Are You Confident of the Diagnosis?
Serum sickness is a type III hypersensitivity reaction from the administration of foreign protein, serum or nonprotein medications. Serum sickness is characterized by rash, fever, arthralgia or arthritis. Classical serum sickness is caused by the injection of heterologous serum proteins such as horse serum. A similar syndrome, serum sickness-like reactions (SRLR), occurs after the administration of a medication.
What you should be alert for in the history
Primary serum sickness occurs 1 to 2 weeks after the initial injection or ingestion of the responsible agent. Repeated exposure leads to a more rapid (within 12-36 hours) and more florid response. At the site of the injection, there can be pain, itching, and redness prior to the onset of systemic symptoms. Classically, serum sickness consists of fever, skin rash, arthralgia and arthritis, malaise, myalgia, and lymphadenopathy. Less common reactions can also include chest pain, dyspnea, gastrointestinal complaints, headaches, and blurred vision. Serum sickness is a self-limiting disorder, and these symptoms resolve within a few weeks of discontinuation of the responsible agent.
Characteristic findings on physical examination
Findings on physical examination can include a skin rash, fever, arthralgia/arthritis, and other less common manifestations including renal, cardiovascular, pulmonary, neurologic, and gastrointestinal systems.
Cutaneous findings (95%): Serum sickness has many dermatologic manifestations, lasting a few days to 1 to 2 weeks. The most common and earliest feature is a pruritic rash. Patients often develop a combination of urticarial lesions and a serpinginous macular rash that starts in the axillary and groin region and later spreads to involve other parts of the body. Mucous membranes are typically spared. There can be well-demarcated skin changes on the hands and feet, especially at the lateral aspect and at the junction between palmar/plantar aspects and the dorsal surfaces. Other variable skin findings can include exanthematous/morbilliform eruptions, papable purpura, erythema multiforme-like lesions, and vasculitis.
Fever (10-20%): Fever higher than 38.5°C can precede the rash. Patients often spike high temperatures then return to normal tempurature within the same day without any pattern.
Arthritis and arthralgia (10-50%): Joint involvement occurs after the rash has started and resolves before the rash resolves. More commonly multiple large joints, and less commonly, small joints, can be affected, including knees, wrists, shoulders, and ankles, and metacarpophalangeal joints. Spine and temporamandibular joint pain have also been described. Swelling and erythema of joints are rare. Myalgias and myosisitis can also occur.
Other findings may include:
-Lymphadenopathy: Can occur at nodes that drain from the injection site or can be generalized. Splenomegaly can also be found.
-Edema: at site of injection or of the face and neck
-Renal: More commonly seen are proteinuria, hematuria, and oliguria. Very rarely acute renal failure and progressive glomerulonephritis can be seen.
-Cardiovascular: Myocarditis and pericarditis can be seen.
-Pulmonary: Dysnea, wheezing, and cyanosis, and rarely, pleuritis can be seen.
-Neurologic: Rarely there are peripheral neuritis, brachial plexus neuritis, optic neuritis, cranial nerve palsies, Guillaine-Barre syndrome, myelitis. Extremely rare are encephalitis, encephalomyelitis, and non-reversible neurological sequelae.
-Gastrointestinal: Abdominal pain, nausea, vomiting, and diarrhea can be seen
Expected results of diagnostic studies
An appropriate work-up includes a thorough history of medications and time of onset of symptoms in relation to medication introduction. Aside from the physical symptoms and signs as stated above, serum sickness also presents with neutropenia, thrombocytopenia, and occasionally eosinophilia. Acute phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated. Patients often develop mild proteinuria and transient, mild hematuria. Serum creatinine can be elevated above baseline, but often resolves in a few days. In serum sickness-like reaction, there is rarely renal involvement. Complement consumption is often seen, as reflected in decreased levels of C3, C4, and the complement hemolytic assay, CH50.
Thus, an appropriate laboratory work-up should include complete blood count and differential, ESR, CRP, urinalysis, complete metabolic panel, complement levels of C3, C4, complete hemolytic assay CH50. An infectious disease work-up should also be intiated if indicated, given many of the differential diagnoses include infectious causes.
