Serum Sickness – Causes, Symptoms, Diagnosis, Treatment

Pathophysiology

After exposure to antigen, an individual’s immune system responds by creating antibodies after 4-10 days. The antibody reacts with the antigen, forming immune complexes that circulate and can diffuse into the vascular walls where they may initiate fixation and activation of complement. These immune complexes, along with complement, produce an influx of polymorphonuclear leukocytes into the site, where tissue damage takes place by the release of proteolytic enzymes.[rx][rx] The process takes place in three steps:

• Immune complex formation: Endogenous or exogenous antigen exposure triggers an antibody formation. Exogenous antigens are foreign proteins such as an infectious microbe or a pharmaceutical product. Endogenous antigens are self-antigens against which autoantibodies are generated (autoimmunity). In both cases, the antigens bind to antibodies, forming circulating immune complexes, which can later migrate out of plasma and deposit in host tissues.
• Immune complex deposition: The pathogenicity of immune complexes is partly dependent on the antigen-antibody ratio. When the antibody is in excess, the complexes are insoluble, do not circulate, and are phagocytosed by macrophages in the lymph nodes? and spleen?. However, when the antigen is in excess, the aggregates are smaller. They freely filter out of circulation in organs where the blood is transformed into other fluids such as urine and synovial fluid. Therefore, immune complexes affect glomeruli? and joints.
• Inflammatory reaction: After the deposition of the immune complexes, the final step is the activation of the classical pathway, leading to the release of C3a and C5a, which then recruit macrophages and neutrophils, and causes inflammatory damage to tissues. Depending on the site, symptoms of vasculitis (blood vessels), arthritis? (joints), or glomerulonephritis? (glomeruli) develop.

When a patient is exposed to a foreign serum protein, it takes approximately 6-10 days for antibodies to develop and form antigen-antibody complexes and is considered a Type III immune-mediated hypersensitivity reaction. [rx] If the macrophage activating system is not functioning properly, these complexes will become saturated in the circulation, leading to immune complex deposition, most commonly in parenchymal tissues and synovial joint fluid. The deposition of immune complexes may also activate the classical complement pathway, leading to lower levels of circulating C3 and C4. These levels can be used to differentiate serum sickness from a serum sickness-like reaction, which will have normal complement levels. [rx] Also, the activation of the complement system will trigger histamine release and increase vascular permeability, which leads to an inflammatory response in the tissues and joints. It is the process of clearing these immune complexes and the subsequent inflammatory reaction that coincides with the onset? of clinical? symptoms. [rx] Note that in patients previously sensitized to the antigen, symptoms may develop within a few days of re-exposure to the causative agent.

Causes of Serum Sickness

The symptoms of serum sickness arise as a result of the formation of immune complexes between human proteins and heterologous (nonhuman) proteins. Medications containing heterologous antigens are the most common cause of serum sickness and include vaccinations (i.e., Rabies), immune-modulating agents (i.e., rituximab, infliximab), and anti-venoms. [rx][rx][rx]

1. Equine-based microbial antitoxins (anti-Rabies, anti-botulinum, and anti-diphtheria Immunoglobulin)
2. Antivenoms (Snake Antivenom, Anti-Lactrodectus Spider venom)
3. Rabies Vaccine?
4. Streptokinase
5. Insect Bite proteins
6. Monoclonal Antibodies (e.g. Rituximab, Infliximab)
7. Rheumatologic Conditions
   1. Hypersensitivity Vasculitis
   2. Reactive Arthritis
   3. Juvenile Rheumatoid Arthritis?
   4. Sweet Syndrome?
8. Drug Reactions
   1. Medication Hypersensitivity
   2. Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis
   3. Drug Reaction with Eosinophilia? and Systemic? Symptoms (DRESS)
9. Bacterial? Syndromes
   1. Acute? Rheumatic Fever
   2. Disseminated Gonorrhea
   3. Meningococcemia
   4. Scarlet Fever
   5. Lyme Disease
10. Viral? syndromes
    1. See Viral Exanthem
    2. Chikungunya
    3. Dengue Fever
    4. Kawasaki Disease
11. Serum Sickness Like Reaction Causes
    1. Cefaclor (Ceclor)
    2. Penicillin (high dose IV)
    3. Amoxicillin
    4. Trimethoprim-Sulfamethoxazole (Bactrim, Septra)
    5. Hepatitis? B Infection?

