Serum sickness, first identified in 1911 by von Pirquet, is a hypersensitivity vasculitis that occurs after exposure to a foreign antigenic material. It may result from exposure to a heterologous protein (classic serum sickness) or to a drug that lacks protein, such as certain antibiotics (serum sickness–like reaction). Serum sickness usually occurs 7 to 10 days (but as long as 3 weeks) after primary exposure and 1 to 4 days after secondary exposure. Second exposures require less antigen to initiate a more intense response. The discovery that immune responses could have pathologic effects, in addition to the known beneficial effects, was a landmark in the understanding of immunity.

Serum sickness occurs when drug–antibody complexes are entrapped on endothelial surfaces as a result of an injected antigen. Contact with the drug antigen initiates a series of reactions, such as immunoglobulin E (IgE) production and binding to mast cell membranes, as well as evidence of profound complement consumption. These antigen–antibody complexes are the basis for an immune complex (type III) hypersensitivity reaction that produces symptoms associated with serum sickness. In the 1950s, the "rabbit model," using radiolabeled isotopes, illustrated for the first time the production of antibodies directed against experimentally injected bovine serum albumin.

Drugs:

• Penicillins—now the most common cause of serum sickness
• Streptomycin
• Cephalosporins
• Fluoxetine
• Sulfonamides
• Carbamazepine
• Streptokinase
• Salicylates
• Barbiturates
• Propylthiouracil
• Thiazide diuretics 
• Hydantoins
• Influenza vaccine

Antitoxin agents—with animal serum proteins:

• Diphtheria antiserum (now prepared with immunoglobulin of human origin, greatly reducing the incidence of serum sickness from this cause) 
• Tetanus antiserum (now prepared with immunoglobulin of human origin, greatly reducing the incidence of serum sickness from this cause) 
• Hymenoptera stings—occasionally 
• Clostridial intoxication (botulism, gas gangrene) 
• Snake venom antiserum (Crotalidae family) 
• Human gamma globulin (rare) 
• Antithymocyte globulin—for aplastic anemia 

• Injection with a drug or antitoxin known to cause serum sickness 
• Risk increases with administration of higher quantities of snake venom antiserum or horse serum
• Previous exposure to a drug or antitoxin known to cause serum sickness (shortened reaction time) 

• First sign—typically erythema and pruritus at injection site
• Cutaneous eruptions—possibly purpuric; faint erythema with a serpiginous border on hands, fingers, feet, toes may precede eruptions; urticaria, often with intense pruritus, most common, also may be scarlatiniform or morbilliform
• Arthralgias—involve multiple joints, typically metacarpophalangeal and knee; intense pain with absence of findings
• Fever
• Malaise
• Lymphadenopathy—may precede onset of other symptoms 
• Edema—especially surrounding the face and neck; reduction may signify resolution
• Wheezing
• Flushing
• Rhinorrhea
• Hypotension characteristic of anaphylaxis (rare)
• Myalgia
• Diarrhea, nausea, abdominal cramping
• Anterior uveitis—case reports associated with administration of streptokinase for thrombosis; may be early sign of serum sickness

• Drug hypersensitivity 
• Anaphylaxis
• Systemic lupus erythematosus
• Periarteritis nodosa

Physical examination reveals cutaneous eruptions, often urticaria; may be purpuric and accompanied by severe pruritus. Fever, malaise, flushing, wheezing, and edema, especially surrounding the face, are all typical physical findings.

• C3 and C4 serum complement levels are depressed; C3a anaphylatoxin possibly increased
• Erythrocyte sedimentation rate is increased
• Leukopenia 
• Thrombocytopenia
• Proteinuria
• Microscopic hematuria
• Antibodies to horse serum proteins: IgG, IgA, IgM, IgE
• Immunofluorescence—reveals immune deposits (IgA, IgM, IgE, C3) at skin lesions

• Pathophysiology less well understood for drug-induced than for foreign antisera-induced serum sickness
• Antigen–antibody (immune) complexes lodge in small vessels and filtering organs; a lattice of antibody and antigen molecules forms
• Circulating phagocytes move into these complexes
• Deposits of immune complexes into tissue are aided by increased vascular permeability due to histamine release from mast cells and basophils (IgE-mediated)
• Bound immune complexes promote accumulation of neutrophils and/or monocytes via chemotactic activity of complement components resulting in phagocytosis
• Phagocytes degranulate, releasing proteolytic enzymes and oxygen-derived free radicals, causing tissue injury
• Arthralgias—from deposition of IgG and IgM antigen-antibody complexes

Except in severe cases, outpatient treatment with antihistamines and analgesics is sufficient. Corticosteroids are administered to patients who do not respond to initial treatment with the agents mentioned.

