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BY CATALINA MATIZ, MD, AND ANDREA WALDMAN, MD
Serum sickness
How does serum sickness–like reaction present?
At the time of initial evaluation, the patient presented with a recent history of fever, edema of the hands and feet, limited gait, and a diffuse, persistent serpiginous and annular dermatitis for 48 hours. Of note, the patient was prescribed a 10-day course of amoxicillin for otitis media 8 days prior to initial presentation.
The distribution and morphology of our patient’s cutaneous eruption, in combination with the systemic symptoms, facial and acral edema, lymphadenopathy, and arthralgia, were highly suggestive of serum sickness–like reaction (SSLR). SSLR is an allergic reaction characterized by a cutaneous eruption, arthralgias, fever, lymphadenopathy, facial edema, and malaise. True serum sickness was originally distinguished in 1905 as a self-limited illness that occurred in several patients after administration of equine diphtheria antitoxin.1 Today this reaction is rarely noted in the pediatric population.
Pathogenically, true serum sickness represents a type III arthus hypersensitivity reaction to proteins in toxins or drugs, mediated by circulating antigen-antibody complexes. In contrast, SSLR is not associated with circulating immune complexes or hypocomplementemia.2 Histopathology frequently resembles the findings of urticaria, including a perivascular and dermal inflammatory infiltrate with associated neutrophils, eosinophils, and lymphocytes.2 Several hypotheses concerning the etiology of SSLR have been suggested in the literature, most commonly including an inflammatory response to defective drug metabolism. However, definitive pathology remains unknown.3
Initially, an urticarial rash and low-grade fever typically develop 7-21 days after exposure to the offending agent or sooner in individuals previously sensitized to the drug. The lesions quickly evolve to the classic purpuric lesions of SSLR over the following 24-48 hours. These dermatologic findings include pink to red oval and/or polycyclic lesions with large central areas of purple discoloration, classically involving the trunk, extremities, and/or face. The lesions may be discrete, scattered, or confluent.2
Several medications are associated with SSLR, but cefaclor is most frequently implicated, occurring in 0.2% of treated children.4,5 Other common culprits include penicillins, tetracycline, sulfonamides, macrolides, ciprofloxacin, rifampin, griseofulvin, bupropion, and fluoxetine.6-10 More recently, biologic agents have been implicated in SSLR, including rituximab, efalizumab, and infliximab.11,12 SSLR also has been described in association with immunizations (hepatitis B, tetanus, and rabies) and active infections with hepatitis B or C.13,14
The diagnosis of SSLR is primarily clinical, formulated based on the constellation of characteristic lesions, fever, adenopathy, facial edema, and/or arthralgia in conjunction with recent history (within 7-21 days) of offending medications or agents. Supporting laboratory findings include normal or mildly low complement C3 and C4 levels and mild proteinuria. Abnormalities in liver and renal function test results are rare, in contrast to true serum sickness. Biopsy and histopathology may be utilized to exclude other diagnoses.2
An extensive variety of cutaneous conditions bearing a resemblance to SSLR were considered in the differential, including urticaria multiforme, Kawasaki disease, erythema multiforme, and urticarial vasculitis. A common challenge for practitioners is distinguishing SSLR from similar dermatoses, particularly urticarial multiforme (UM), which some experts consider clinically related to SSLR. Despite the cutaneous similarities of UM and SSLR, including urticarial plaques with an associated central duskiness, SSLR tends to have a more delayed onset following offending agent exposure and more extracutaneous symptoms, especially arthralgias and/or arthritis, lymphadenopathy, and higher fevers.15 The rash of UM classically presents 1-3 days following agent exposure or illness, whereas SSLR presentation is delayed 1-3 weeks. Further distinguishing UM is the transient nature of the individual lesions, each lasting less than 24 hours.
Urticarial vasculitis (UV), morphologically similar to SSLR and UM, causes persistent urticarial-like plaques that last longer than 24-48 hours and resolve with bruising. Biopsy results revealing leukocytoclastic vasculitis distinguish UV, but case reports exist reporting leukocytoclastic vasculitis in association with SSLR.
Erythema multiforme (EM), a hypersensitivity reaction usually triggered by infections (most commonly herpes simplex virus), also may appear morphologically similar to SSLR. These lesions also persist for longer than 24-48 hours and often have a target appearance with central duskiness that sometimes can blister. Patients may have mucosal involvement with vesicles and erosions, compared with patients with SSLR in whom mucosal lesions are rarely seen. Medications are an uncommon trigger for EM, occurring in less than 10% of cases, and alternative drug eruptions including SSLR should be excluded prior to diagnosis.
