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Immune Globulins and Autism Ranking: Mildly Hazardous Limited negative evidence

SyringeImmunoglobulins are proteins derived from human blood plasma.

The plasma, processed from donated human blood, contains antibodies that protect the body against diseases.

Immunoglobulins are used to treat patients with a range of conditions including some immune deficiency disorders.

Some people think that some of the core features of autism and some of the associated conditions, such as gastrointestinal problems, are caused by or made worse by defective immune systems.

They also think that immunoglobulin therapy can be used to repair those defective immune systems in some autistic people.

Our Opinion

There is some scientific evidence of a link between immune deficiency disorders and some autistic people but the nature of that link is unclear.

There is no high quality research evidence to suggest that immunoglobulin therapy has any effect on the core symptoms of autism.

There is a limited amount of high quality research evidence (a single, large, multi-site randomised controlled trial) to suggest that immunoglobulin therapy has no effect on bowel disorders in autistic individuals.

Immunoglobulins are expensive, inconvenient to use, and potentially harmful. In the UK, their use is restricted to patients who meet the priorities set out in the document, “Clinical guidelines for immunoglobulin use”, published by the Department of Health in 2011. This document makes no mention of autism.

We therefore strongly recommend that immunoglobulin therapy is not used as a treatment for autistic people because of the potential risks and the lack of proven benefit.

Disclaimer

Please read our Disclaimer on Autism Interventions


Audience

According to the Department of Health (2011) immunoglobulin injections or infusions are used to treat patients with a wide range of immune deficiency disorders. These include

  • Antibody deficiency states, such as thymoma with immunodeficiency.
  • Haematological conditions, such as acquired red cell aplasia.
  • Neurological conditions, such as Guillain-Barré syndrome.
  • Other conditions, such as Kawasaki disease.

According to the University of Maryland Medical Centre (2017) immunoglobulins can also be used 

  • To help prevent infections or make the infection less severe. 
  • To treats disorders that involve the muscle and nervous systems. 
  • To improve muscle strength and disability in certain patients.

Some people, such as Gupta et al (2010), believe that a subset of autistic individuals may have defective immune systems and that these defective immune systems cause or worsen the symptoms of autism and related conditions. 

Notes

Red cell aplasia (condition characterised by a decrease in the number of red blood cells); Guillain-Barré syndrome (condition in which the body's immune system attacks part of the peripheral nervous system); haematological (concerning blood); Kawasaki disease (condition that causes swelling of the blood vessels of the heart); thymoma (tumour that affects the thymus gland).

 

Aims and Claims

Aims

Immunoglobulin injections or infusions are normally used to treat patients with a wide range of immune deficiency disorders. The treatment is designed to replace the immunoglobulin which is missing in those patients.

Some people believe that a subset of autistic individuals may also have insufficient immunoglobulin in their bodies. For example, Gupta et al (2010) stated

“Because patients with autism display IgG or IgG subclass deficiency, the presence of autoantibodies, and an increased production of proinflammatory cytokines and chemokines, and IVIG is used as a replacement therapy and plays an important immunomodulatory role in autoantibody production and proinflammatory chemokine and cytokine secretion, a good rationale exists for the use of IVIG in at least a subset of patients with autism.” 

Please note: There is no scientific consensus on the underlying mechanism of action of immunoglobulins in the treatment of immune deficiency disorders.

Claims 

There have been various claims made for the use of immunoglobulins as an intervention for autistic people. For example, 

  • Boris et al (2006) claimed that immunoglobulin therapy resulted in a substantial reduction of overall aberrant behaviours soon after the participants received their first dose. They also claimed that some participants showed “decreases in hyperactivity, inappropriate speech, irritability, lethargy and stereotypy”.
  • Gupta et al (1996) claimed that immunoglobulin therapy resulted in improved eye contact, speech, behaviour, echolalia, and other autistic features.  
  • Schneider et al (2006) claimed that immunoglobulin therapy led to improvements in gastrointestinal signs and symptoms, as well as significant behavioural improvements.

Key Features

Immunoglobulins are proteins derived from human blood plasma. The plasma, processed from donated human blood, contains antibodies that protect the body against diseases.

