Basics
Description
- Serum sickness
- Type III hypersensitivity reaction that occurs 7 " “21 days after injection of foreign protein or serum (usually in the form of antiserums)
- Immune complexes deposit in the skin, joints, and other organs.
- Clinical syndrome consists of skin rash, itching, fever, malaise, proteinuria, vasculitis, and joint pain.
- Serum sickness " “like reactions
- Characterized by fever, rash, lymphadenopathy, and arthralgia
- Occur 1 " “3 weeks after drug exposure
- Immune complexes, vasculitis, and hypocomplementemia are absent.
- This type of reaction, most commonly associated with medications, is commonly referred to as serum sickness as well.
- More common than true serum sickness because equine serum antitoxins have been replaced with human antitoxin sera
- Clinically, these entities present and are treated in the same manner.
Epidemiology
- Limited information is available regarding the incidence of adverse drug reactions in children; generally believed to occur less frequently in children than in adults.
- >90% of serum sickness cases are drug-induced.
- <5% of serum sickness cases are fatal.
Risk Factors
Genetics
People with a genetic predisposition to produce IgE are more susceptible. ‚
General Prevention
- No known way to prevent first occurrence
- Take careful history of previous allergic reactions.
- Skin testing prior to antiserum administration will prevent anaphylaxis but not serum sickness.
- When the need for antiserum arises, consider prophylactic antihistamines.
Pathophysiology
- Serum sickness " ”type III immune complex, antigen " “antibody complement reaction
- Antibodies form 6 " “10 days after the introduction of foreign material.
- Antibodies interact with antigens, forming immune complexes that diffuse across the vascular walls.
- They become fixated in tissue and activate the complement cascade.
- C3a and C5a are produced, resulting in increased vascular permeability and activated inflammatory cells.
- Polymorphonuclear cells and monocytes cause diffuse vasculitis.
- Serum sickness " “like reaction
- Abnormal inflammatory reaction in response to defective metabolism of drug by-products
Etiology
- Common causative agents:
- Horse antithymocyte globulins
- Human diploid-cell rabies vaccine
- Streptokinase
- Hymenoptera venom
- Penicillins
- Cephalosporins (especially cefaclor)
- Sulfonamides
- Hydralazine
- Thiouracils
- Metronidazole
- Naproxen
- Dextrans
- Case-reported agents:
- Minocycline
- Amoxicillin
- Infliximab
- Bupropion
- H1N1 vaccination
Diagnosis
History
- Suspect in any patient who has been taking any new drug during the past 2 months and who has an unexplained vasculitic rash.
- Presentation and evolution of rash
- Typically, the rash first appears on the sides of the fingers, hands, and feet before becoming widespread.
- Previous history of a similar rash
- Was it associated with any medications in the past? The rash and symptoms of serum sickness will occur sooner on repeat exposure.
- Exposure history
- Has patient had any drug or antitoxin exposure in the past month?
- Especially exposures to penicillins, cephalosporins, sulfonamides, hydralazine, thiouracils, streptokinase, metronidazole, naproxen, monoclonal antibodies, or dextrans?
- Timing of the rash and exposure
- Try to differentiate from simple drug rash; timing of rash after exposure is important in differentiating the two entities.
- Hypersensitivity reactions occur closer to the time of administration of the offending agent.
- Pruritus is often present.
- Fever
- Present in 10 " “20% of cases
- Usually mild
- Arthritis or arthralgia
- Present >50% of the time
- Usually involves the metacarpophalangeal and knee joints
- Associated abdominal pain
- Some cases may have visceral involvement.
- History of hematuria
- There can be modest renal involvement, usually presenting as proteinuria and microscopic hematuria.
- Case reports of renal failure
- Neurologic symptoms
- Peripheral neuropathy, brachial plexus involvement, and Guillain-Barre syndrome have been reported associations.
Physical Exam
- Erythematous purpuric rash starts at the sides of the feet, toes, hands, and fingers and then becomes more widespread.
- Erythema multiforme, maculopapular, purpuric, or urticarial type rash
- Mild to severe fever
- Generalized lymphadenopathy; may be localized to lymph nodes that drain the injection site
- Splenomegaly, occasionally
- Edema of the face and neck
- Joint swelling and tenderness
Diagnostic Tests & Interpretation
Lab
- Not extremely helpful in establishing diagnosis because no abnormality is universally present. Diagnosis usually apparent by classic findings and history of foreign protein or drug exposure:
- Urinalysis: may show proteinuria and/or hematuria
- Complement levels variably reduced before returning to normal
- Leukocytosis or leukopenia with or without eosinophilia
- Erythrocyte sedimentation rate may be slightly elevated.
- Skin biopsy of rash with direct immunofluorescent (not routinely recommended as part of workup) shows deposits of IgM and C3 complement in capillary walls.
Differential Diagnosis
- Erythema multiforme
- Mononucleosis
- Systemic lupus erythematosus
- Rocky Mountain spotted fever
- Henoch-Sch ƒ ¶nlein purpura
- Hypersensitivity syndrome reaction
- Drug-induced pseudoporphyria
- Acute generalized exanthematous pustulosis
- Granulomatosis with polyangiitis (Wegener granulomatosis)
- Pitfalls
- A history of fever, rash, and arthralgias is commonly seen with many infectious childhood illnesses. One must always consider a broad set of differential diagnoses.
- Symptoms may be so minimal that patient does not seek medical attention.
- Often misdiagnosed as simple drug allergy
Treatment
General Measures
- Stop suspected medication/antigen immediately.