Other disorders commonly presenting with similar extracutaneous manifestations to SSLR and concomitant dermatitis were further excluded based on the morphologic appearance of the lesions and other clinical dissimilarities. Henoch-Schönlein purpura, which also may present with arthralgia, fever, GI symptoms, and extremity edema, was unlikely given the urticarial appearance of the lesions, rather than palpable purpura. Furthermore, the arthritis/arthralgia of Henoch-Schönlein purpura is typically oligoarticular, affecting the large joints of the lower extremities most frequently.
If the patient presents with persistent fever for more than 5 days, Kawasaki disease may be considered in the differential and ruled out with clinical and laboratory assessment. The presence of fever, lymphadenopathy, and acute rash similarly should prompt consideration of a clinical and laboratory work-up for drug reaction with eosinophilia and systemic symptoms. Morphologically, this drug reaction is characterized by a maculopapular eruption more than 3 weeks after exposure to an offending agent. Patients with SSLR respond favorably to cessation of the causative drug and supportive care with antipyretics, NSAIDs, and antihistamines. The cutaneous and extracutaneous manifestations of this drug reaction typically disappear within 2-3 weeks after discontinuation of the offending agent. If symptoms are severe, a short systemic corticosteroid course may be warranted. Our patient’s symptoms completely resolved within 2-3 weeks of discontinuing amoxicillin therapy.
Dr. Matiz is assistant professor of dermatology at Rady Children’s Hospital–San Diego, University of California, San Diego. Dr. Waldman is a clinical research fellow at the hospital. Email them at [email protected].
References
1. von Pirquet, C. Frh, and Bela Schick. “Serum Sickness.” Translated by B. Schick. (London: Bailliere, Tindall and Cox, 1951).
2. Cutis. 2002 May;69(5):395-7.
3. J Pediatr. 1994 Nov;125(5 Pt 1):805-11.
4. J Am Acad Dermatol. 1991 Nov;25(5 Pt 1):805-8.
5. J Paediatr Child Health. 2003 Dec;39(9):677-81.
6. Ann Pharmacother. 1996 May;30(5):481-3.
7. J Hosp Med. 2011 Apr;6(4):231-2.
8. Allergy Asthma Immunol Res. 2014 Mar;6(2):183-5.
9. Ann Pharmacother. 2004 Apr;38(4):609-11.
10. Ann Pharmacother. 2000 Apr;34(4):471-3.
11. J Clin Rheumatol. 2013 Sep;19(6):360.
12. Int J Rheum Dis. 2012 Feb;15(1):e6-7.
13. Am J Med Sci. 2013 May;345(5):412-3.
14. Semin Cutan Med Surg. 2007 Sep;26(3):179-87.
15. J Clin Aesthet Dermatol. 2013 Mar;6(3):34-9.
BY CATALINA MATIZ, MD, AND ANDREA WALDMAN, MD
Serum sickness
How does serum sickness–like reaction present?
At the time of initial evaluation, the patient presented with a recent history of fever, edema of the hands and feet, limited gait, and a diffuse, persistent serpiginous and annular dermatitis for 48 hours. Of note, the patient was prescribed a 10-day course of amoxicillin for otitis media 8 days prior to initial presentation.
The distribution and morphology of our patient’s cutaneous eruption, in combination with the systemic symptoms, facial and acral edema, lymphadenopathy, and arthralgia, were highly suggestive of serum sickness–like reaction (SSLR). SSLR is an allergic reaction characterized by a cutaneous eruption, arthralgias, fever, lymphadenopathy, facial edema, and malaise. True serum sickness was originally distinguished in 1905 as a self-limited illness that occurred in several patients after administration of equine diphtheria antitoxin.1 Today this reaction is rarely noted in the pediatric population.