Antibodies are substances made by the body's immune system in response to bacteria, viruses, fungus, animal dander, or cancer cells. Antibodies attach to the foreign substances so the immune system can destroy them.

According to the WebMD website, accessed on 19 May 2017, the five major types of antibodies are:
 

  • “IgA. IgA antibodies are found in areas of the body such the nose, breathing passages, digestive tract, ears, eyes, and vagina. IgA antibodies protect body surfaces that are exposed to outside foreign substances. This type of antibody is also found in saliva, tears, and blood. About 10% to 15% of the antibodies present in the body are IgA antibodies. A small number of people do not make IgA antibodies.
  • IgG. IgG antibodies are found in all body fluids. They are the smallest but most common antibody (75% to 80%) of all the antibodies in the body. IgG antibodies are very important in fighting bacterial and viral infections. IgG antibodies are the only type of antibody that can cross the placenta in a pregnant woman to help protect her baby (fetus).
  • IgM. IgM antibodies are the largest antibody. They are found in blood and lymph fluid and are the first type of antibody made in response to an infection. They also cause other immune system cells to destroy foreign substances. IgM antibodies are about 5% to 10% of all the antibodies in the body.
  • IgE. IgE antibodies are found in the lungs, skin, and mucous membranes. They cause the body to react against foreign substances such as pollen, fungus spores, and animal dander. They are involved in allergic reactions to milk, some medicines, and some poisons. IgE antibody levels are often high in people with allergies.
  • IgD. IgD antibodies are found in small amounts in the tissues that line the belly or chest. How they work is not clear.”

The body makes specific antibodies in response to specific illnesses. For example, the IgM antibody for glandular fever is different to the IgM for herpes. For this reason, the plasma used in immunoglobulins is collected from thousands of screened donors and is used to generate a single batch, providing a wide variety of antibodies to protect against a wide variety of pathogens. Immunoglobulin products are mostly made of IgG, and contain only trace amounts of IgA and IgM. 

Administration

Immunoglobulins may be administered in a variety of ways 

  • Intravenous: infusion directly into a vein, usually via a drip.
  • Subcutaneous: infusion into the fat layer between the skin and muscle, via an injection or drip. 

Brands

Immunoglobulins are sold under a variety of brand names, each of which may come in different strengths and be administered in different ways. 

  • Intravenous immunoglobulin products include Baxter Kiovig; BPL Gammaplex; BPL Vigam; Biotest Intratect; CSL Privigen; Grifols Flebogamma; Grifols Flebogamma; Octapharma Octagam; and Octapharma Octagam.
  • Subcutaneous immunoglobulin products include CSL Vivaglobin; Baxter Subcuvia; Octapharma Gammanorm; and BPL Subgam.

Dosage

The dosage will depend on the nature of the condition being treated, the body weight of the patient, the brand of immunoglobulin being used and the treatment mechanism. Please see the document, “Clinical guidelines for immunoglobulin use” published by the Department of Health in 2011 for guidance on dosages and administration of different brands of immunoglobulin.

Notes

Herpes (any of a group of diseases caused by the herpes viruses); glandular fever (viral infection caused by the Epstein-Barr virus that can cause symptoms including swollen glands, fever, sore throat and fatigue); plasma (liquid part of the blood and lymphatic fluid). 

Cost and Time

Cost

The cost of using immunoglobulins will depend on a number of factors including the supplier, the brand, the dosage, and the length and frequency of treatment.
According to the BNF website accessed on 12 April 2018, the NHS indicative price for three of the commonly used brands was as follows

  • Kiovig 10g/100ml solution for infusion vials, £490 per vial
  • Octagam 10g/100ml solution for infusion bottles, £586.50 per bottle
  • Privigen 10g/100ml solution for infusion vials, £459.00 per vial

According to the Choosing Wisely website, accessed on 12 April 2018, 

“The … procedure can cost more than $30,000 a year. Because the treatment provides only temporary protection, it must be repeated regularly and usually for the patient’s whole life.”

Time

The amount of time it takes to use immunoglobulin therapy will depend on a number of factors including the overall length of treatment, the frequency of infusions and the time taken to administer a single infusion.

