Medicine:Immunoglobulin therapy

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Short description: Medical treatment
Immunoglobulin therapy
Clinical data
Trade namesFlebogamma, Gammagard, Hizentra, others
Other namesnormal human immunoglobulin (HNIG), human normal immunoglobulin (HNIG)
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administration		Intravenous, intramuscular, subcutaneous
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Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin or NHIG) to treat several health conditions.[6][7] 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.[6] Depending on the formulation it can be given by injection into muscle, a vein, or under the skin.[6] The effects last a few weeks.[7]

Common side effects include pain at the site of injection, muscle pain, and allergic reactions.[6] Other severe side effects include kidney problems, anaphylaxis, blood clots, and red blood cell breakdown.[6] Use is not recommended in people with some types of IgA deficiency.[6] Use appears to be relatively safe during pregnancy.[6] Human immunoglobulin is made from human blood plasma.[6] It contains antibodies against many viruses.[7]

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.[8] It is on the World Health Organization's List of Essential Medicines.[9][10] Each formulation of the product is somewhat different.[7] A number of specific immunoglobulin formulations are also available including for hepatitis B, rabies, tetanus, varicella infection, and Rh positive blood exposure.[7]

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 (usually involving IgG2 or IgG3), 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 (HIV), some autoimmune disorders (such as immune thrombocytopenia and Kawasaki disease), some neurological diseases (multifocal motor neuropathy, stiff person syndrome, multiple sclerosis and myasthenia gravis) some acute infections and some complications of organ transplantation.[11]

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.[12][13] 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.[14]

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 (unless a specific toxin has been identified), multiple sclerosis, neonatal sepsis, and pediatric HIV/AIDS.[15]

United States

The American Academy of Allergy, Asthma, and Immunology 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,[16] including neonatal sepsis (citing a sixfold decrease in mortality), considered in cases of HIV (including pediatric 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 (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) until further evidence to support its use is found (though noting that it may be useful in PANDAS patients with an autoimmune component), cystic fibrosis, and a number of other conditions.[11]

Brands include

  • Alyglo (immune globulin intravenous human-stwk)[17]
  • Asceniv (immune globulin intravenous, human – slra)[18]
  • Bivigam (immune globulin intravenous – human 10% liquid)[19]
  • Gamunex-C, (immune globulin injection human)[20]
  • Hizentra (immune globulin subcutaneous human)[21]
  • Hyqvia (immune globulin 10 percent – human with recombinant human hyaluronidase)[22]
  • Octagam (immune globulin intravenous, human)[23][24]
  • Panzyga (immune globulin intravenous, human – ifas)[25]
  • Xembify (immune globulin subcutaneous, human – klhw)[26]

Canada

The National Advisory Committee on Blood and Blood Products of Canada (NAC) 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.[27]

Australia

The Australian Red Cross Blood Service developed their own guidelines for the appropriate use of immunoglobulin therapy in 1997.[28] 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.[29]

Subcutaneous immunoglobulin access programs have been developed to facilitate hospital based programs.[30]

Human normal immunoglobulin (human immunoglobulin G) (Cutaquig) was approved for medical use in Australia in May 2021.[31]

European Union

Brands include HyQvia (human normal immunoglobulin), Privigen (human normal immunoglobulin (IVIg)), Hizentra (human normal immunoglobulin (SCIg)), Kiovig (human normal immunoglobulin), and Flebogamma DIF (human normal immunoglobulin).[32][33][34][35]

In the EU human normal immunoglobulin (SCIg) (Hizentra) is used in people whose blood does not contain enough antibodies (proteins that help the body to fight infections and other diseases), also known as immunoglobulins.[33] It is used to treat the following conditions:

  • primary immunodeficiency syndromes (PID, when people are born with an inability to produce enough antibodies);[33]
  • low levels of antibodies in the blood in people with chronic lymphocytic leukaemia (a cancer of a type of white blood cell) or myeloma (a cancer of another type of white blood cell) and who have frequent infections;[33]
  • low levels of antibodies in the blood in people before or after allogeneic haematopoietic stem cell transplantation (a procedure where the patient's bone marrow is cleared of cells and replaced by stem cells from a donor);[33]
  • chronic inflammatory demyelinating polyneuropathy (CIDP). In this rare disease, the immune system (the body's defence system) works abnormally and destroys the protective covering over the nerves.[33]

It is indicated for replacement therapy in adults and children in primary immunodeficiency syndromes such as:

  • congenital agammaglobulinaemia and hypogammaglobulinaemia (low levels of antibodies);[33]
  • common variable immunodeficiency;[33]
  • severe combined immunodeficiency;[33]
  • immunoglobulin-G-subclass deficiencies with recurrent infections;[33]
  • replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.[33]

Flebogamma DIF is indicated for the replacement therapy in adults, children and adolescents (0–18 years) in:

  • primary immunodeficiency syndromes with impaired antibody production;[36]
  • hypogammaglobulinaemia (low levels of antibodies) and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (a cancer of a type of white blood cell), in whom prophylactic antibiotics have failed;[36]
  • hypogammaglobulinaemia (low levels of antibodies) and recurrent bacterial infections in plateau-phase-multiple-myeloma (another cancer of a type of white blood cell) patients who failed to respond to pneumococcal immunisation;[36]
  • hypogammaglobulinaemia (low levels of antibodies) in patients after allogenic haematopoietic-stem-cell transplantation (HSCT) (when the patient receives stem cells from a matched donor to help restore the bone marrow);[36]
  • congenital acquired immune deficiency syndrome (AIDS) with recurrent bacterial infections.[36]

and for the immunomodulation in adults, children and adolescents (0–18 years) in:

  • primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count;[36]
  • Guillain–Barré syndrome, which causes multiple inflammations of the nerves in the body;[36]
  • Kawasaki disease, which causes multiple inflammation of several organs in the body.[36]

Side effects

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.[citation needed]

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.[37] 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.[37]

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.[37] 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.[37] Some immunoglobulin solutions also contain isohemagglutinins, which in rare circumstances can cause hemolysis by the isohemagglutinins triggering phagocytosis.[38]

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.[39]

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,[37] can result in falsely elevated blood glucose levels,[37] and can interfere with many of the IgG-based assays often used to diagnose a patient with a particular infection.[40]

Routes of administration

1950s – intramuscular

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.[41] During the mid and late 1950s,[vague] 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.[41]

1980s – intravenous

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).[41]

1990s – subcutaneous

The first description of a subcutaneous route of administration for immunoglobulin therapy dates back to 1980,[42] 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.[41]

During the late 1980s and early 1990s,[vague] 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.[41]

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).[41][43] 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 (CVID) may develop intolerable side effects with subcutaneous immunoglobulin (SCIg) that they do not with intravenous immunoglobulin (IVIg).[41]

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.[41]

Mechanism of action

The precise mechanism by which immunoglobulin therapy suppresses harmful inflammation is likely multifactorial.[44] For example, it has been reported that immunoglobulin therapy can block Fas-mediated cell death.[45]

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.[46][47][48] 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.[46] 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.[46]

Sialylated-Fc-dependent mechanism was not reproduced in other experimental models suggesting that this mechanism is functional under a particular disease or experimental settings.[49][50][51][52] 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,[53] induction of autophagy,[54] induction of COX-2-dependent PGE-2 in human dendritic cells leading to expansion of regulatory T cells,[55] inhibition of pathogenic Th17 responses,[56] and induction of human basophil activation and IL-4 induction via anti-IgE autoantibodies.[57][58] 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.[59] Once these immune complexes are formed, they can interact with Fc receptors on dendritic cells,[60] 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.[46][61]

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.[62]

Hyperimmune globulin

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.[citation needed]

Hyperimmune serum and plasma contain high amounts of an antibody, as a consequence of disease convalescence[63] or of repeated immunization.[64] Hyperimmune plasma is used in veterinary medicine,[65] and hyperimmune plasma derivatives are used to treat snakebite.[66] It has been hypothesized that hyperimmune serum may be an effective therapy for persons infected with the Ebola virus.[67]

