Dott. M.M. CIAMMAICHELLA

Dirigente Medico

UOC Medicina Interna I° per l'Urgenza

(Direttore: Dott. G. Cerqua)

A.C.O. S. Giovanni – Addolorata, Roma

 

 

 

SERUM SICKNESS

 

 

 

KEY-WORDS: Serum sickness

 

 

INTRODUCTION
CLINICAL
WORKUP
TREATMENT
MEDICATION
FOLLOW-UP
MISCELLANEOUS
BIBLIOGRAPHY

 


INTRODUCTION

 

Background: Serum sickness is a Type III hypersensitivity reaction that results from injection of heterologous or foreign protein or serum. Serum sickness-like reactions that are secondary to the administration of non-protein drugs are clinically similar.

Pathophysiology: Not all substances that are recognized by the immune system as being foreign 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, the 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 are released that can mediate tissue damage.

Immune complex deposition and the subsequent inflammatory response are responsible for the widespread vasculitic lesions seen in serum sickness.

Frequency:

  • In the U.S.: The incidence of serum sickness is decreasing as a result of public health vaccination programs that have decreased the need for specific antitoxins. Also, many horse serum antitoxins have been refined of the antigenic components that cause serum sickness.
    Products derived from human serum have replaced the most frequently used antitoxins, rabies and tetanus horse serum antitoxins. When rabies and tetanus horse serum were used, the incidence of serum sickness in patients receiving tetanus antitoxin was 2-5% and 16% in patients receiving rabies antitoxin.
    The frequency and severity of reactions were found to be directly related to the amount and type of antiserum administered. Currently, nonprotein drugs are the most common cause of serum sickness-like reactions.
    The incidence of serum sickness-like reactions caused by non-protein drug is difficult to determine. From 1972 to 1985, among the adverse drug reactions reported to the FDA, there were 10 cases of serum sickness related to amoxicillin (Amoxil, Polymox), 638 cases related to cefaclor (Ceclor), 28 cases related to cephalexin (Keflex) and 51 cases related to trimethoprim/sulfamethoxazole (Bactrim, Cotrim, Septra, and Sulfatrim).

Mortality/Morbidity:

  • Symptoms usually last 1-2 weeks before spontaneously subsiding. There are generally no long-lasting sequelae. Fatalities are rare and are usually due to the continued administration of the antigen.

Age:

  • Individuals older than 15 years may experience more frequent and severe disease. This may be due to the fact that older individuals received larger volumes of antitoxin.

 

 


 CLINICAL

 

 

History: Primary serum sickness occurs 6-21 days after the administration of the inciting antigen. The onset may be more rapid with subsequent exposures to the same antigen, with symptoms occurring 1-4 days after exposure.

  • The classic clinical manifestations consist of fever, arthralgia, lymphadenopathy and skin eruption.
  • Pain, pruritus and erythematous swelling at the injection site usually precede the onset of disease.
  • Patients may also complain of joint and muscle aches, chest pain and difficulty breathing.

Physical:

  • Cutaneous symptoms (95%):
    • Urticaria
    • Scarlatiniform rash
    • Maculopapular or purpuric lesions
    • Erythema multiforme (EM)
    • Characteristic serpiginous, erythematous and purpuric eruption at the junction of the palmar or plantar skin with the dorsolateral surface of the hands, feet, fingers and toes.
  • Fever of 101-104 degrees Farenheit is invariably present and may precede rash in 10-20% of cases.
  • Lymphadenopathy (10-20%) may be generalized or may be tender in nodes that drain the injection site; splenomegaly may occur.
  • Arthritis or arthralgias (10-50%):
    • It usually affects multiple large joints but, occasionally, small joints and joints of spine and temporomandibular joint may be inflamed.
    • Myalgias or myositis may also occur.
  • Edema, particularly about the face and neck
  • Renal manifestations include proteinuria, microscopic hematuria and oliguria but significant disease does not usually result.
  • Cardiovascular:
    • Myocardial and pericardial inflammation may occur.
    • Generalized vasculitis occurs rarely.
  • Neurologic manifestations include peripheral neuropathy, brachial plexus neuritis, optic neuritis, cranial nerve palsies, Guillain-Barre syndrome and encephalomyelitis.
  • Pulmonary manifestations such as pleurisy are rare, but it is not uncommon for patients to demonstrate dyspnea and cyanosis.