Immunoglobulin therapy is normally considered as a long-term treatment for immune dysfunction conditions because the infusions need to be repeated on a regular basis and usually for the patient’s whole life. In all of the studies we identified which included autistic participants, the researchers administered immunoglobulin therapy for a period between two to six months, with some suggesting that it needed to be continued for longer.

Immunoglobulin infusions may be given as much as five times a day or only once every three weeks. Infusions can take between five and 30 minutes to administer depending on the brand and the mechanism used (intravenous versus subcutaneous).

Risks and Safety

Hazards

Immunoglobulin therapy can cause a wide range of side effects. For example, according to the University of Maryland Medical Center (2017), immunoglobulin therapy can cause minor side effects, such as

  • Diarrhea, stomach pain or upset
  • Low fever
  • Mild headache or back, joint, or muscle pain
  • Pain, itching, burning, redness, swelling, warmth, or a lump under your skin where the shot is given
  • Stuffy or runny nose

It can also cause more significant side effects, such as

  • Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble breathing
  • Blistering, peeling, or red skin rash
  • Blue lips or fingernails, trouble breathing
  • Change in how much or how often you urinate
  • Chills, cough, sore throat, nausea, or vomiting during the infusion
  • Confusion, weakness, muscle twitching

It can also cause potentially life-threatening side effects such as 

  • Serious kidney problems
  • Blood clots in your heart, lungs, or brain
  • Haemolysis (bleeding) or haemolytic anemia
  • Aseptic meningitis syndrome (AMS)
  • Serious lung problems
  • Low sodium or high protein levels in your blood

For a full list of potential side effects please see University of Maryland Medical Center (2017) Immune globulin (Injection) . Baltimore, MD:  University of Maryland Medical Center.

Contraindications

There are some contraindications (something which makes a particular treatment or procedure potentially inadvisable) for immunoglobulins. For example, according to the University of Maryland Medical Center (2017), immunoglobulin therapy may be contraindicated for individuals with “… kidney problems, anemia or blood clotting problems, diabetes, heart disease, atherosclerosis, a history of heart attack or stroke, idiopathic thrombocytopenic purpura (ITP), or protein problems such as paraproteinemia or hyperproteinemia”. 

Notes

Aseptic meningitis syndrome (serous inflammation of the linings of the brain not caused by bacteria); atherosclerosis (build-up of fatty material inside your arteries); haemolysis (internal bleeding); haemolytic anaemia (anaemia caused by bleeding hyperproteinemia (increase in the concentration of protein in the bloodstream); idiopathic (relating to or denoting any disease or condition which arises spontaneously or for which the cause is unknown); thrombocytopenic purpura (blood disorder characterized by clotting in small blood vessels of the body); paraproteinemia (excessive quantities of paraprotein present in the blood).
 

 

Suppliers and Availability

Suppliers 

Immunoglobulins are powerful drugs with some potentially dangerous side effects and are contraindicated for some groups of people. They are also in very short supply. For this reason, they should only be given by a qualified medical practitioner and in line with national guidelines. 

In the UK, the use of immunoglobulins within the NHS is set out within the document, “Clinical guidelines for immunoglobulin use”, published by the Department of Health in 2011. These guidelines are designed to ensure that immunoglobulins are only provided to patients who meet clinical priorities, for example, those with life threatening conditions such as Kawasaki disease.  

In the UK, immunoglobulins are not provided for the treatment of autistic people, unless they also happen to meet the clinical priorities set out in “Clinical guidelines for immunoglobulin use.” These guidelines make no separate mention of autism.

Credentials

Immunoglobulins are powerful drugs with some potentially dangerous side effects. They are also contraindicated for some groups of people. For this reason, they should only be given by a qualified medical practitioner. 

In the UK, the prescribing clinician will need to seek approval from other qualified medical personnel, such as the Medical Director and the Chief Pharmacist within a NHS trust, in line with Department of Health guidance.

History

According to Sewell et al (2014), the use of immunoglobulins as a treatment for immunological disorders began in the 1940s.

“Plasma fractionation for the preparation of albumin, clotting factors, and subcutaneous/intramuscular Ig began in the 1940s; industrial scale plasma fractionation started in 1943. Intravenous Ig (IVIg) was introduced in the early 1970s and became the driving market force in the 1990s when plasma-derived Factor VIII and Factor IX were increasingly replaced by recombinant products”. 

