Serum Sickness

Serum sickness is an example of the type III, or immune complex–mediated, hypersensitivity disease. The molecular size, charge, structure, amount, and valence of the antigen involved influence the type of immune complexes formed.[2]

After the initial exposure to a foreign antigen in the absence of a preexisting antibody, serum sickness can develop within 1-2 weeks. Upon subsequent exposure, however, serum sickness develops sooner. The disease appears as the antibody formation begins, and the pathogenesis of serum sickness is related to protracted interaction between antigen and antibody in the circulation, with antigen-antibody complex formation in an environment of antigen excess.

The immunologic interactions observed in serum sickness occur when antigens capable of remaining in the circulation for long periods incite antibody formation.[6] Typically, serum protein molecules are removed from the circulation by nonimmune processes that are not yet completely understood.

Immune complex formation is a common event and does not typically cause symptoms.[7] Small complexes usually circulate without triggering inflammation, and large complexes are cleared by the reticuloendothelial system. However, intermediate-sized complexes that develop in the context of slight antigen excess may deposit in blood vessel walls and tissues, where they induce vascular and tissue damage resulting from activation of complement and granulocytes.[8]

Endothelial cells increase the expression of adhesion molecules, and monocytes and macrophages release proinflammatory cytokines. Subsequently, additional inflammatory cells are recruited, and necrosis of the small vessels develops. Complement activation promotes chemotaxis and adherence of neutrophils to the site of immune complex deposition. This may be facilitated by increased vascular permeability due to release of vasoactive amines from tissue mast cells.[8]

At this point, complement levels fall to half their levels prior to the antibody response.[6] This clinicopathological syndrome usually develops within 1-2 weeks of antigen injection.

Free antigen continues to clear from the blood, leading to antibody excess and the formation of large immune complexes, which are quickly removed by circulating macrophages. Finally, the antigen is no longer detectable, and the level of circulating antibodies continues to rise. Clinical recovery is usually apparent after 7-28 days, as intermediate-sized immune complexes are cleared by the reticuloendothelial system.

Secondary serum sickness is the result of antigen recognition by presensitized cells of the immune system. It is characterized by a shorter latent period, exaggerated symptoms, and a brief clinical course.

Why immune complex disease occurs under certain circumstances is not known. Possible factors may include high levels of immune complexes and a relative deficiency of some complement components leading to a decreased ability to eliminate immune complexes.[7]

In an epidemiological study of 37 cases of rituximab-induced serum sickness, Bayer and colleagues reported that 54% of cases occurred after the first injection, mainly in individuals treated for an autoimmune disease (78%), particularly systemic lupus erythematosus (SLE). The investigators concluded this may be due to B-cell lysis, leading to the release of intracellular antigens into the serum and subsequent antigen-antibody complex formation, particularly in patients with elevated autoantibodies.[9]

Not all substances that are recognized as foreign by the immune system elicit an immune response. The antigen must be of characteristic size or have specific antigenic determinants and physiological properties to be an effective stimulator of the immune system.

After an appropriate antigen is introduced, an individual's immune system responds by synthesizing antibodies after 4-10 days. The antibody reacts with the antigen, forming soluble circulating immune complexes that may diffuse into the vascular walls, where they may initiate fixation and activation of complement.

Complement-containing immune complexes generate an influx of polymorphonuclear leukocytes into the vessel wall, where proteolytic enzymes that can mediate tissue damage are released. Immune complex deposition and the subsequent inflammatory response are responsible for the widespread vasculitic lesions seen in serum sickness.

Currently, the most common cause of serum sickness and serum sickness–like is hypersensitivity reaction to drugs.[5] Drugs containing proteins of other species include the following:

• Antitoxins
• Antivenins ^[10]
• Hormones from other species
• Streptokinase
• Vaccines

Polyclonal and monoclonal antibodies prepared from horse, rabbit, or mouse serum (eg, antithymocyte globulin, OKT-3) have also been found to cause serum sickness.[11]

Antibiotics and other antimicrobials that can cause serum sickness include the following:

• Cephalosporins
• Ciprofloxacin
• Griseofulvin
• Lincomycin
• Metronidazole
• Para-aminosalicylic acid
• Penicillins
• Streptomycin
• Sulfonamides
• Tetracyclines

Other drugs associated with serum sickness include the following:

• Allopurinol
• Barbiturates
• Bupropion ^{[12, 13]}
• Captopril
• Carbamazepine
• Fluoxetine
• Gold salts
• Halothane
• Hydantoins (eg, phenytoin)
• Hydralazine
• Indomethacin
• Iodides
• Iron dextran
• Methimazole
• Methyldopa
• Mirabegron ^[14]
• Penicillamine
• Procainamide
• Procarbazine
• Propranolol
• Thiouracil

Monoclonal antibodies have been reported to cause a serum sickness–like syndrome. These include infliximab, which is used to treat disorders including rheumatoid arthritis, psoriatic arthritis, Crohn disease, ulcerative colitis, and akylosing spondylitis[15, 16] ; omalizumab, which is used to treat allergy-related asthma and chronic idiopathic urticaria[17, 18, 19, 20] ; and rituximab, which is used to treat various  rheumatologic and neoplastic disorders.[18, 21, 22, 23]  