Society and culture

Economics

In the United Kingdom a dose cost the NHS between GB£11.20 and GB£1,200.00 depending on the type and amount.[7] In the United States, antivenoms may cost thousands of dollars per dose because of markups that occur after manufacturing.[68]

Brand names

As biologicals, various trade names of immunoglobulin products are not necessarily interchangeable, and care must be exercised when changing between them.[69] Trade names of intravenous immunoglobulin formulations include Flebogamma, Gamunex, Privigen, Octagam and Gammagard, while trade names of subcutaneous formulations include Cutaquig, Cuvitru, HyQvia, Hizentra,[33][70][71] Gamunex-C, and Gammaked.[72]

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 (including immunoglobulin) used across the world, including more than 50% of the European Union's supply.[73] 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.[73]

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.[74]

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.[75][76][77] 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.[78] Efficacy of heterologous immunoglobulin derivatives has been demonstrated in clinical trials of antivenoms for scorpion sting[79] and for snakebite.[80]

References

  1. ↑ 1.0 1.1 "Xembify APMDS". 15 July 2022. https://www.tga.gov.au/resources/auspmd/xembify. 
  2. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2016". 21 June 2022. https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016. 
  3. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2014". 21 June 2022. https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014. 
  4. ↑ "Regulatory Decision Summary - Xembify". 23 October 2014. https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00596. 
  5. ↑ "Summary Basis of Decision - HyQvia". 23 October 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00592&lang=en. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Immune Globulin". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/immune-globulin.html. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. pp. 867–71. ISBN 9780857111562. 
  8. ↑ (in en) Primary Immunodeficiency Disorders: A Historic and Scientific Perspective. Academic Press. 2014. pp. 283–84. ISBN 9780124115545. https://books.google.com/books?id=SF9zAwAAQBAJ&pg=PA283. 
  9. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  11. ↑ 11.0 11.1 "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". The Journal of Allergy and Clinical Immunology 117 (4 Suppl): S525–S553. April 2006. doi:10.1016/j.jaci.2006.01.015. PMID 16580469. 
  12. ↑ "IVIG treatment and prognosis in Guillain-Barré syndrome". Journal of Clinical Immunology 30 (S1): S74–S78. May 2010. doi:10.1007/s10875-010-9407-4. PMID 20396937. 
  13. ↑ "Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology 61 (6): 736–740. September 2003. doi:10.1212/WNL.61.6.736. PMID 14504313. 
  14. ↑ "The IVIg dilemma". American Journal of Transplantation 14 (10): 2195–2196. October 2014. doi:10.1111/ajt.12995. PMID 25231064. 
  15. ↑ "Clinical Guidelines for Immunoglobulin Use". http://www.ivig.nhs.uk/documents/dh_129666.pdf. 
  16. ↑ "Eight guiding principals for safe, effective and appropriate use of IVIG". American Association of Allergists and Immunologists. https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20Resources/IVIG-guiding-principles.pdf. 
  17. ↑ "Alyglo". 15 December 2023. https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/alyglo. 
  18. ↑ "Asceniv – human immunoglobulin g liquid". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d74f4360-3b51-496c-96fb-84c3976958d2. 
  19. ↑ "Bivigam (immune globulin intravenous – human 10% liquid". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a2244aa0-a6d0-11df-b385-0002a5d5c51b. 