We have yet to identify by whom and when the use of immune globulin for autistic people was first suggested but we think it is likely to have been in the late 1980s.  The first study to appear in a peer-reviewed journal was Gupta et al. (1996).

Current Research

Current Research Studies

We have identified seven studies of immunoglobulins as a treatment for autistic people published in English-language, peer-reviewed journals. These studies included more than 190 individuals aged from 2-17.

  • Three studies (Boris et al, 1996; Gupta et al, 1996; Schneider, 2006) reported significant improvements in a range of areas including an increase in social communication skills (such as speech), a decrease in gastrointestinal symptoms (such as diarrhoea), and a reduction in challenging behaviours (such as irritability).
  • Three studies (DelGiudice-Asch et al, 1999; Handen et al, 2009; Plioplys, 1998) reported no effects.
  • One study (Niederhofer et al 2003; reported limited/mixed results). 

The most rigorous of these studies was Handen et al (2009) which stated that “Endpoint analysis revealed no significant differences across treatment groups on a modified global improvement scale (validated in irritable bowel syndrome studies), number of daily bowel movements, days of constipation, or severity of problem behaviors.”

Status of Current Research Studies

There are a number of limitations to all of the research studies published to date. For example,

  • Four of the studies (DelGiudice-Asch et al, 1999; Niederhofer et al, 2003; Plioplys, 1998; Schneider et al 2006)) had less than 20 participants. 
  • Four of the studies (Boris et al 2006; DelGiudice-Asch et al, 1999; Plioplys, 1998; Schneider et al 2006) were open label, that is non-blinded trials, and none of them had a comparison control group. 
  • One of the studies (Gupta et al, 1996) was a retrospective case series which used arbitrary, non-standard outcome measures.
  • The study by Niederhofer et al, 2003 was reported in a letter to a journal, rather than being a detailed write up of the intervention. 
  • In one of the studies (Schneider et al, 2006) the participants were taking a wide range of other substances including various vitamins, minerals and other dietary supplements, making it difficult to know what caused the reported benefits. 
  • The authors of the single, large, randomised trial (Handen et al, 2009) listed a number of potential limitations to their study including the lack of evaluation by a gastroenterologist at the start of the study.

For a comprehensive list of potential flaws in research studies, please see ‘Why some autism research studies are flawed’.

 

Future Research

Summary of Existing Research

  • There is some evidence of a link between immune deficiency disorders and some autistic people but the nature of that link is unclear. 
  • There is no high quality research evidence to suggest that immunoglobulin therapy has any effect on the core symptoms of autism.
  • There is a limited amount of high quality research evidence (a single, large, multi-site randomised controlled trial) to suggest that immunoglobulin therapy has no effect on bowel disorders in autistic individuals.

Recommendations for Future Research

At this stage research into the use of immune globulin as an intervention for autistic people is not a priority.

Studies and Trials

This section provides details of scientific studies into the effectiveness of this intervention for people with autism which have been published in English-language, peer-reviewed journals. 

If you know of any other publications we should list on this page please email info@informationautism.org

Please note that we are unable to supply publications unless we are listed as the publisher. However, if you are a UK resident you may be able to obtain them from your local public library, your college library or direct from the publisher.

Related Studies and Trials


Other Reading

This section provides details of other publications on this topic.

You can find more publications on this topic in our publications database.

If you know of any other publications we should list on this page please email info@informationautism.org

Please note that we are unable to supply publications unless we are listed as the publisher. However, if you are a UK resident you may be able to obtain them from your local public library, your college library or direct from the publisher.

Related Other Reading


Additional Information

There is some evidence of a link between immune deficiency disorders and some autistic people but the nature of that link is unclear. For example, in 2016, Mandy and Lai noted 

“There is now increasing evidence suggesting a central role of immune dysregulation in ASC. Neuro-immune processes are not only key to the neurobiological characteristics of individuals with ASC themselves but such processes may also play a contributing’ role in atypical neurodevelopment as early as the gestational period and may explain the pathogenesis of the autism phenotype in a subgroup of individuals”.

 

Related Additional Information


Updated
16 Jun 2022
Last Review
31 May 2018
Next Review
01 Jun 2024