What Is a Systematic Review?

A systematic review is a type of research study that seeks to summarize all of the available primary research (i.e., research that has collected data first-hand) that has been conducted to answer a research question. It involves a systematic search for data using a specific, repeatable method with a clearly defined set of objectives. The search is usually conducted using databases that hold information about research publications and aims to identify all studies within them that meet predefined eligibility criteria.

The validity of the findings for each study is then assessed, particularly regarding whether there is any risk that the results may be biased, following which the results are considered together and any conclusions drawn. Systematic reviews enable up-to-date assessment of what is known about a subject and are often used in the development and updating of clinical guidelines.

What Did This Study Investigate?

The authors of this study conducted a systematic review to summarize the results of studies that have reported adverse reactions when patients with neurological disorders – conditions that affect the brain, spinal cord, and/or nerves throughout the body – are treated with intravenous immunoglobulin. Intravenous immunoglobulin is a product that is made up of different human antibodies (immunoglobulins is another word for antibodies) that have been pooled together and are given intravenously (through a vein).

Antibodies are specialized protective proteins that are made by the immune system and recognize anything that is foreign to the body (these are called “antigens”), like bacteria and viruses. Different antibodies specifically recognize and neutralize different antigens and, once they have recognized and responded to a particular antigen once, antibodies against that antigen continue to circulate in the blood to provide protection against it if it is encountered again (this is how we become immune to some diseases).

Because intravenous immunoglobulin is prepared from blood samples donated from a large number of different people (depending on the manufacturer, the number of donors can be between 1,000 and 100,000) it contains a diverse collection of antibodies, which reflects the exposure of everyone who has donated blood to their environment, against a broad range of antigens. As a result, intravenous immunoglobulin can be effective in preventing or treating infections in people who are unable to make enough antibodies (known as “humoral immunodeficiency”) or who have an autoimmune disease (where the body mistakenly recognizes a cell type or specific protein in the body as foreign, treats it as an antigen, and attacks it).

Although a large number of clinical trials have reported that treatment with intravenous immunoglobulin is safe and generally well tolerated, some patients experience adverse reactions (an undesired effect of the treatment). The authors of this study therefore set out to systematically review studies that have reported adverse reactions to intravenous immunoglobulin therapy when it is used to treat more than one neurological disorder, to investigate whether any particular characteristics of individual neurological disorders are associated with patients experiencing adverse reactions.

How Was the Study Conducted?

The authors of the study searched three electronic databases for all research studies published up until that date using the following combination of search terms:

• IVIg (the acronym for intravenous immunoglobulin), intravenous immunoglobulin, or immunoglobulin G (the type of immunoglobulin that makes up the greatest proportion of intravenous immunoglobulin), and
• any term beginning with “neurolog”, and
• adverse reaction, adverse effect, side effect, or any term beginning with “allerg”.

Articles were then included in the review if they described primary research, reported adverse reactions to intravenous immunoglobulin therapy in more than one neurological disorder, and were available as full-text publications in English. Although 2,196 studies were identified initially, only 65 met all of the eligibility criteria and were included in the final analysis.

What Did the Study Find?

After systematically reviewing the eligible studies, the authors of this study reported that when the results from all the studies were combined, the chance of patients developing an adverse reaction was estimated to be between 24 and 34%. In many studies the definition of specific adverse reactions was unclear or not specified. In addition, a large proportion of studies were conducted retrospectively, which increased the chance of selection bias. Selection bias is introduced when a group of patients is selected for analysis in a way that does not allow the sample population to be truly randomized, which means that it isn’t representative of the population as a whole, potentially leading to errors when the researchers draw conclusions about associations or outcomes.

Overall, there was a lack of high-quality comparative data (data that can be used to estimate the extent of similarity or dissimilarity between two things), which made it difficult for the authors to determine whether any specific neurological symptoms or signs are associated with patients having an increased risk of having an adverse reaction if treated with intravenous immunoglobulin therapy. Although intravenous immunoglobulin treatment was found to be generally well tolerated by patients with neurological conditions, headache was a common adverse reaction and there were some reports of “thromboembolic” complications (caused by the obstruction of a blood vessel by a blood clot that has become dislodged from another site in the circulatory system, which circulates the blood and lymph fluid through the body).

The authors concluded that patients with limited mobility (as seen in some conditions that affect both nerves and muscles), paraproteinemia, which occurs when an abnormal protein called a paraprotein starts to be secreted by a population of antibody-producing cells (as seen in some conditions where nerve damage causes pain, weakness, or numbness, often in the hands, arms, and feet), and cardiomyopathy (a general term that describes problems with your heart that make it harder for it to pump blood) were likely to have an increased risk of experiencing adverse reactions. They also found some evidence that children might be at increased risk of experiencing them.

Although the systematic review was unable to identify neurological disease characteristics that are definitely associated with adverse reactions in patients treated with intravenous immunoglobulin, the knowledge gained from this study can be used to guide the design of research studies in the future. Systematic reviews like this one play a key role in shaping future research directions by identifying areas relating to research questions that remain poorly understood or that need further investigation because different studies have reported conflicting results. This increases the chance of positive discoveries in the future that may improve the prevention and treatment of adverse reactions.