Skin biopsies show nonspecific findings and are rarely performed as they are not diagnostic to confirm serum sickness. Skin biopsies from patients with serum sickness from equine antithymocyte globulin (ATG) show mild lymphocytic and histiocytic perivascular infiltrates, with no vessel necrosis. Immunofluorescence study shows IgM and C3, but no IgG. Rarely, as reported in a few patients with serum sickness, leukocytoclastic vasculitis with neutrophilic infiltrate and fibrinoid necrosis is seen. Immunofluorescence shows IgG and C3 deposition in the small vessel cell walls.
The diagnosis of serum sickness is often made clinically when evaluating patients with an acute to subacute onset of rash, fever, and arthralgias occurring after exposure to the offending agent. Oftentimes the offending agent is hard to identify if patients are on multiple medications.
Differential diagnosis of serum sickness and serum sickness-like reactions includes infection, rheumatologic disease, various vaculitidies, or other types of drug reactions.
-Viral illnesses with exanthems such as mononucleosis. [While viral infections can cause similar fever, skin rash, myalgias as serum sickness, the arthragias and arthritis are not as acute and severe as serum sickness. Viral infections can often have mucosal and pharyngeal lesions which are not often seen in serum sickness.
– Bacterial infections such as gonococcal or menigococcal infection, Rocky Mountain Spotted Fever, Lyme disease, or acute rheumatic fever. [Disseminated gonococcemia or menigococcemia often have cutaneous pustules or purpuric macules or papules containing the organisms. Gonococcemia can have septic arthritis with swelling, and organisms can be detected from joint aspirate. Menigococcemia has signs of meningitis of headache and neck stiffness. Rocky Moutain Spotted Fever is a tick-borne rickettsial infection that presents with fever, headache, and a centripedal or “outward to inward” pattern rash. Lyme disease is another tick borne infection with a distinct rash of erythema migrans (an expanding erythematous ring like lesion with central clearing and center of erythema or purpura, resembling a bullseye) and monoarthritis of the knee. Acute rheumatic fever follows a recent streptococcal infection, presents as migratory arthritis with joint swelling, cardiac murmurs, carditis, and an evanescent ring like rash that spreads outward.]
-Still’s disease [Still’s disease, also known as systemic onset juvenile rheumatoid arthritis, can have similar fever, arthralgias, arthritis, and a rash. However, this rash is evanescent, lasting a few hours. Still’s disease is also likely to persist or recur with no treatment.]
-Systemic lupus erythematosus [SLE can have nonspecific fever, arthragias, and rash, however, that also include serologic testings consistent with automimmune disease (eg, positive ANA, dsDNA) that serum sickness lacks.]
-Kawasaki’s disease [Kawasaki’s disease is often seen in children, with fever, acral erythema rash that then desquamates, peripheral edema, and mucosal involvement of mouth and conjunctiva.
-Reactive arthritis [Reactive arthritis can have fever and joint pain, however, also includes symptoms of urethritis and conjunctivitis. Skin rashes of reactive arthritis differ from that of serum sickness and include circinate balanitis with gyrate white plaques on the glans penis, and the typical keratoderma blenorrhagica that resembles kertatotic plaques on the palms and soles.]
-Hypersensitivity vasculitis, urticarial vasculiti, or leukocytoclastic vasculitis [Primary vascultis often presents with vasculitic rash with palpable purpura, which is not often seen with serum sickness. Arthralgias and arthritis is seen more pronunced in serum sickness.
-Henoch-Scholein purpura. [Henoch-Scholein purpura are often seen in children and also have gastrointestinal symptoms which can include bloody diarhea, proteinuria, palpable purpura, and an IgA deposit on skin biopsy.]
Other drug reactions
-Drug hypersensitivity sydrome [Also known as Drug Reaction with Eosinophila and Systemic Symptoms (DRESS), involves fever, erythematous rash, and internal organ involvement. Lab abnormality of eosinophilia and elevated liver function test is often seen.]