• Antihistamine
• Aspirin
• Corticosteroids—no controlled studies; prednisone 20 to 40 mg bid for 3 to 5 days and then tapering dose for 10 to 14 days; prednisone also used for peripheral neuritis or myocarditis
• Plasmapheresis—for severe, refractory cases

Treatment of serum sickness requires immediate conventional medical attention. Although the effectiveness of CAM therapies in the treatment of serum sickness has not been assessed by scientific research, nutritional and herbal treatments to minimize inflammation and to stabilize immune function may prove beneficial as supportive measures. Certain CAM measures may help alleviate symptoms of serum sickness while others may actually exacerbate serum sickness by increasing the number of circulating immune complexes.

Nutrients used in clinical practice to stabilize mast cells, inhibit histamine release, and enhance histamine catabolism include:

• Vitamin C
• L-methionine
• Choline
• Inositol

An animal study further suggests that vitamin C may enhance humoral immune function, thereby reducing the likelihood of an anaphylactic reaction that may occur from serum sickness (Feigen et al. 1982).

• Omega-3 oils may actually exacerbate serum sickness. Although widely used for their anti-inflammatory effects, a recent study that compared the effects of fish oil, safflower oil, and beef tallow on induced immune-complex nephritis in mice showed elevated proteinuria, increased titers of anti-bovine serum albumin antibodies, and higher levels of circulating immune complexes in the fish oil group. The authors suggest that decreased prostanoid (e.g. prostaglandins and thromboxanes) production induced by eicosapentaenoic acid (EPA) suppressed the elimination of circulating immune complexes by the liver, lungs, or spleen. As a result, in spite of the anti-inflammatory actions of EPAs, the accumulation of immune complexes and higher antibody levels in the blood might increase immune complex deposition and exacerbate glomerulonephritis (Tateno et al. 1997). Theoretically, this increased circulation of immune complexes may worsen serum sickness as well.

Anti-inflammatory herbs commonly used in clinical practice may, in theory, lessen some of the symptoms associated with serum sickness. However, scientific studies have not confirmed their use for treatment of serum sickness. The following are a few herbs with anti-inflammatory and other activities as indicated (Blumenthal et al. 2000):

• Ginkgo (Ginkgo biloba) inhibits platelet-activating factor and decreases edema. 
• Turmeric (Curcuma longa), milk thistle (Silybum marianum), and licorice root (Glycyrrhiza glabra) also have anti-inflammatory activities. Turmeric is believed to potentiate the effects of bromelain, a proteolytic enzyme that inhibits edema; the two are often used together (rare cases of allergies to bromelain have been reported).
• Peppermint oil (Mentha x piperita—approved by the German Commission E for urticaria. 
• Eleuthro root (Eleutherococcus senticosis), frequently marketed as Siberian ginseng—approved by the German Commission E for inflammatory conditions. 

In addition, Toki-shakuyaku-san (TSS), a Japanese (Kampo) formulation that contains six herbs, was found to decrease circulating immune complexes in mice injected with an immune complex model. Additional evaluation of the components of TSS found that the following active ingredient was instrumental in enhancing clearance of immune complexes (Iijima et al. 1994):

• Angelica root (Angelica archangelica) 

Although scientific research has not yet evaluated their application for serum sickness, it would be wise to avoid herbal substances such as cayenne pepper (Capsicum spp.) that may cause hypersensitivity reactions (Blumenthal et al. 2000).

Homeopathic remedies matched to the acute presentation may provide symptomatic relief of serum sickness. Although they have not been scientifically evaluated, remedies that may be considered by a certified homeopath include the following:

• Apis for urticaria with intense burning and severe tense edema; patients for whom this treatment is appropriate describe stinging pains relieved by cold applications.
• Rhus toxicodendron for urticaria with severe itching that is relieved with hot water; patient for whom this is appropriate tends to be restless and must change positions frequently.
• Urtica urens (small stinging nettles) for urticaria with red, raised rash; pains are described as burning and stinging and are relieved by rubbing.

Considered contraindicated in this setting as it may enhance inflammatory response and lower blood pressure.

Patients should be monitored in the acute phase for rare instances of myocarditis and peripheral neuritis.

• Avoid horse or animal serum; use only when no other treatment option is available.
• Perform skin tests for serum sensitivity—puncture test with 1:10 dilution; if negative, intradermal test with 0.02 ml of 1:10,000 dilution; if negative, puncture test with 1:1,000 dilution; if negative, final intradermal test with 1:100 dilution. 
• For treatment with known reaction, antitoxin can be administered by a rapid desensitization process; however, the desensitization is usually transient.
• For snakebite, use of fragment antigen-binding (Fab) preparations minimizes risk.

• Guillain-Barré syndrome 
• Peripheral neuritis—especially of the brachial plexus (C5 to C6)
• Anaphylaxis

Serum sickness is usually self-limited, resolving in 7 to 10 days, with full recovery in 2 to 3 weeks.

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