Serum sickness is not to be confused with a serum sickness-like reaction, which results in a similar clinical presentation but does not involve the formation of immune complexes. The most common offending medications include penicillins, cephalosporins (most commonly cefaclor), sulfonamides, bupropion, fluoxetine, and thiouracil. [rx][rx] Also, several infections can lead to the development of serum sickness-like reactions, including streptococcus and hepatitis B. [rx][rx]

Antitoxins and antisera

Serum sickness is usually a result of exposure to antibodies derived from animals.^[rx][rx] These sera or antitoxins are generally given to prevent or treat an infection or envenomation (venomous bite).^[rx]

Drugs

Serum sickness may be caused by some routine medications. Some of the drugs associated with serum sickness are:

• allopurinol.
• barbiturates.
• captopril.
• cephalosporins.
• crontab.
• griseofulvin.
• penicillins.
• phenytoin.
• procainamide.
• quinidine.
• streptokinase.
• sulfonamides.
• rituximab.
• ibuprofen.
• infliximab.
• oxycodone.

Others

Allergenic extracts, hormones, and vaccines can also cause serum sickness. However, according to the Johns Hopkins Bloomberg School of Public Health, routinely recommended vaccinations to the general population in the U.S have not been shown to cause serum sickness, as of 2012.^[rx]

Effects of Serum sickness

Serum sickness is caused by nonhuman proteins in certain medications and treatments that your body mistakes as being harmful, causing an immune reaction.

One of the most common types of medication that causes serum sickness is antivenom. This is given to people who’ve been bitten by a venomous snake. In a five U.S. study, the reported range of serum sickness after antivenom treatment is between 5 and 23 percent.

Other possible causes of serum sickness include:

• Monoclonal antibody therapy. This type of treatment often uses antibodies from mice and other rodents. It’s used to treat autoimmune? conditions, such as rheumatoid arthritis and psoriasis?. It’s also used in some cancer treatments.
• Anti-thymocyte globulin. This usually contains antibodies from rabbits or horses. It’s used to prevent organ rejection in people who’ve recently had a kidney? transplant.
• Bee venom injection. This is an alternative and complementary treatment for inflammatory conditions and chronic? pain?.

Symptoms of Serum Sickness

Serum sickness usually develops within several days to three weeks of being exposed to the medication or antiserum, but it may develop as quickly as one hour after exposure in some people. Such as the symptoms are after bee stings like color in the skin or whole body.

Unlike other drug allergies, which occur very soon after receiving a certain medicine, serum sickness develops 7 to 21 days after the first exposure to a medicine. Some people develop symptoms in 1 to 3 days if they have already been exposed to the medicine.

The three main symptoms of serum sickness include fever, rash, and painful swollen joints.

Other possible symptoms of serum sickness include:

• rashes and redness.^[rx]
• itching and urticaria?.^[rx]
• joint pain (arthralgia?), especially in finger and toe joints.^[rx][rx]
• fever usually appears before the rash.^[rx][rx] This may be as high as 40 °C (104 °F).
• lymphadenopathy (swelling of lymph nodes), particularly near the site of injection.
• malaise.^[rx]
• hives
• muscle pain and weakness
• soft tissue swelling
• flushed skin
• nausea
• diarrhea
• stomach cramping
• itching
• headache
• facial swelling
• blurred vision
• shortness of breath swollen lymph nodes

Diagnosis of Serum Sickness

History and Physical

A thorough history and physical exam are essential to investigate the serum sickness problem. The history should focus on the how, where, when the first symptoms are found then identification of an offending agent (maybe bee stings, certain drugs, overdosage drugs) within the two weeks before the onset of symptoms, or, in the case of potential exposure, within the few days before presentation.