A possible case of serum sickness after a third infusion of ocrelizumab for treatment of relapsing remitting multiple sclerosis (MS) has been reported.[24]  Although the patient in this case did not have the classic presentation of fever, rash, and arthralgia, serum sickness could not be ruled out; a case commentary recommends considering serum sickness in patients with delayed hypersensitivity reactions to anti-CD20 monoclonal therapies.[25]

Stings from insects in the order Hymenoptera (eg, bees, wasps), mosquitoes, and tick bites may cause serum sickness.[26]

Infectious diseases involving circulating immune complexes (eg, hepatitis B, infective endocarditis) may cause serum sickness–like reactions. These conditions are often associated with circulating cryoglobulins.

The annual incidence of serum sickness is decreasing as the administration of foreign antigens in medical therapeutics is refined.[4] The likelihood of developing serum sickness is dose-related. In one study, 10% of patients who received 10 mL of tetanus antitoxin developed serum sickness; the administration of 80 mL or more produced the disease in almost all patients.[4]

The likelihood also varies by antigen type. Antirabies serum is associated with a higher likelihood (16.3%) of serum sickness than tetanus antitoxin (2.5%-5%).[4] The reported rate of serum sickness–like reaction per course of cefaclor in United States children is 0.2%.[27]

In one study, serum sickness was more common in patients older than 15 years who were given antirabies serum.[28] Antibiotic-associated serum sickness–like disease, however, is more frequently described in children younger than 5 years.

In a prospective cohort study of 109 patients who received snake antivenom in Australia, serum sickness occurred in 29% of the patients.[10]

Serum sickness is typically self-limited and resolves within days.[5] The prognosis of serum sickness in patients without internal organ involvement is good.[7] Although occasional reports show mortality resulting from progressive glomerulonephritis or severe neurological complications.

Complications of serum sickness may include the following:

• Vasculitis
• Neuropathy
• Acute kidney injury
• Glomerulonephritis (rare)
• Anaphylaxis
• Shock

Serum sickness develops 1-3 weeks after initial administration of the causative agent (in many cases a medication) but can occur within 12-36 hours in individuals who have been previously sensitized through an antecedent exposure.[5]

Symptoms described in serum sickness include the following[5] :

• Fever/malaise - ~100%
• Cutaneous eruptions - 93%
• Arthralgias - 77%
• Gastrointestinal (GI) complaints - 67%
• Headaches - 57%
• Myalgias - 37%
• Blurred vision - 37%
• Dyspnea/wheezing - 20%
• Lymphadenopathy - 17%

Specific GI symptoms may include abdominal pain, nausea, vomiting, or diarrhea.[2] Chest pain or breathlessness due to pleuritis, pericarditis, or myocarditis is possible but rare.

Fever develops in almost all patients with serum sickness, preceding skin rash in 10-20% of cases. The fever is characterized by high spikes that normalize within the same day.[8]

Most rashes associated with serum sickness are urticarial (92%) and/or serpiginous.[2] They typically start on the anterior lower trunk or the periumbilical or axillary regions and spread to the back, upper trunk, and extremities.[8] In the extremities, eruptions occur at the junction of the palmar or plantar skin with the dorsolateral surface of the hands, feet, fingers, and toes.

Morbilliform or scarlatiniform rash, palpable purpura, erythema simplex, or erythema multiforme are less common. Pruritus and erythema are possible at injection sites. Edema can be limited to site of injection but can also be observed in the face.[2]

Lymphadenopathy (10-20%) may be generalized or may involve tenderness in the nodes that drain the injection site. Splenomegaly may occur.

Arthritis (10%-50%) is usually in the metacarpophalangeal and knee joints and usually symmetrical.[4] Occasionally, small joints, joints of the spine, and the temporomandibular joint may be inflamed. Myalgias or myositis also may occur.

Edema may occur, particularly about the face and neck.

Kidney manifestations include proteinuria, microscopic hematuria, and oliguria; however, significant disease usually does not result.

Cardiovascular findings may include myocardial and pericardial inflammation. Generalized vasculitis occurs rarely.

Neurologic manifestations include the following[2, 4] :

• Peripheral neuropathy
• Brachial plexus neuritis
• Optic neuritis
• Cranial nerve palsies
• Guillain-Barré syndrome
• Encephalomyelitis (rare)

Pulmonary manifestations, such as pleurisy, are rare. However, dyspnea and cyanosis are not uncommon.