  20. ↑ "Gamunex-C (immune globulin – human injection". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ade6b84a-e95b-0a49-3296-f56208fdf35b. 
  21. ↑ "Hizentra – human immunoglobulin g liquid". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b58f5ff-0316-49a3-b585-1f6003ddb953. 
  22. ↑ "Hyqvia (immune globulin 10 percent – human with recombinant human hyaluronidase kit". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ca2c26f-4be2-48cd-be5b-486e350654ba. 
  23. ↑ "Octagam immune globulin (human) – immune globulin solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=de00abeb-d635-eddc-b603-10708ecef5aa. 
  24. ↑ "Octagam immune globulin (human) – immune globulin solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a36a12dc-16be-b135-466f-393954f428a7. 
  25. ↑ "Panzyga (immune globulin intravenous – human solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68a5ee5f-0352-b3ae-3321-c0a22947a31d. 
  26. ↑ "Xembify – immune globulin subcutaneous, human-klhw solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8c174b11-a061-412e-a3b2-7bf7e1adaace. 
  27. ↑ "Guidelines on the use of intravenous immune globulin for hematologic conditions". Transfusion Medicine Reviews 21 (2 Suppl 1): S9-56. April 2007. doi:10.1016/j.tmrv.2007.01.001. PMID 17397769. 
  28. ↑ "Criteria for the Clinical Use of Intravenous Immunoglobulin in Australia | National Blood Authority". https://www.blood.gov.au/ivig-criteria. 
  29. ↑ "Access to Intravenous Immunoglobulin (IVIg)". https://www.blood.gov.au/Intravenous-Ig. 
  30. ↑ "Access to Subcutaneous Immunoglobulin (SCIg)". https://www.blood.gov.au/SCIg. 
  31. ↑ "Cutaquig". 12 May 2021. https://www.tga.gov.au/apm-summary/cutaquig. 
  32. ↑ "HyQvia EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/hyqvia. 
  33. ↑ 33.00 33.01 33.02 33.03 33.04 33.05 33.06 33.07 33.08 33.09 33.10 33.11 "Hizentra EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/hizentra.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  34. ↑ "Privigen EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/privigen. 
  35. ↑ "Kiovig EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/kiovig. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 36.6 36.7 "Flebogamma DIF". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/flebogamma-dif.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  37. ↑ 37.0 37.1 37.2 37.3 37.4 37.5 "Immune Globulin". http://www.dynamed.com/topics/dmp~AN~T356495/Immune-Globulin#Contraindications-Warnings. (Subscription may be required or content may be available in libraries.)
  38. ↑ "Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis". Transfusion 48 (8): 1598–1601. August 2008. doi:10.1111/j.1537-2995.2008.01721.x. PMID 18466176. 
  39. ↑ "Hyqvia (immune globulin 10 percent- human with recombinant human hyaluronidase) kit". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ca2c26f-4be2-48cd-be5b-486e350654ba. 
  40. ↑ "Laboratory Serologic Problems Associated with Administration of Intravenous IgG". Current Issues in Transfusion Medicine (The University of Texas M. D. Anderson Cancer Center) 3: 1–7. April 1994. http://www3.mdanderson.org/~citm/H-94-04.html. Retrieved 23 November 2015. 
  41. ↑ 41.0 41.1 41.2 41.3 41.4 41.5 41.6 41.7 "Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease". Therapeutics and Clinical Risk Management 6: 1–10. February 2010. doi:10.2147/tcrm.s4353. PMID 20169031. 
  42. ↑ "Subcutaneous immunoglobulin: opportunities and outlook". Clinical and Experimental Immunology 158 (Suppl 1): 51–59. December 2009. doi:10.1111/j.1365-2249.2009.04027.x. PMID 19883424. 
  43. ↑ "Re: A Message from CSL Behring to Current Vivaglobin Patients in the United States". http://primaryimmune.org/wp-content/uploads/2011/05/Vivaglobin_Letter.pdf. 