The physical exam

• The physical exam should be carefully undertaken to determine the severity of symptoms and signs of systemic illness, skin problem, previous allergic reaction or patients are hypersensitivity to certain drugs or food. A close inspection of the skin rash may reveal an urticarial, maculopapular, or vasculitic (purpuric) eruption are present or not.
• Importantly, the mucous membranes sample test can be helpful in distinguishing serum sickness from Stevens-Johnson syndrome or toxic epidermal necrolysis. If associated with subcutaneous injection, the rash may first appear around the site of the injection. The skin rash typically takes days to weeks to resolve.
• Less common findings on the physical exam include edema (i.e., of the hands, feet, and face, eye), lymphadenopathy, headache or blurry vision, splenomegaly, anterior uveitis, peripheral neuropathy, nephropathy, and vasculitis. [rx] Of note, these systemic symptoms are less likely in serum sickness-like reactions, which is usually limited to fever, arthralgias, rash/urticaria, and pruritus-like problem.

Lab Test

Urinalysis  – The evaluation or test of urine is well-appearing patients with suspected serum sickness can be limited to urinalysis to determine the presence of renal involvement, which would require close follow-up. However, if the patient is ill-appearing or if there is any degree of diagnostic uncertainty based on the history or physical exam, further testing should be performed.

The clinician should consider the following laboratory tests to evaluate for other etiologies and multi-organ system involvement:

• complete blood count with differential,
• erythrocyte sedimentation rate,
• C-reactive protein,
• total hemolytic complement (CH50), C3, C4,
• the basic metabolic panel,
• liver transaminases,
• antinuclear antibody, and rheumatoid factor. [rx]
• Hepatitis B screen Test -Depending on the clinical history, testing for infectious diseases may include hepatitis B screen and heterophile antibody testing for EBV.
• Electrocardiogram  – If carditis is suspected, an electrocardiogram should be obtained. Stool hematocrit should be obtained in any patient with gastrointestinal symptoms. Neuroimaging with a computed tomography scan should be considered in patients with neurological complaints.
• Serum creatinine – may be elevated, but typically returns to baseline within days-weeks of discontinuing the offending agent. Inflammatory markers will be elevated in serum sickness. Complement levels including CH50, C3, and C4, will be decreased, reflecting activation and consumption of complement.

Recall that patients with serum sickness-like reactions will generally not manifest with additional multi-organ system symptoms as outlined above. Also, the lab results in a serum sickness-like reaction will not show hypocomplementemia or renal dysfunction. [rx]

Treatment of Serum Sickness

Serum sickness is a self-limited entity that will usually resolve upon discontinuation of the drugs or food you are taking.

Injection –

• Thus, treatment is generally aimed at reducing symptom severity and removing the agent, or reducing exposure to it if complete removal is not possible (for example, potentially life-saving anti-thymocyte globulin in the treatment of aplastic anemia) may be given in supervision of your doctors. [rx]
• For more severe symptoms, a 7 to 10-day course of 0.5 – 2 mg/kg of systemic glucocorticoids can be helpful. [rx]
• If the condition is more severe then you can use triamcinolone acetonide injection instantly, which will help you more

Oral Tablet –

• For mild or moderate symptomatic problems and relief can be achieved with NSAIDs such as tramadol, ketorolac, diclofenac, etoricoxib, and/or antihistamines such as loratadine, desloratadine, fexofenadine. The patient should be counseled that the rash and pruritis should stop progressing within 48 hours of initiation of these medications.
• In rare cases, you may need a plasma exchange may be needed.

Most children can be safely treated as outpatients, but inpatient hospitalization should be considered for those with severe symptoms, multi-organ system involvement, or evidence of an underlying infection or more serious etiology.

References