-Erythema multiforme [Erythema multiforme often follows herpes simplex virus infections, and presents with targetoid patches and plaques on acral and mucosal surfaces. Arthralgias is not often seen in erythema multiforme.]
-Steven’s Johnson syndrome, toxic epidermal necrosis [SJS and TEN are severe drug hypersensitivity reactions with fever, full thickness vesicular and bullous lesions on an erythematous background and mucous membrane involvement is common.]
Who is at Risk for Developing this Disease?
The incidence of serum sickness is not well documented and can vary depending on the agents involved. In the United States, the incidence of serum sickness has declined due to vaccination initiatives that decrease the need for use of specific antitoxins. In addition, many horse serums used in antitoxins against rabies and tentanus have been replaced with human serum.
Risk factors include higher dosing, the specific antigen type, age, and prior exposure of the agent.
Dosing: Higher dosing of the antigen increases the likelihood for developing serum sickness.
Specific antigen type: In one study looking at antithymocyte globulin (ATG), 85% developed serum sickness. Antirabies serum is associated with a higher likelihood of serum sickness than with tetanus antitoxin. Antivenoms for snake bites has been shown to cause serum sickess in 40-80% of treated patients. Serum sickness-like reaction is seen the highest with cefaclor compared to other antibiotics. Conversely, with antidiphtheria serum, serum sickness is seen in only 1.5%.
Age: Adults are at higher likelihood of developing serum sickness. Adults often require higher dosing, which can be a factor; however serum sickess itself is unusual in children overall. In one study looking at antirabies serum, serum sickness was more common in patients older than 15 years. In another study, serum sickness developed in less than 0.5% of children under age of 10 when given antirabies serum. On the contrary, serum-sickness-like reaction with antibiotics, especially with cefaclor, have been more frequently described in childen under age of 5.
Prior exposure: Patients with prior exposure to rabbits are more likely to develop serum sickness after receiving rabit antithymocyte globulin, and similarly patients who have had multiple insect stings or bites are more likely to develop serum sickness after repeated stings.
What is the Cause of the Disease?
Serum sickness is a type III hypersensitivity reaction, also known as immune complex mediated hypersensitivity disease, resulting from the administration of foreign protein, serum or nonprotein medications. This reaction requires a foreign antigen of a specific size or specific physiological components that can stimulate the immune system to synthesize specific antibody against the antigen. Symptoms develop 1 to 2 weeks after initial introdution to the antigen (as this primary immunization causes IgM antibodies to develop around 7-14 days later, and IgG antibodies appear a few days after IgM).
When the antibody binds to the antigen, they form antigen-antibody complex or immune complexes that are normally cleared by the mononuclear phagocyte system. An excess of this soluble immune complexes can deposit in tissues and cause an inflammatory response through activation of the complement cascade. Various complement split products, including C3a and C5a act as anaphylatoxins and chemoattractants to degranulate mast cells and to recruit neutrophils to the tissue and create tissue damage.
Complement fragments also coat the immune complexes through a process called opsonization to increase the immune complexes by the mononulcear phagocyte system. When the entire antigen is removed from the serum, the serum sickess resolves. If there is a re-introduction of the antigen, the serum sickness will develop more rapidly, and more severely. Rather than requiring 7-14 days for the development of IgM as in the primary immunization, with re-exposure, the IgG (more efficient opsonization and complement activation) and response to the antigen can develop within 12-36 hours.
Agents that are linked to the classical serum sickness are heterologous antitoxins that are still used to treat snake bites and rabies exposure. In the literature, there are case reports linking various other agents including murine or chimeric monoclonal antibodies such as anti-CD20, rituximab, and the anti-TNF alpha, infliximab. Other agents also include equine or rabbit antithymocyte globulin (ATG). Two reports link insect stings and mosquito bites to a serum sickness-like reaction. A single report links allogeneneic human plasma given during blood transfusion resulting in serum sickness.