- Topical steroids to relieve itching
- Antihistamines to inhibit the action of vasoactive mediators
- Antipyretics for fever
- NSAIDs to relieve joint pain
- Oral corticosteroids for severe cases
- Recommended to administer and taper over 10 " “14-day period
- Shorter course may result in relapse, and recurrent symptoms are more difficult to alleviate.
- Admit if symptoms are severe or diagnosis is unclear.
- Future avoidance of triggering agent if identified
Ongoing Care
Follow-up Recommendations
When to expect improvement: ‚
- Usually self-limited illness that resolves in a few days to weeks
- If symptoms persist for more than 1 month, reconsider the diagnosis.
Patient Education
- An initial episode of serum sickness cannot be prevented.
- Future episodes can be prevented by avoiding the causative medication (and class of medications) if it has been identified.
Prognosis
Excellent. Most cases are mild and transient with no long-term sequelae. ‚
Complications
- Shock
- Digital necrosis
- Guillain-Barre syndrome (rare)
- Generalized vasculitis (rare)
- Peripheral neuropathy (rare)
- Glomerulonephritis (rare)
- Acute flaccid paralysis (case report)
- Increased risk of anaphylaxis with repeat exposure to precipitating substance
- Fatality (rare, usually due to continued administration of antigen)
Additional Reading
- Bettge ‚ AM, Gross ‚ G. A serum sickness-like reaction to a commonly used acne drug. JAAPA. 2008;21(3):33 " “34. ‚ [View Abstract]
- Bonds ‚ RS, Kelly ‚ BC. Severe serum sickness after H1N1 influenza vaccination. Am J Med Sci. 2013:345(5):412 " “413. ‚ [View Abstract]
- Guidry ‚ MM, Drennan ‚ RH, Weise ‚ JW, et al. Serum sepsis, not sickness. Am J Med Sci. 2011;341(2):88 " “91. ‚ [View Abstract]
- McCollom ‚ R, Elbe ‚ DH, Ritchie ‚ AH. Bupropion-induced serum sickness-like reaction. Ann Pharmacother. 2000;34(4):471 " “473. ‚ [View Abstract]
- Roujeau ‚ J, Stern ‚ RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331(19):1272 " “1285. ‚ [View Abstract]
- Tolpinrud ‚ B, Bunick ‚ C, King ‚ B. Serum sickness-like reaction: histopathology and case report. J Am Acad Dermatol. 2011;65(3):e83 " “e85. ‚ [View Abstract]
Codes
ICD09
- 999.59 Other serum reaction
- 999.52 Other serum reaction due to vaccination
- 999.51 Other serum reaction due to administration of blood and blood products
ICD10
- T80.69XA Other serum reaction due to other serum, initial encounter
- T80.62XA Other serum reaction due to vaccination, initial encounter
- T80.61XA Oth serum reaction due to admin blood/products, init
SNOMED
- 403608009 Serum sickness due to drug
- 213323001 Serum rash (disorder)
- 72284000 transfusion reaction due to serum protein reaction (disorder)
- 402658008 Serum sickness type vasculitis (disorder)
FAQ
- Q: My child broke out all over her body with an itchy rash and hives a few days after taking cefaclor. Was this serum sickness?
- A: It is more likely that she is allergic to cefaclor. The difference is that drug allergies are type I IgE-mediated hypersensitivity reactions that occur very soon after drug exposure in a previously sensitized individual. Serum sickness is a type III antibody " “antigen immune complex and complement amplified hypersensitivity reaction that occurs 1 " “3 weeks after an initial exposure.
- Q: If my child has had serum sickness, is she at risk for getting it again?
- A: Yes, if she receives the same medication or related medications again. The symptoms will occur more quickly, usually in 2 " “4 days, and may be more severe.
- Q: Can the vaccines that my doctor recommends for my child give my child serum sickness?
- A: It is possible but very rare. There have been a few reports of serum sickness " “like reactions occurring after receiving vaccines submitted to the Vaccine Adverse Event Reporting System (VAERS).
- Q: Is there any way to prevent my child from getting serum sickness?
- A: Unfortunately, there is no way to predict if your child will have a serum sickness " “like reaction to a particular medication. It is extremely important to be aware of your child 's exact allergies to medications and to inform all health care providers caring for your child.
- Q: My oldest child had serum sickness after taking cefaclor. Is it true that all my children should now avoid taking cefaclor?
- A: No. There is no known genetic predisposition to serum sickness. Your other children do not need to avoid the medication that caused serum sickness.
- Q: How is the Arthus reaction different from serum sickness?
- A: The Arthus reaction is also a type III hypersensitivity reaction but causes only a local reaction. This phenomenon was first described in 1903 by the French physiologist Nicolas Maurice Arthus. The Arthus reaction is a local vasculitis caused by formation of antigen " “antibody complexes in local vessel walls, which then activate the inflammation process. The reaction occurs within hours after an individual is injected intradermally with an antigen against which he or she has been actively immunized.
- Q: My child was diagnosed with serum sickness 1 year ago. He still gets episodes of rash, fever, and joint pain every now and then. How can this be cured?
- A: Serum sickness is a self-limited disease, and as long as the offending agent is stopped, your child will completely recover. If there are continuing symptoms and your child is no longer taking the offending agent, then other causes for these symptoms need to be considered.
- Q:My child 's best friend was recently diagnosed with serum sickness. Do I need to be concerned?
- A: No. Serum sickness in not contagious.