Pathogenically, true serum sickness represents a type III arthus hypersensitivity reaction to proteins in toxins or drugs, mediated by circulating antigen-antibody complexes. In contrast, SSLR is not associated with circulating immune complexes or hypocomplementemia.2 Histopathology frequently resembles the findings of urticaria, including a perivascular and dermal inflammatory infiltrate with associated neutrophils, eosinophils, and lymphocytes.2 Several hypotheses concerning the etiology of SSLR have been suggested in the literature, most commonly including an inflammatory response to defective drug metabolism. However, definitive pathology remains unknown.3
Initially, an urticarial rash and low-grade fever typically develop 7-21 days after exposure to the offending agent or sooner in individuals previously sensitized to the drug. The lesions quickly evolve to the classic purpuric lesions of SSLR over the following 24-48 hours. These dermatologic findings include pink to red oval and/or polycyclic lesions with large central areas of purple discoloration, classically involving the trunk, extremities, and/or face. The lesions may be discrete, scattered, or confluent.2
Several medications are associated with SSLR, but cefaclor is most frequently implicated, occurring in 0.2% of treated children.4,5 Other common culprits include penicillins, tetracycline, sulfonamides, macrolides, ciprofloxacin, rifampin, griseofulvin, bupropion, and fluoxetine.6-10 More recently, biologic agents have been implicated in SSLR, including rituximab, efalizumab, and infliximab.11,12 SSLR also has been described in association with immunizations (hepatitis B, tetanus, and rabies) and active infections with hepatitis B or C.13,14
The diagnosis of SSLR is primarily clinical, formulated based on the constellation of characteristic lesions, fever, adenopathy, facial edema, and/or arthralgia in conjunction with recent history (within 7-21 days) of offending medications or agents. Supporting laboratory findings include normal or mildly low complement C3 and C4 levels and mild proteinuria. Abnormalities in liver and renal function test results are rare, in contrast to true serum sickness. Biopsy and histopathology may be utilized to exclude other diagnoses.2
An extensive variety of cutaneous conditions bearing a resemblance to SSLR were considered in the differential, including urticaria multiforme, Kawasaki disease, erythema multiforme, and urticarial vasculitis. A common challenge for practitioners is distinguishing SSLR from similar dermatoses, particularly urticarial multiforme (UM), which some experts consider clinically related to SSLR. Despite the cutaneous similarities of UM and SSLR, including urticarial plaques with an associated central duskiness, SSLR tends to have a more delayed onset following offending agent exposure and more extracutaneous symptoms, especially arthralgias and/or arthritis, lymphadenopathy, and higher fevers.15 The rash of UM classically presents 1-3 days following agent exposure or illness, whereas SSLR presentation is delayed 1-3 weeks. Further distinguishing UM is the transient nature of the individual lesions, each lasting less than 24 hours.
Urticarial vasculitis (UV), morphologically similar to SSLR and UM, causes persistent urticarial-like plaques that last longer than 24-48 hours and resolve with bruising. Biopsy results revealing leukocytoclastic vasculitis distinguish UV, but case reports exist reporting leukocytoclastic vasculitis in association with SSLR.
Erythema multiforme (EM), a hypersensitivity reaction usually triggered by infections (most commonly herpes simplex virus), also may appear morphologically similar to SSLR. These lesions also persist for longer than 24-48 hours and often have a target appearance with central duskiness that sometimes can blister. Patients may have mucosal involvement with vesicles and erosions, compared with patients with SSLR in whom mucosal lesions are rarely seen. Medications are an uncommon trigger for EM, occurring in less than 10% of cases, and alternative drug eruptions including SSLR should be excluded prior to diagnosis.
Other disorders commonly presenting with similar extracutaneous manifestations to SSLR and concomitant dermatitis were further excluded based on the morphologic appearance of the lesions and other clinical dissimilarities. Henoch-Schönlein purpura, which also may present with arthralgia, fever, GI symptoms, and extremity edema, was unlikely given the urticarial appearance of the lesions, rather than palpable purpura. Furthermore, the arthritis/arthralgia of Henoch-Schönlein purpura is typically oligoarticular, affecting the large joints of the lower extremities most frequently.
If the patient presents with persistent fever for more than 5 days, Kawasaki disease may be considered in the differential and ruled out with clinical and laboratory assessment. The presence of fever, lymphadenopathy, and acute rash similarly should prompt consideration of a clinical and laboratory work-up for drug reaction with eosinophilia and systemic symptoms. Morphologically, this drug reaction is characterized by a maculopapular eruption more than 3 weeks after exposure to an offending agent. Patients with SSLR respond favorably to cessation of the causative drug and supportive care with antipyretics, NSAIDs, and antihistamines. The cutaneous and extracutaneous manifestations of this drug reaction typically disappear within 2-3 weeks after discontinuation of the offending agent. If symptoms are severe, a short systemic corticosteroid course may be warranted. Our patient’s symptoms completely resolved within 2-3 weeks of discontinuing amoxicillin therapy.
Dr. Matiz is assistant professor of dermatology at Rady Children’s Hospital–San Diego, University of California, San Diego. Dr. Waldman is a clinical research fellow at the hospital. Email them at [email protected].
References
1. von Pirquet, C. Frh, and Bela Schick. “Serum Sickness.” Translated by B. Schick. (London: Bailliere, Tindall and Cox, 1951).