Serum sickness-like reactions (SSLR) are caused by various medications, especially antibiotics including cefaclor, penicillin, amoxicillin, and bactrim, and also following infections (Hepatitis B and endocarditis) and vaccines. While clinically they present with similar symptoms to the classical serum sickness, the pathogenesis does not involve immune complexes deposition. It is thought that drug metabolites have a direct toxic effect on cells, causing symptoms of fever, rash, and arthralgias one to three weeks after medication introduction. The symptoms of SSLR are often less severe than classical serum sickness.
Systemic Implications and Complications
As mentioned above in discussing the physical exam, serum sickness has many systemic manifestations, including, skin rash, fever, arthritis or arthralgias, and other less common manifestations including renal, cardiovascular, pulmonary, neurologic, and gastrointestinal systems.
The following treatments (Table I) are based on literature reports, although there have not been randomized control trials evaluating these treatments.
|Class||Subtypes||Adult Dosing||Pediatric Dosing|
|ASA||325-650mg by mouth four to six times per day. Max: 4000mg per day.||10-15mg/kg by mouth four to six times per day. Max: 60-80mg/kg per day.|
|Ibuprofen||200-800mg by mouth four to six times per day. Max: 3200mg per day.||<12 years old: 5-10mg/kg by mouth four to six times per day. Max: 40 mg/kg per day.|
|>12 years old: adult dosing|
|Diphenhydramine||25-50mg by mouth/intravenous/intramuscular four to six times per day. Max: 400 mg per day.||6.25-50mg by mouth/intravenous/intramuscular four to six times per day.|
|Max: 300mg per day|
|Prednisone||0.5-2mg/kg by mouth per day, divided once, twice, or four times per day.||0.2-2mg/kg by mouth per day, divided by once, twice, or four times per day dosing.|
|Max:60 to 80mg per day||Max: 60mg per day|
|Taper from 1 to 2 weeks.||Taper from 1 to 2 weeks.|
|1-2mg/kg intravenous per day divided into once to twice per day dosing.||0.5-1.7mg/kg by mouth per day, divided by twice to four times a day dosing.|
|Methylprednisolone||Taper from 1 to 2 weeks.||Taper from 1 to 2 weeks.|
|**(not reported in literature for pediatric, dosing extrapolated from Epocrates for corticosteroid-responsive conditions)|
Optimal Therapeutic Approach for this Disease
Patients should initially be evaluated and be admitted to inpatient care if comorbidities exist such as extreme ages of young or old, immunocompromised, severe symptoms, or hemodynamic instability.
First treatment choices
The most common treatment based on the literature involves cessation of the offending agent. With this intervention, the fever, arthrathria and new cutaneous manifestations are halted by 48 hours. Once the offending agent is identified, it should be avoided to prevent recurrences in the future. Supportive and symptomatic treatments as described below can also be used.
Nonsteroidal antiinflammatory drugs (NSAIDS) such as aspirin or ibuprofen can have analgesic, antiinflammatory, and antipyretic properties. These can be used for the mild symptoms of arthralgias, myalgias, and low-grade fever. Antihistamines such as Benadryl and others can be used for symptomatic treatement of pruritus as well as mild rash such as urticaria. Prophylactic antihistamines may also decrease incidence of serum sickess when given with the suspected agent by decreasing the vascular permeability that is produced from the deposition of the immume complexes.
Second treatment choices
In cases when patients have high fever, more severe arthralgias and myalgias, or if patients have more extensive cutaneous involvement including vasculitis, then corticosteroids can be used. These agents have antiinflammatory properties and salt-retaining properties. They can also alter the immune response to various antigens by immunosuppression. A short course of prednisone should be used orally, and in the more acutely ill patient, intravenous methylprednisolone can be used. Tapering of these agents should be from one to two weeks as the symptoms resolve.
As serum sickess is a self-limited immune complex disease that will resolve after cessation of the offending agent, most symptoms resolve after a few weeks of cessation due to the clearance of the immune complexes from the serum. There are usually no long-term sequelae and the prognosis is better in the absence of internal organ involvement.