  44. ↑ Lee Martin N, Butani Lavjay (2005). "Intravenous Immunoglobulin (IVIG) in Rheumatologic Diseases: A Review of its Mechanism of Action". Current Rheumatology Reviews 1 (3): 289–93. doi:10.2174/157339705774612355. 
  45. ↑ "Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin". Science 282 (5388): 490–493. October 1998. doi:10.1126/science.282.5388.490. PMID 9774279. Bibcode: 1998Sci...282..490V. 
  46. ↑ 46.0 46.1 46.2 46.3 "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review". Journal of Autoimmunity 57 (6): 1–13. February 2015. doi:10.1016/j.jaut.2014.12.002. PMID 25578468. 
  47. ↑ Gern JE (August 2002). "Antiinflammatory Activity of IVIG Mediated through the Inhibitory FC Receptor". Pediatrics 110 (2): 467–68. doi:10.1542/peds.110.S2.467a. https://pediatrics.aappublications.org/content/110/Supplement_2/467.1.full. 
  48. ↑ "The antiinflammatory activity of IgG: the intravenous IgG paradox". The Journal of Experimental Medicine 204 (1): 11–15. January 2007. doi:10.1084/jem.20061788. PMID 17227911. 
  49. ↑ "IVIG-mediated effector functions in autoimmune and inflammatory diseases". International Immunology 29 (11): 491–498. December 2017. doi:10.1093/intimm/dxx039. PMID 28666326. 
  50. ↑ "Circulating Normal IgG as Stimulator of Regulatory T Cells: Lessons from Intravenous Immunoglobulin". Trends in Immunology 38 (11): 789–792. November 2017. doi:10.1016/j.it.2017.08.008. PMID 28916232. https://hal.sorbonne-universite.fr/hal-01630293/file/Trends%20Immunol%20Forum%20BAYRY_R1_JD_JB.pdf. Retrieved 12 January 2022. 
  51. ↑ "Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin". European Journal of Immunology 44 (7): 2059–2063. July 2014. doi:10.1002/eji.201444440. PMID 24700174. 
  52. ↑ "Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils". Journal of Immunology 192 (11): 5031–5038. June 2014. doi:10.4049/jimmunol.1301611. PMID 24760152. 
  53. ↑ "Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin". Blood 101 (2): 758–765. January 2003. doi:10.1182/blood-2002-05-1447. PMID 12393386. 
  54. ↑ "Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy". Cell Death & Disease 11 (1): 50. January 2020. doi:10.1038/s41419-020-2249-y. PMID 31974400. 
  55. ↑ "Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2-dependent prostaglandin E2 in human dendritic cells". Blood 122 (8): 1419–1427. August 2013. doi:10.1182/blood-2012-11-468264. PMID 23847198. 
  56. ↑ "Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin". The Journal of Allergy and Clinical Immunology 127 (3): 823–30.e1–7. March 2011. doi:10.1016/j.jaci.2010.12.1102. PMID 21281961. 
  57. ↑ "Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE". The Journal of Allergy and Clinical Immunology 144 (2): 524–535.e8. August 2019. doi:10.1016/j.jaci.2018.10.064. PMID 30529242. https://hal.sorbonne-universite.fr/hal-02284256/file/Galeotti%20et%20al.%20-%202019%20-%20Intravenous%20immunoglobulin%20induces%20IL-4%20in%20human%20b.pdf. Retrieved 8 July 2022. 
  58. ↑ "Anti-IgE IgG autoantibodies isolated from therapeutic normal IgG intravenous immunoglobulin induce basophil activation". Cellular & Molecular Immunology 17 (4): 426–429. April 2020. doi:10.1038/s41423-019-0334-x. PMID 31797906. 
  59. ↑ "Immune complexes as therapy for autoimmunity". The Journal of Clinical Investigation 115 (1): 25–27. January 2005. doi:10.1172/JCI23994. PMID 15630438. 
  60. ↑ "Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells". Nature Medicine 12 (6): 688–692. June 2006. doi:10.1038/nm1416. PMID 16715090. 
  61. ↑ "Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases". Neurological Sciences 24 (Suppl 4): S217–S221. October 2003. doi:10.1007/s10072-003-0081-7. PMID 14598046. 