Causes:

  • Heterologous serum used in prophylaxis and treatment of botulism, diphtheria, gas gangrene, organ transplant rejection and the management of snake and spider bites
  • Drugs that have been implicated in the development of serum sickness-like reactions include: allopurinol (Zyloprim), arsenicals and mercurial derivatives, barbiturates, captopril (Capoten), cephalosporins, furazolidone (Furoxone), gold salts, griseofulvin (Fulvicin, Grifulvin), halothane, hydralazine (Apresoline), iodides, methyldopa, para-aminosalicylic acid, penicillamine, penicillins, phenytoin (Dilantin), piperazine, procainamide (Procan SR, Procanbid, Pronestyl-SR), quinidine (Quinaglute, Quinalan, Quinidex, Quinora), streptokinase (Streptase, Kabikinase), sulfonamides and thiouracils.
  • Allergen extracts
  • Blood products
  • Hormones
  • Hymenopteran venom
  • Infectious agents
  • Vaccines

 

WORKUP

 

 

Lab Studies:

  • Laboratory studies are not very helpful in establishing a diagnosis. Certain laboratory findings have been reported.
  • Complement levels (outside of ED) are variable.
  • Complete Blood Count (CBC) and Differential: Leukocytosis or leukopenia with or without eosinophilia.
  • The erythrocyte sedimentation rate (ESR) is usually slightly elevated.
  • Serum Protein Electrophoresis (outside of ED): Hypergammaglobulinemia with free circulating light chains may be present.
  • Urinalysis: Proteinuria and/or hematuria

 

 

 


 TREATMENT

 

 

Emergency Department Care:

  • Cessation of therapy of the suspected antigen.
  • Supportive and symptomatic therapy.

 

 


MEDICATION

 

 

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 either originate from the administration of heterologous antisera or the administration of drugs known to cause serum sickness.

Drug Category: Antihistamines - Symptomatic treatment with antihistamines for pruritus. Antihistamines may prevent the deposition of immune complexes. Prophylactic antihistamines may decrease the incidence of serum sickness by negating the action of vasoactive amines and preventing the increased vascular permeability they induce.

Drug Name

Diphenhydramine (Benadryl) - It is used for the symptomatic relief of allergic symptoms caused by histamine released in response to allergens.

Adult Dose

Initial dose: 50-100 mg IV, IM, po

Maintenance dose: 10-50 mg q6-8h IM, IV, po

Do not exceed 400 mg/d

Pediatric Dose

po: Administer 12.5-25 mg, tid or qid, or 5 mg/kg/d, or 150 mg/m 2 /d divided tid or qid

Do not exceed 300 mg/d

IM or IV: 5 mg/kg/d or 150 mg/m 2 /d, divided qid

Do not exceed 300 mg/d

Contraindications

Avoid use in patients with documented hypersensitivity to this medication or related products.

Interactions

This medication potentiates the effect of CNS depressants.

Due to its alcohol content, do not give the syrup dosage form to patients taking medications that can cause disulfiram reactions.

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Use with caution in patients diagnosed with angle closure glaucoma, peptic ulcer, urinary tract obstruction, and hyperthyroidism. Diphenhydramine may exacerbate these conditions.

Drug Category: Antipyretics - Bed rest and mild analgesic-antipyretic therapy are often helpful in relieving the associated fever, arthralgias and myalgias associated with the syndrome.

Drug Name

Aspirin - It blocks prostaglandin synthetase action which in turn inhibits prostaglandin synthesis and prevents formation of the platelet-aggregating thromboxane A 2 . It also acts on the hypothalamus heat-regulating center to reduce fever.

Adult Dose

325-650 mg q4-6h

Do not exceed 4 g/d

Pediatric Dose

10-15 mg/kg/dose q4-6h

Do not exceed 60-80 mg/kg/d

Contraindications

Avoid use in patients with documented hypersensitivity to this drug or related products and those with liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, and asthma.

Due to the association of aspirin with the Reye's syndrome do not use in children that have the flu and are younger than 16 years.

Interactions

Antacids and urinary alkalinizers can decrease the pharmacologic effects of salicylates. Conversely, corticosteroids decrease salicylate serum levels by increasing salicylate clearance. When administered concurrently with other anticoagulants, it can have an additive hypoprothrombinemic effect and may increase bleeding time.

Aspirin may also antagonize probenecid's uricosuric effects and increase free phenytoin and valproic acid levels increasing their toxicity. In doses greater than 2 g/d aspirin may alter pancreatic beta-cell function and potentiate the glucose lowering effect of sulfonylurea drugs.

Pregnancy

D - Unsafe in pregnancy

Precautions

Exercise caution in patients with chronic renal insufficiency. Aspirin may cause a transient decrease in renal function, and may aggravate chronic kidney diseases.

Patients diagnosed with severe anemia, history of blood coagulation-defects, or are taking anticoagulants should avoid aspirin use.