If steroids are tapered too quickly, symptoms of serum sickness can reappear. Another course of steroids can halt these symptoms.
There have been very rare cases of progressive glomerulonephritis, neurologic damage, and even death linked to serum sickness. Oftentimes this is with continued administration of the suspected antigen.
Avoidance of the offending agent is critical to prevent serum sickness. When this is not possible, premedication with an antihistamine, often 50-100mg of diphenhydramine (Benadryl) can decrease the symptoms of serum sickness. Premedication with steroids does not prevent serum sickness.
In patients with a history of receiving antiserum in the past, or a history of allergy to horse dander, skin testing, including prick and intradermal, can help identify individuals at risk for developing anyphylaxis for future administration of antiserum. However, these tests do not predict those at risk for developing serum sickness.
Unusual Clinical Scenarios to Consider in Patient Management
One small study detailed five renal transplant patients who developed severe serum sickness after receiving anti-thymocyte globulin (ATG). After failing to respond to systemic steroids, they had complete resolution of symptoms after receiving one to two courses of plasmaphoresis. Similarly, in another study when the the offending agent could not be discontinued (an insulin injection used in a type I diabetic patient), it caused a serum sickness reaction. The patient failed methylprednisolone, methothrexate, and azathioprine so repeated plasmaphoresis with fresh frozen plasma was used.
What is the Evidence?
Bayraktar, F, Akinci, B, Demirkan, F. “Serum sickness-like reactions associated with type III insulin allergy responding to plasmapheresis”. Diabet Med. vol. 26. 2009. pp. 659-60. (Single case report of plasmaphoresis as a temporary effective treatment for type III allergy to insulin.)
Clark, BM, Kotti, GH, Shah, AD, Conger, NG. “Severe serum sickness reaction to oral and intramuscular penicillin”. Pharmacotherapy. vol. 26. 2006. pp. 705(Single case report of corticosteroids being used to treat severe and prolonged serum sickness reaction to intramuscular penicillin depot injection.)
Finger, E, Scheinberg, M. “Development of serum sickness-like symptoms after rituximab infusion in two patients with severe hypergammaglobuinemia”. J Clin Rheumatolol. vol. 13. 2007. pp. 94(Two case reports of patients developing serum sickness-like symptoms after rituximab infusion who were sucessfully treated with intravenous corticosteroids.)
Lundquist, AL, Chari, RS, Wood, JH. “Serum sickness following rabbit antithymocyte-globulin induction in a liver transplant recipient: case report and literature review”. Liver Transp. vol. 13. 2007. pp. 647(Single case report of serum sickness in a patient receiving thymoglobulin, and rapid resolution of symptoms after a course of intravenous corticosteroids. Article also reviewed treatment for serum sickness with steroids and plasmapheresis.)
Rana, JS, Sheikh, J. “Serum-sickness-like reactions after placement of sirolimus-eluting stents”. Ann Allergy Asthma Immunol. vol. 98. 2007. pp. 201(Two case reports of patients developing serum sickness-like reactions after placement of sirolimus-eluting stents, and resolution of symptoms after oral prednisone treatment.)
Tatum, AJ, Ditto, AM, Pattterson, R. “Severe serum sickness-like reaction to oral penicillin drugs: three case reports”. Ann Allergy Asthma Immunol. vol. 86. 2001. pp. 330(Three case reports of severe serum sickness-like reactions in adults after receiving oral penicillin and symptom resolution occuring within 24 hours of starting therapy with oral prednisone 40 to 60mg daily.)
Tanriover, B, Chuang, P, Fishbach, B. “Polyclonal antibody-induced serum sickness in renal transplant recipients: treatment with theraputic plasma exchange”. Transportation. vol. 80. 2005. pp. 279-81. (Five case reports of renal transplant patients who developed serum sickness after polyclonal antibody treatment with severe symptoms that persisted even after starting systemic steroids, and had subsequent resolution of symptoms ater one to two courses of therapeutic plasma exchange.)
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