  62. ↑ "Impact of IVIg on the interaction between activated T cells and microglia". Neurological Research 28 (3): 270–274. April 2006. doi:10.1179/016164106X98143. PMID 16687052. 
  63. ↑ "The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis". The Journal of Infectious Diseases 211 (1): 80–90. January 2015. doi:10.1093/infdis/jiu396. PMID 25030060. 
  64. ↑ "Antivenoms" (in en). https://www.who.int/teams/control-of-neglected-tropical-diseases/snakebite-envenoming/antivenoms. 
  65. ↑ "What is Hyperimmunized Plasma?" (in en-US). 2021-05-20. https://plasvaccusa.com/what-is-hyperimmunized-plasma/. 
  66. ↑ "Antibodies as Snakebite Antivenoms: Past and Future". Toxins 14 (9): 606. September 2022. doi:10.3390/toxins14090606. PMID 36136544. 
  67. ↑ "Preparation and use of hyperimmune serum for prophylaxis and therapy of Ebola virus infections". The Journal of Infectious Diseases 179 (Suppl 1): S218–S223. February 1999. doi:10.1086/514294. PMID 9988187. 
  68. ↑ "The crazy reason it costs $14,000 to treat a snakebite with $14 medicine" (in en-US). Washington Post. 2021-11-25. ISSN 0190-8286. https://www.washingtonpost.com/news/wonk/wp/2015/09/09/the-crazy-reason-it-costs-14000-to-treat-a-snakebite-with-14-medicine/. 
  69. ↑ "Eight Guiding Principles for Effective Use of IVIG for Patients with Primary Immunodeficiency". American Association of Allergists and Immunologists. http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20Resources/IVIG-guiding-principles.pdf. 
  70. ↑ "Hizentra". 15 March 2018. https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/hizentra. 
  71. ↑ Summary Basis for Regulatory Action – Hizentra (Report). Review Office Signatory Authority Tejashri Purohit-Sheth. U.S. Food and Drug Administration (FDA). 14 March 2018. https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM601862.pdf. Retrieved 20 March 2018. 
  72. ↑ "SCIG: New Therapeutic Uses Beyond PI?". IG Living (February–March 2015): 28–32. http://www.igliving.com/magazine/articles/IGL_2015-02_AR_SCIG-New-Therapeutic-Uses-Beyond-PI.pdf. Retrieved 23 November 2015. 
  73. ↑ 73.0 73.1 "An EU-wide overview of the market of blood, blood components and plasma derivatives focusing on their availability for patients Creative Ceutical Report, revised by the Commission to include stakeholders' comments". Creative Ceutical & EU commission. http://ec.europa.eu/health/blood_tissues_organs/docs/20150408_cc_report_en.pdf. 
  74. ↑ "transfusion.com.au" (in en). https://transfusion.com.au/bsib_april2017_5. 
  75. ↑ Andrew Pollack (17 July 2012). "Small Trial Hints Drug Can Slow Alzheimer's". New York Times. https://www.nytimes.com/2012/07/18/business/study-shows-drug-may-help-alzheimers-patients.html. 
  76. ↑ "Experimental Alzheimer's drug Gammagard may stall memory decline, small study suggests". CBS News. 17 July 2012. http://www.cbsnews.com/8301-504763_162-57474035-10391704/experimental-alzheimers-drug-gammagard-may-stall-memory-decline-small-study-suggests/. 
  77. ↑ "Another Alzheimer's Drug Fails Phase III Trial". http://www.genengnews.com/gen-news-highlights/another-alzheimer-s-drug-fails-phase-iii-trial/81248326/. 
  78. ↑ "FDA Approves Octapharma USA Investigational New Drug Application for Severe COVID-19 Patients" (in en). 20 May 2020. https://www.businesswire.com/news/home/20200520005133/en/FDA-Approves-Octapharma-USA-Investigational-New-Drug. 
  79. ↑ "Antivenom for critically ill children with neurotoxicity from scorpion stings". The New England Journal of Medicine 360 (20): 2090–2098. May 2009. doi:10.1056/NEJMoa0808455. PMID 19439743. 
  80. ↑ "Clinical studies of the effectiveness and safety of antivenoms". Toxicon 150: 1–10. August 2018. doi:10.1016/j.toxicon.2018.05.001. PMID 29746978. 



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