2. Cutis. 2002 May;69(5):395-7.
3. J Pediatr. 1994 Nov;125(5 Pt 1):805-11.
4. J Am Acad Dermatol. 1991 Nov;25(5 Pt 1):805-8.
5. J Paediatr Child Health. 2003 Dec;39(9):677-81.
6. Ann Pharmacother. 1996 May;30(5):481-3.
7. J Hosp Med. 2011 Apr;6(4):231-2.
8. Allergy Asthma Immunol Res. 2014 Mar;6(2):183-5.
9. Ann Pharmacother. 2004 Apr;38(4):609-11.
10. Ann Pharmacother. 2000 Apr;34(4):471-3.
11. J Clin Rheumatol. 2013 Sep;19(6):360.
12. Int J Rheum Dis. 2012 Feb;15(1):e6-7.
13. Am J Med Sci. 2013 May;345(5):412-3.
14. Semin Cutan Med Surg. 2007 Sep;26(3):179-87.
15. J Clin Aesthet Dermatol. 2013 Mar;6(3):34-9.
BY CATALINA MATIZ, MD, AND ANDREA WALDMAN, MD
Serum sickness
How does serum sickness–like reaction present?
At the time of initial evaluation, the patient presented with a recent history of fever, edema of the hands and feet, limited gait, and a diffuse, persistent serpiginous and annular dermatitis for 48 hours. Of note, the patient was prescribed a 10-day course of amoxicillin for otitis media 8 days prior to initial presentation.
The distribution and morphology of our patient’s cutaneous eruption, in combination with the systemic symptoms, facial and acral edema, lymphadenopathy, and arthralgia, were highly suggestive of serum sickness–like reaction (SSLR). SSLR is an allergic reaction characterized by a cutaneous eruption, arthralgias, fever, lymphadenopathy, facial edema, and malaise. True serum sickness was originally distinguished in 1905 as a self-limited illness that occurred in several patients after administration of equine diphtheria antitoxin.1 Today this reaction is rarely noted in the pediatric population.
Pathogenically, true serum sickness represents a type III arthus hypersensitivity reaction to proteins in toxins or drugs, mediated by circulating antigen-antibody complexes. In contrast, SSLR is not associated with circulating immune complexes or hypocomplementemia.2 Histopathology frequently resembles the findings of urticaria, including a perivascular and dermal inflammatory infiltrate with associated neutrophils, eosinophils, and lymphocytes.2 Several hypotheses concerning the etiology of SSLR have been suggested in the literature, most commonly including an inflammatory response to defective drug metabolism. However, definitive pathology remains unknown.3
Initially, an urticarial rash and low-grade fever typically develop 7-21 days after exposure to the offending agent or sooner in individuals previously sensitized to the drug. The lesions quickly evolve to the classic purpuric lesions of SSLR over the following 24-48 hours. These dermatologic findings include pink to red oval and/or polycyclic lesions with large central areas of purple discoloration, classically involving the trunk, extremities, and/or face. The lesions may be discrete, scattered, or confluent.2
Several medications are associated with SSLR, but cefaclor is most frequently implicated, occurring in 0.2% of treated children.4,5 Other common culprits include penicillins, tetracycline, sulfonamides, macrolides, ciprofloxacin, rifampin, griseofulvin, bupropion, and fluoxetine.6-10 More recently, biologic agents have been implicated in SSLR, including rituximab, efalizumab, and infliximab.11,12 SSLR also has been described in association with immunizations (hepatitis B, tetanus, and rabies) and active infections with hepatitis B or C.13,14
The diagnosis of SSLR is primarily clinical, formulated based on the constellation of characteristic lesions, fever, adenopathy, facial edema, and/or arthralgia in conjunction with recent history (within 7-21 days) of offending medications or agents. Supporting laboratory findings include normal or mildly low complement C3 and C4 levels and mild proteinuria. Abnormalities in liver and renal function test results are rare, in contrast to true serum sickness. Biopsy and histopathology may be utilized to exclude other diagnoses.2
An extensive variety of cutaneous conditions bearing a resemblance to SSLR were considered in the differential, including urticaria multiforme, Kawasaki disease, erythema multiforme, and urticarial vasculitis. A common challenge for practitioners is distinguishing SSLR from similar dermatoses, particularly urticarial multiforme (UM), which some experts consider clinically related to SSLR. Despite the cutaneous similarities of UM and SSLR, including urticarial plaques with an associated central duskiness, SSLR tends to have a more delayed onset following offending agent exposure and more extracutaneous symptoms, especially arthralgias and/or arthritis, lymphadenopathy, and higher fevers.15 The rash of UM classically presents 1-3 days following agent exposure or illness, whereas SSLR presentation is delayed 1-3 weeks. Further distinguishing UM is the transient nature of the individual lesions, each lasting less than 24 hours.
