoglobulin formulations include Flebogamma, Gamunex, Privigen, Octagam, and Gammagard, while brand names of subcutaneous formulations include Cutaquig, Cuvitru, HyQvia, Hizentra,[27][74][75] Gamunex-C, and Gammaked.[76]
Supply issues[edit]
The United States is one of a handful of countries that allow plasma donors to be paid, meaning that the US supplies much of the plasma-derived medicinal products (including immunoglobulin) used across the world, including more than 50% of the European Union's supply.[77] The Council of Europe has officially endorsed the idea of not paying for plasma donations for both ethical reasons and reasons of safety, but studies have found that relying on entirely voluntary plasma donation leads to shortages of immunoglobulin and forces member countries to import immunoglobulin from countries that do compensate donors.[77]
In Australia, blood donation is voluntary and therefore to cope with increasing demand and to reduce the shortages of locally produced immunoglobulin, several programs have been undertaken including adopting plasma for first time blood donors, better processes for donation, plasma donor centres and encouraging current blood donors to consider plasma only donation.[78]
Research[edit]
Experimental results from a small clinical trial in humans suggested protection against the progression of Alzheimer's disease, but no such benefit was found in a subsequent phase III clinical trial.[79][80][81] In May 2020, the US approved a phase three clinical trial on the efficacy and safety of high-concentration intravenous immune globulin therapy in severe COVID-19.[82] Efficacy of heterologous immunoglobulin derivatives has been demonstrated in clinical trials of antivenoms for scorpion sting[83] and for snakebite.[84]