Drug Category: Corticosteroids - Have both anti-inflammatory (glucocorticoid) and salt retaining (mineralocorticoid) properties. Corticosteroids cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli. 

Drug Name

Prednisone - It is used as an immunosuppressant in the treatment of autoimmune disorders.

Adult Dose

Administer 0.05-2 mg/kg/d po, divided bid-qid

Alternatively, administer a maximum of 80 mg/d qd, or divided bid-qid.

Taper over 2 wks as symptoms resolve.

Pediatric Dose

Administer 4-5 mg/m 2 /d

Alternatively, administer 1.0-2.0 mg/kg po qd

Taper over 2 wk as symptoms resolve.

Contraindications

Avoid use in patients with documented hypersensitivity to this drug and those with viral, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections.

Interactions

Prednisone clearance may decrease when used concurrently with estrogens. In addition, when used with digoxin, it may increase digitalis toxicity secondary to hypokalemia.

Phenobarbital, phenytoin and rifampin may also increase the metabolism of glucocorticoids and thus should consider increasing the maintenance dose.

Monitor patients for hypokalemia when taking this medication concurrently with diuretics.

Pregnancy

B – Usually safe but benefits must outweigh the risks.

Precautions

Use with caution in patients diagnosed with hyperthyroidism, peptic ulcer, diabetes, cirrhosis, nonspecific ulcerative colitis, osteoporosis, and myasthenia gravis.

Patients receiving glucocorticoids are at risk for multiple complications including severe infections.

The abrupt discontinuation of glucocorticoids may cause an adrenal crisis. Hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use.


 

 

FOLLOW-UP

 

 

Further Outpatient Care:

  • Admit if severe or if the diagnosis is unclear.

Deterrence/Prevention:

  • Avoidance of the offending agent is the best way to prevent occurrence of serum sickness. However, there are circumstances where avoidance is not possible.
  • Skin tests are indicated before antiserum administration, particularly with a history of allergy to horse dander or if the patient has received the material previously. Skin tests detect the presence of IgE antibodies and, thus, predict the individuals at risk of anaphylaxis, but will not reliably predict increased risk of serum sickness.
  • If rapid administration of antiserum is necessary, establish IV in each arm, one for the infusion of antiserum and the other for the treatment of complications and premedicate with 50-100 mg of diphenhydramine (Benadryl). If a reaction occurs, the infusion is temporarily discontinued and epinephrine and other necessary medications are given. Once the adverse reaction is halted, the slow infusion is resumed.

 

Complications:

  • Vasculitis
  • Neuropathy
  • Glomerulonephritis (rare)
  • Anaphylaxis
  • Shock
  • Death

Prognosis:

  • Most cases are mild and resolve within a few days. However, subjective complaints and objective findings may persist for several weeks.



 

MISCELLANEOUS

 

 

Medical/Legal Pitfalls:

  • The primary medical legal pitfall is not considering serum sickness in your differential diagnosis. Cessation of the offending antigen is important in the treatment of serum sickness.

 

 

 


 BIBLIOGRAPHY

  • Berman BA, Ross RN : Acute serum sickness. Cutis 1983; 32: 420-422.
  • Bigby M, Stern RS, Arndt KA: Allergic cutaneous reactions to drugs. Primary Care-Clinics in Office Practice 1989; 16: 713-727.
  • Erffneyer JE: Serum sickness. Annals of Allergy 1986; 56: 105-110.
  • Hart FD: Drug induced arthritis and arthralgia. Drugs 1984; 28: 347-354.
  • Heckbert SR, Stryker WS, Coltin KL: Serum sickness in children after antibiotic exposure-estimates of occurence and morbidity in a health maintenance organization population. American Journal of Epidemiology 1990; 132: 336-342.
  • Lawley TJ, Bielory L, Gascon P: Human serum sickness. Transactions of the Association of American Physicians 1984; 97: 49-55.
  • Lazoglu AH, Boglioli LR, Taff ML: Serum sickness reaction following multiple insect stings. Annals of Allergy, Asthma, and Immunology 1995; 75: 522-524.
  • Naguwa SM, Nelson BL: Human serum sickness. Clinical Reviews in Allergy 1985; 3: 117-126.
  • Parker CW: Allergic reactions in man. Pharmacological Reviews 1982; 34: 85-104.
  • Platt R, Dreis MW, Kennedy DL: Serum sickness-like reactions to amoxicillin, cefaclor, cephalexin, and trimethoprim-sulfamethoxazole. Journal of Infectious Disease 1988; 158: 474-477.
  • Reynolds JS: Serum sickness- an old problem with new implications. Annals of Allergy 1966; 24: 337-344.