What Is Serum Sickness?

An Immune System Response to Nonhuman Proteins

Medically reviewed by Jurairat J. Molina, MD

Serum sickness and serum sickness-like reactions (SSLRs) are similar syndromes. Exposure to a foreign substance produces an abnormal immune response in these conditions.

You can think of serum sickness and SSLRs as specific types of allergic reactions. However, they differ from other allergies with which you might be more familiar, like food or seasonal allergies, regarding their symptoms and underlying causes.

This article will explain the difference between serum sickness and serum sickness-like reactions and help you understand the causes and treatments for each.

Serum Sickness vs. Serum Sickness-Like Reactions

Serum Sickness

In 1905, two pediatricians first described serum sickness syndrome. At the time (before the invention of antibiotics), scientists had developed treatments for infectious diseases such as diphtheria. These treatments used serum from horses who had recovered from these diseases.

Serum is the pale-yellow component of blood from which blood cells and clotting factors have been removed. It contains proteins carried in the blood.

Scientists used the serum to access a protein called antitoxin, a component of the horse's immune response to infections. They then gave this to people suffering from certain diseases to help them recover from their symptoms or to prevent illness.

Although this helped treat the disease, some people had side effects that began a week or two after treatment. This was eventually named serum sickness.

The three most important symptoms of serum sickness are:

• Rash

• Joint pain

• Fever

However, some people may not have all three. Other less common symptoms may occur, like headache, upset stomach, muscle aches, and blurry vision. Notably, people with serum sickness don't usually develop life-threatening allergic reactions (anaphylaxis), with difficulty breathing and other symptoms that people with specific allergies do.

This specific serum is only now rarely used for diphtheria. But scientists learned that other foreign proteins could trigger similar reactions in some people.

Serum Sickness-Like Reactions

Eventually, scientists learned that some other substances not made of serum or foreign proteins could trigger similar symptoms. They were referred to as serum sickness-like reactions.

These reactions are not life-threatening and typically occur without a fever. They may also present between five and 10 days after exposure and are more common in children than adults.

Symptoms of SSLR may develop after a viral infection or completion of an antibiotic, and typically include:

• Itchy rash (appearing similarly to hives)

• Hands, feet, or facial swelling

• Joint stiffness and pain

The terms "serum sickness" and "serum sickness-like reactions" are used inconsistently by healthcare providers and scientific literature. However, the terminology used doesn't make a difference in most cases because serum sickness and SSLRs have similar symptoms, diagnoses, prognoses, and treatments.

Serum Sickness and SSLR Causes

Scientists have classified different allergic reactions into different types based on the parts of the immune system involved and the resulting symptoms. For example, the type of allergy responsible for seasonal allergies' drippy nose and itchy eyes is classified as a type 1 hypersensitivity reaction.

A type 3 hypersensitivity reaction causes serum sickness. It involves a component made by immune cells known as an IgG antibody. These antibodies can bind to antigens from foreign substances.

An antigen is any small substance component that might bind to a person’s antibodies and cause the body to activate its immune response.

Antigens can lock together with many antibodies in clumps in a type 3 hypersensitivity reaction. These clumps can get stuck in places like the skin and joints, triggering other parts of the immune system and causing symptoms.

Another confusing aspect of serum sickness and SSLR is that classic serum sickness is a straightforward type 3 hypersensitivity reaction. In contrast, SSLRs do not produce the same complexities when viewed under a microscope. Scientists don’t fully understand what triggers the abnormal immune response in SSLRs.

Serum sickness is not the only type 3 hypersensitivity reaction. Another type 3 hypersensitivity reaction, called the Arthus reaction, can occur after certain vaccine injections, injected drugs like insulin, and insect bites. It may cause redness, swelling, skin hardening, and pain at the injection site.

Triggers

There are various potential triggers for serum sickness or SSLRs, including the following:

• Certain antibiotics may trigger an SSLR in a small percentage of people. Symptoms may begin after the person has completed their course of treatment.

• Biologics (biologic agents), such as Rituxan (rituximab), are therapies made with components of living things and can trigger serum sickness.

• Some vaccines, such as the rabies vaccine or some types of flu vaccine, can cause serum sickness or SSLRs in rare cases.

• Infectious diseases, like hepatitis B, can cause these reactions in response to a foreign antigen. The serum sickness response occurs in addition to infection-related symptoms.

• Bites or stings from insects or spiders might also cause serum sickness or an SSLR. Snakebite treatment, called antivenin, can also trigger it.

Not every bad reaction to a drug or other substance is serum sickness or an SSLR. For example, a more common reaction to an antibiotic might be a rash without fever or joint pain.

How Long Do Serum Sickness or SSLRs Last?

The pattern and timeline of symptoms help healthcare providers diagnose serum sickness or SSLRs. However, clinicians don’t have a single test that they can use to diagnose serum sickness or an SSLR.

If your healthcare provider suspects you have serum sickness, they may order additional blood tests to rule out other potential causes of your symptoms. Once other illnesses are ruled out, serum sickness becomes more likely the cause.

However, the symptoms of serum sickness usually go away within a few weeks, even without diagnosis and treatment. It’s not a chronic disease, and symptoms should not return.

Avoid future exposure to the triggering substance whenever possible. If you reencounter the substance, you may suffer another bout of symptoms, which may occur more quickly than after your first exposure.

Treating Serum Sickness and SSLRs

The approach to treatment is the same for serum sickness and SSLRs. If applicable, the first step is removing the triggering agent, such as stopping the medication that brought on the symptoms.

Some helpful treatments include:

• Pain-relieving drugs, like Advil or Motrin (ibuprofen)

• Antihistamines, like Benadryl (diphenhydramine), to reduce symptoms

• Steroids, like prednisone

Summary

Serum sickness and serum sickness-like reactions (SSLRs) are specific types of allergic responses to foreign substances, such as antibiotics, biologic therapies, insect stings, vaccines, or other triggers. Serum sickness and SSLRs cause rash, joint pain, and fever beginning approximately ten days after exposure to the foreign substance.

You can treat your symptoms with pain relievers or antihistamines. People generally recover entirely within a few weeks, but they should avoid the triggering substance in the future.