Serum Sickness-Like Reaction

Column Author: Maya Gibson, MD | Pediatric Resident

Column Editor: Kathleen Berg, MD, FAAP | Hospitalist - Pediatrics; Associate Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Clinical Assistant Professor of Pediatrics, University of Kansas School of Medicine

A patient comes to the emergency department with a faint maculopapular rash. He is experiencing joint pain and edema in his left hand and right knee. Upon arrival, he is febrile with a temperature of 38.3 degrees Celsius. Mom feels frustrated because this is the third time her child has been evaluated by a doctor, and each time they have been told a different diagnosis. She says, “I am just so tired; he was sick earlier this month with an ear infection, and now he is sick again!” What’s on your differential?

Serum sickness-like reaction (SSLR) is an immunologic response well described in the literature. However, the pathophysiology is not well understood. The current theory is that drug metabolites bind to plasma proteins inducing an immunologic response.¹ The reaction’s name derives from its resemblance to classic serum sickness or type III immune hypersensitivity. In classic serum sickness, foreign serum proteins form antigen-antibody complexes that may lead to an enhanced immunologic response that activates the complement pathway lowering levels of C3 and C4.² SSLR differs in that the trigger is most commonly a drug and does not produce antigen-antibody complexes. Therefore complement levels are often normal.³

SSLR is most often associated with antibiotic usage, with which β-lactams are most common.³ Other implicated medications include anticonvulsants, antidepressants, antihypertensives and antidysrhythmics among others.^1,3,4 SSLR was initially described in reactions associated with cefaclor with an estimated incidence of 0.4%-0.5% of all cefaclor antibiotic courses,^4,6 a major reason why this medication is no longer routinely used in pediatrics. SSLR represents 4% of all adverse drug reactions associated with amoxicillin.⁷ There are also reports in the literature of SSLR cases during or following viral illness such as hepatitis B.⁴ The mechanism is unknown.  

Symptoms often present five to 21 days following drug exposure. Although there are no specific diagnostic criteria, the commonly described triad is rash, joint involvement and fever.^1,3,4 The presentation of rash varies and has been described as urticarial, morbilliform, annular plaques and erythema multiforme-like lesions. The rash is typically fixed. Joint presentation includes symptoms of erythema, edema and pain, most commonly affecting the hands and feet.¹ This presentation may lead practitioners to consider septic arthritis on the differential and perform unnecessary joint aspiration. Although SSLR is well described in the literature, there are no current diagnostic criteria. Laboratory values are nonspecific with signs of inflammation including leukocytosis, thrombocytosis and an elevated C-reactive protein. Complement levels will be normal.

No standardized treatment guidelines exist. However, discontinuation of the inciting drug is always recommended. Symptoms are self-resolving; therefore, management is focused on supportive care with antihistamines and anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs).⁷ Both first- and second-generation antihistamines have been used. Second-generation antihistamines may be preferred due to their less sedating side effect. There have been reports of using steroids or intravenous immunoglobulin (IVIG) for SSLR. However, there is no evidence that steroids hasten the resolution of symptoms, and IVIG treatment is typically used only when Kawasaki disease is in the differential diagnosis.^4,8 In patients experiencing drug-associated SSLR, documentation of the adverse drug reaction should be outlined in the medical record. Whether similar drugs such as β-lactam antibiotics should be avoided when a β-lactam is implicated remains controversial.^8,9 However, successful drug challenges have been performed in patients with previous SSLR after receiving amoxicillin and other β-lactams. Thus, a drug challenge can be considered through shared decision-making when taking into account how long ago the reaction occurred, the importance of the drug, and the likelihood the reaction was drug related.¹⁰

Keeping SSLR on the differential is important. The lack of diagnostic criteria often results in subspecialty consults such as dermatology, infectious diseases and orthopedics. Consider SSLR if you see a patient with rash, fever and joint pain following a course of antibiotics. Antibiotic stewardship and avoidance of unnecessary antibiotics are key to avoiding unintended consequences such as SSLR.     

Takeaways:

1. In patients with new or recent drug exposure now presenting with fever, joint swelling, erythema or pain, consider SSLR.
2. More work is needed to understand the mechanism of SSLR.
3. Diagnosis is clinical.
4. Treatment is focused on immediate removal of the offending agent, as well as supportive care with antihistamines, acetaminophen and NSAIDs. The role of steroids is unclear.

References:

1. Zhang Z, Xiang Y, Wang B, et al. Intestinal mucosal permeability of children with cefaclor-associated serum sickness-like reactions. Eur J Pediatr. 2013;172(4):537-543. PMID: 23296953. doi:10.1007/s00431-012-1926-y
2. Rixe N, Tavarez MM. Serum sickness. Updated August 29, 2022. In: StatPearls [Internet]. StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK538312/
3. Del Pozzo-Magana B, Lazo-Langner A. Serum sickness-like reaction in children: review of the literature. EMJ Dermatol. 2019;7(1):106-111.
4. Del Pozzo-Magana BR, Abuzgaia A, Murray B, Rieder MJ, Lazo-Langner A. Paediatric serum sickness-like reaction: a 10-year retrospective cohort study. Paediatr Child Health. 2021;26(7):428-435
5. Coker TR, Chan LS, Newberry SJ, et al. Diagnosis, microbial epidemiology, and antibiotic treatment of acute otitis media in children: a systematic review. JAMA. 2010;304(19):2161-2169. PMID: 21081729. doi:10.1001/jama.2010.1651
6. King B, Geelhoed G. Adverse skin and joint reactions associated with oral antibiotics in children: the role of cefaclor in serum sickness-like reactions. J Paediatr Child Health. 2003;39:677-681.
7. Yorulmaz A, Akın F, Sert A, Ağır MA, Yılmaz R, Arslan Ş. Demographic and clinical characteristics of patients with serum sickness-like reaction. Clin Rheumatol. 2008;37(1):1389-1394.
8. Patterson-Fortin J, Harris CM, Niranjan-Azadi A, Melia M. Serum sickness-like reaction after the treatment of cellulitis with amoxicillin/clavulanate. BMJ Case Rep. 2016;2016:bcr2016217608. PMID: 27756758. PMCID: PMC5073577. doi:10.1136/bcr-2016-217608
9. Joubert GI, Hadad K, Matsui D, Gloor J, Rieder MJ. Selection of treatment of cefaclor-associated urticarial, serum sickness-like reactions and erythema multiforme by emergency pediatricians. Lack of a uniform standard of care. Can J Clin Pharmacol. 1999;6:197-201.
10. Khan DA, Banerji A, Blumenthal KG, et al. Drug allergy: a 2022 practice parameter update. J Allergy Clin Immunol. 2022;150:1333-1393. doi:10.1016/j.jaci.202