Immunoglobulin therapy


Immunoglobulin therapy, also known as normal human immunoglobulin, is the use of a mixture of antibodies to treat a number of health conditions. 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. Depending on the formulation it can be given by injection into muscle, a vein, or under the skin. The effects last a few weeks.
Common side effects include pain at the site of injection, muscle pain, and allergic reactions. Other severe side effects include kidney problems, anaphylaxis, blood clots, and red blood cell breakdown. Use is not recommended in people with some types of IgA deficiency. Use appears to be relatively safe during pregnancy. Human immunoglobulin is made from human blood plasma. It contains antibodies against many viruses.
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. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system. Each formulation of product is somewhat different. In the United Kingdom a dose cost the NHS between 11.20 and 1,200.00 pounds depending on the type and amount. A number of specific immunoglobulin formulations are also available including for hepatitis B, rabies, tetanus, varicella infection, and Rh positive blood exposure.

Medical uses

Immunoglobulin therapy is used in a variety of conditions, many of which involve decreased or abolished antibody production capabilities, which range from a complete absence of multiple types of antibodies, to IgG subclass deficiencies, to other disorders in which antibodies are within a normal quantitative range, but lacking in quality - unable to respond to antigens as they normally should – resulting in an increased rate or increased severity of infections. In these situations, immunoglobulin infusions confer passive resistance to infection on their recipients by increasing the quantity/quality of IgG they possess. Immunoglobulin therapy is also used for a number of other conditions, including in many autoimmune disorders such as dermatomyositis in an attempt to decrease the severity of symptoms. Immunoglobulin therapy is also used in some treatment protocols for secondary immunodeficiencies such as human immunodeficiency virus, some autoimmune disorders, some neurological diseases some acute infections and some complications of organ transplantation.
Immunoglobulin therapy is especially useful in some acute infection cases such as pediatric HIV infection and is also considered the standard of treatment for some autoimmune disorders such as Guillain–Barré syndrome. The high demand which coupled with the difficulty of producing immunoglobulin in large quantities has resulted in increasing global shortages, usage limitations and rationing of immunoglobulin.
Different national bodies and medical associations have established varying standards for the use of immunoglobulin therapy.

United Kingdom

The United Kingdom's National Health Service recommends the routine use of immunoglobulin for a variety of conditions including primary immunodeficiencies and a number of other conditions, but recommends against the use of immunoglobulin in sepsis, multiple sclerosis, neonatal sepsis, and pediatric HIV.

United States

The American Academy of Allergy, Asthma, and Immunology most strongly supports the use of immunoglobulin for primary immunodeficiencies, while noting that such usage actually accounts for a minority of usage and acknowledging that immunoglobulin supplementation can be appropriately used for a number of other conditions, including neonatal sepsis, considered in cases of HIV, considered as a second line treatment in relapsing-remitting multiple sclerosis, but recommending against its use in such conditions as chronic fatigue syndrome, PANDAS until further evidence to support its use is found, cystic fibrosis, and a number of other conditions.

Canada

The National Advisory Committee on Blood and Blood Products of Canada and Canadian Blood Services have also developed their own separate set of guidelines for the appropriate use of immunoglobulin therapy, which strongly support the use of immunoglobulin therapy in primary immunodeficiencies and some complications of HIV, while remaining silent on the issues of sepsis, multiple sclerosis, and chronic fatigue syndrome.

Australia

The Australian Red Cross Blood Service developed their own guidelines for the appropriate use of immunoglobulin therapy in 1997. Immunoglobulin is funded under the National Blood Supply and indications are classified as either an established or emerging therapeutic role or conditions for which immunoglobulin use is in exceptional circumstances only.
Subcutaneous immunoglobulin access programs have been developed to facilitate hospital based programs. In Australia subcutaneous immunoglobulin is approved for primary immunodeficiency disease, specific antibody disease, acquired or secondary hypogammaglobulinemia and chronic inflammatory demyelinating polyneuropathy.

European Union

Brands include HyQvia, Privigen, Hizentra, Kiovig, and Flebogamma DIF.
In the EU human normal immunoglobulin is used in people whose blood does not contain enough antibodies, also known as immunoglobulins. It is used to treat the following conditions:
It is indicated for replacement therapy in adults and children in primary immunodeficiency syndromes such as:
Flebogamma DIF is indicated for the replacement therapy in adults, children and adolescents in:
and for the immunomodulation in adults, children and adolescents in:
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. 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, prednisone or another oral steroid.
Local side effects of immunoglobulin infusions most frequently include an injection site reaction, itching, rash, and hives. 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.
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. 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. Some immunoglobulin solutions also contain isohemagglutinins, which in rare circumstances can cause hemolysis by the isohemagglutinins triggering phagocytosis.
In the case of less serious side effects, a patient's infusion rate can be adjusted downwards until the side effects become tolerable, while in the case of more serious side effects, emergency medical attention should be sought.
Immunoglobulin therapy also interferes with the ability of the body to produce a normal immune response to an attenuated live virus vaccine for up to a year, can result in falsely elevated blood glucose levels, and can interfere with many of the IgG-based assays often used to diagnose a patient with a particular infection.

Routes of administration

1950s – intramuscular

After immunoglobulin therapy's discovery and description in Pediatrics in 1952, weekly intramuscular injections of immunoglobulin were the norm until intravenous formulations began to be introduced in the 1980s. 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.

1980s – intravenous

Intravenous formulations began to be approved in the 1980s, which represented a significant improvement over intramuscular objections, 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.

1990s - subcutaneous

The first description of a subcutaneous route of administration for immunoglobulin therapy dates back to 1980, 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.
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, 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.
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. A number of other trade 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 may suffer intolerable side effects with subcutaneous immunoglobulin that they do not with intravenous immunoglobulin.
Although intravenous was the preferred route for immunoglobulin therapy for many years, in 2006, the US Food and Drug Administration approved the first preparation of immunoglobulin that was designed exclusively for subcutaneous use.

Mechanism of action

The precise mechanism by which immunoglobulin therapy suppresses harmful inflammation is likely multifactorial. For example, it has been reported that immunoglobulin therapy can block Fas-mediated cell death.
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. 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. 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.
There are several other proposed mechanisms of action and the actual primary targets of immunoglobulin therapy in autoimmune disease are still being elucidated. 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. Once these immune complexes are formed, they can interact with Fc receptors on dendritic cells, 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, 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.
A recent 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.

Society and culture

Brand names

As biologicals, various trade names of immunoglobulin products are not necessarily interchangeable, and care must be exercised when changing between them. Trade names of intravenous immunoglobulin formulations include Flebogamma, Gamunex, Privigen, Octagam and Gammagard, while trade names of subcutaneous formulations include Cutaquig, Cuvitru, HyQvia, Hizentra, Gamunex-C, and Gammaked.

Supply issues

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 used across the world, including more than 50% of the European Union's supply. 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.
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.

Research

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. In May 2020, the USA approved a phase three clinical trial on the efficacy and safety of high-concentration intravenous immune globulin therapy in severe COVID-19.