Urticarial vasculitis (UV), morphologically similar to SSLR and UM, causes persistent urticarial-like plaques that last longer than 24-48 hours and resolve with bruising. Biopsy results revealing leukocytoclastic vasculitis distinguish UV, but case reports exist reporting leukocytoclastic vasculitis in association with SSLR.
Erythema multiforme (EM), a hypersensitivity reaction usually triggered by infections (most commonly herpes simplex virus), also may appear morphologically similar to SSLR. These lesions also persist for longer than 24-48 hours and often have a target appearance with central duskiness that sometimes can blister. Patients may have mucosal involvement with vesicles and erosions, compared with patients with SSLR in whom mucosal lesions are rarely seen. Medications are an uncommon trigger for EM, occurring in less than 10% of cases, and alternative drug eruptions including SSLR should be excluded prior to diagnosis.
Other disorders commonly presenting with similar extracutaneous manifestations to SSLR and concomitant dermatitis were further excluded based on the morphologic appearance of the lesions and other clinical dissimilarities. Henoch-Schönlein purpura, which also may present with arthralgia, fever, GI symptoms, and extremity edema, was unlikely given the urticarial appearance of the lesions, rather than palpable purpura. Furthermore, the arthritis/arthralgia of Henoch-Schönlein purpura is typically oligoarticular, affecting the large joints of the lower extremities most frequently.
If the patient presents with persistent fever for more than 5 days, Kawasaki disease may be considered in the differential and ruled out with clinical and laboratory assessment. The presence of fever, lymphadenopathy, and acute rash similarly should prompt consideration of a clinical and laboratory work-up for drug reaction with eosinophilia and systemic symptoms. Morphologically, this drug reaction is characterized by a maculopapular eruption more than 3 weeks after exposure to an offending agent. Patients with SSLR respond favorably to cessation of the causative drug and supportive care with antipyretics, NSAIDs, and antihistamines. The cutaneous and extracutaneous manifestations of this drug reaction typically disappear within 2-3 weeks after discontinuation of the offending agent. If symptoms are severe, a short systemic corticosteroid course may be warranted. Our patient’s symptoms completely resolved within 2-3 weeks of discontinuing amoxicillin therapy.
Dr. Matiz is assistant professor of dermatology at Rady Children’s Hospital–San Diego, University of California, San Diego. Dr. Waldman is a clinical research fellow at the hospital. Email them at [email protected].
References
1. von Pirquet, C. Frh, and Bela Schick. “Serum Sickness.” Translated by B. Schick. (London: Bailliere, Tindall and Cox, 1951).
2. Cutis. 2002 May;69(5):395-7.
3. J Pediatr. 1994 Nov;125(5 Pt 1):805-11.
4. J Am Acad Dermatol. 1991 Nov;25(5 Pt 1):805-8.
5. J Paediatr Child Health. 2003 Dec;39(9):677-81.
6. Ann Pharmacother. 1996 May;30(5):481-3.
7. J Hosp Med. 2011 Apr;6(4):231-2.
8. Allergy Asthma Immunol Res. 2014 Mar;6(2):183-5.
9. Ann Pharmacother. 2004 Apr;38(4):609-11.
10. Ann Pharmacother. 2000 Apr;34(4):471-3.
11. J Clin Rheumatol. 2013 Sep;19(6):360.
12. Int J Rheum Dis. 2012 Feb;15(1):e6-7.
13. Am J Med Sci. 2013 May;345(5):412-3.
14. Semin Cutan Med Surg. 2007 Sep;26(3):179-87.
15. J Clin Aesthet Dermatol. 2013 Mar;6(3):34-9.
Make the diagnosis
The day prior to presentation, the family took the patient to the ED for evaluation of the lesions and concomitant swelling of the face, eyelids, hands, and feet, as well as fever and irritability. The ED discharged the patient after comprehensive examination and arranged follow-up in the dermatology clinic the following day. Review of systems further revealed limited gait. Parents denied any recent travel or pets residing in the home. Family history is noncontributory.
Physical exam
The patient is a well-appearing toddler, who is in no acute distress but is irritable. Patient is afebrile, with a temperature of 99.5°F, and vital signs are within normal limits. On skin examination, there are serpiginous and annular confluent erythematous urticarial plaques with a central ecchymotic discoloration over the eyes, peripheral malar distribution, neck, chest, abdomen, back, buttock, extremities, hands, and feet. There is notable eyelid, hand, and feet edema. There was no mucosal involvement. The patient has posterior cervical lymphadenopathy but no hepatomegaly or splenomegaly. The patient refused to walk.