Laboratory studies are not helpful in establishing a diagnosis of serum sickness. However, certain laboratory findings have been reported, including the following:

• Leukopenia or mild leukocytosis, with or without eosinophilia
• Plasma cells on peripheral blood smear ^[2]
• Erythrocyte sedimentation rate elevation ^[2]
• Polyclonal gammopathy or a transient monoclonal immunoglobulin G (IgG) spike ^[4]
• Mild proteinuria or hematuria
• Transient elevation of serum creatinine levels
• Decreased complement levels (C3, C4) ^[2]
• Cryoglobulinemia, often of the mixed (IgM-IgG) type

Numerous histological changes may be found in serum sickness, depending on the organ involved and, possibly, the nature of the antigen. The tissues most commonly involved include those of the heart, arteries, joints, and kidneys. Arteritic lesions are focal, necrotizing, and inflammatory processes that usually involve all layers of the artery.

Acute inflammatory exudate, necrosis of the arterial wall, fibrinoid material, or primarily a mononuclear reaction may be observed. Joints may have focal mononuclear infiltrates with edema and fibrinoid formation in the synovial tissues. Kidneys develop endothelial proliferation of the glomerular capillaries with slight basement membrane thickenings.[6]

Withdrawal of the offending agent is the mainstay of treatment in serum sickness. Nonsteroidal anti-inflammatory drugs and antihistamines provide symptomatic relief.

Severe cases (multisystem involvement with significant symptoms) may warrant a 7- to 10-day course of corticosteroids.[4] In some cases, plasmapheresis can attenuate serum sickness.[5]

Hospitalize the patient if any significant comorbidities are present (eg, advanced or very young age, immunocompromise), if any severe symptoms or hemodynamic instability/hypotension is present, or if the diagnosis is unclear.

The presenting features of fever, rash, and joint pain may be observed in numerous infectious and autoimmune diseases. Consider a consultation with an allergist or a rheumatologist.

Avoidance of the offending agent is the best way to prevent serum sickness. However, in some circumstances, avoidance is not possible.

Skin tests are indicated before antiserum administration, particularly in patients with a history of allergy to horse dander or in those who have previously received the substance. Skin tests reveal the presence of immunoglobulin E antibodies and, thus, help to identify individuals at risk of anaphylaxis. However, these tests are not reliable in the identification of individuals with an increased risk for serum sickness.

If rapid administration of antiserum is necessary, establish intravenous access in each arm (one site for the infusion of antiserum and the other for the treatment of complications) and premedicate the patient with 50-100 mg of diphenhydramine. If a reaction occurs, temporarily discontinue the infusion, and administer epinephrine and other necessary medications. Once the adverse reaction is halted, resume slow infusion.

Premedication with steroids is not protective.

Desensitization

Fajt and Petrov reported the first case of successful drug desensitization in a patient with rituximab-induced serum sickness. Although drug desensitization has traditionally been used to treat type I IgE-mediated hypersensitivity reactions, a rapid 12-step intravenous rituximab desensitization protocol allowed resumption of treatment in a 37-year-old woman who had developed serum sickness 72 hours following rituximab infusion for a gastric mucosa-associated lymphoid tissue lymphoma (MALToma).[29]

The patient’s MALToma, which had progressed after stopping rituximab, went into remission after the completion of four rituximab desensitizations. She received 25 maintenance rituximab doses using this desensitization protocol quarterly without complications.[29]

Dilley et al report on the successful use of a new patient weight–based protocol in two children who had experienced hypersensitivity reactions to rituximab. The authors conclude that desensitization to rituximab is a safe and effective procedure in the pediatric population.[30]

Long-term monitoring

Reconsider the diagnosis of serum sickness if symptoms persist beyond 3-4 weeks. Symptoms may reappear in severe cases if steroids are tapered too quickly; this recurrence is usually responsive to another course of treatment. After identifying the causative agent, inform the patient and advise that future exposure may cause a similar or more severe response.

The goal of therapy is to treat the clinical syndrome resulting from the effects of soluble circulating immune complexes that form under conditions of antigen excess. These immune complexes can originate from the administration of either heterologous antisera or drugs known to cause serum sickness.

Class Summary

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Ibuprofen (Motrin, Ibuprin, Advil, Caldolor, Addaprin, Ultraprin)

Ibuprofen decreases inflammation by blocking prostaglandin synthesis and reduces fever by acting on the hypothalamic temperature-regulating center. It is usually administered for mild symptoms of arthralgia, myalgia, or fever.

Naproxen (Anaprox, Aleve, Naprosyn, Naprelan)

Naproxen is indicated for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Ketoprofen

Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in those with renal or liver disease. Doses of more than 75 mg do not increase therapeutic effects. Administer high doses with caution and closely observe patient for response.

Class Summary

Antihistamines act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.

Diphenhydramine HCL (Benadryl, Aler-Cap, Aler-Dryl, Anti-Hist)

Diphenhydramine blocks histamine H1 receptors on the target tissue. It used for urticarial rash.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone

Prednisone acts by altering the number and availability of leukocytes, reducing vascular permeability, and suppressing cytokines. This agent is the mainstay of treatment in severe cases; it is usually administered in moderate doses for 1-2 weeks. Prednisone, or other oral corticosteroids (eg, prednisolone), is useful in managing mild-to-moderate serum sickness treated in an outpatient setting.