Dermatologic Look-Alikes

Erythematous Plaques

DINA ZAMIL, BS; TARA L. BRAUN, MD; CHRISTOPHER RIZK, MD

CASE #1

A 50-year-old man presents to the dermatology clinic with a 1-week history of an itchy rash. He has tried hydrocortisone cream on the rash, which has helped relieve the itching. His wife, who has been helping to apply the steroid cream, noticed that the lesions seem to come and go and have moved to different locations on the patient’s back. The patient takes medications for hypertension and hyperlipidemia but denies starting any new medications recently. On examination, there are several well-demarcated erythematous plaques with central pallor on the lower back, buttocks, and ankles, with nearby heme-crusted excoriations.

CASE #2

A 15-month-old boy with a 2-day history of worsening rash presents to the emergency department with his parents. He recently was diagnosed with otitis media by his primary care provider, for which he was given amoxicillin. His parents report that the rash began about a week after the boy started taking amoxicillin and has been progressively worsening. No prescription or over-the-counter treatments have been tried for the rash, and the patient has no other significant medical history. On examination, the patient has well-demarcated erythematous plaques with central areas of violaceous discoloration on the face, chest, back, and upper and lower extremities.

Dermatologic Look-Alikes

CASE #1 Acute Urticaria

Acute urticaria is a common pruritic condition that presents with transient wheals and swelling. Acute urticaria typically lasts 6 weeks or less whereas chronic urticaria lasts longer than 6 weeks.1,2 Urticaria was recognized in the fourth century BC by Hippocrates, who noticed an association between the condition and nettles, or Urtica. 3,4 The modern term urticaria was introduced by Frank in 1792.3

Urticaria is one of the most common dermatologic conditions seen in emergency departments (EDs), with a lifetime prevalence ranging from 12% to 20%.1,2,4 Although, acute urticaria occurs in only 7.6% to 16% of patients with urticaria, the condition is more common than chronic urticaria in infants and toddlers.1 Acute urticaria also is more prevalent among individuals with atopic diseases, such as atopic dermatitis.4

Acute urticaria affects individuals of all ages but the average age at presentation is in the early 20s.1 Reports indicate a female preponderance for acute urticaria, except in young children; in this population, the condition affects boys and girls equally.1

Urticaria arises from release of histamine and other proinflammatory mediators from mast cells and basophils in the dermis.2 This release often is mediated by immunoglobin E (IgE) but can occur without IgE or immunologic activation.2

Attacks can be caused by food, medications, and infections, but approximately 30% to 50% of acute urticarial attacks are considered idiopathic.1 Drugs implicated in urticaria include sulfonamide and beta-lactam antibiotics, opioids, acetylsalicylic acid, and nonsteroidal anti-inflammatory drugs (NSAIDs).5 When acute urticaria occurs with an infection, it can be difficult to determine whether the attack was precipitated by the infection or a medication used to treat it. Other etiologies for acute urticaria include ingestion of Anisakis simplex nematode, contact with latex, insect bites, systemic lupus erythematosus, and thyroid disease.1 More recently, reports have indicated that infection with SARS-CoV-2 can manifest with acute urticaria.6-8

In children, the most common etiology is viral infections (eg, rhinovirus and Epstein-Barr virus), as well as streptococcal, urinary tract, and parasitic infections.2

Urticarial wheals range in size from small (several millimeters) to much larger and tend to be well-circumscribed and pruritic. The wheals can be serpiginous, round, or polymorphic, and they may be pale or erythematous.2 Urticaria can affect the skin anywhere on the body and may become generalized, involving 50% or more of the patient’s body surface area.1,2

Associated pruritus in patients with acute urticaria may impair sleep and/or daily functioning.2 Although urticaria usually is self-limiting, acute attacks accompanied by systemic symptoms, such as wheezing, dizziness, cough, flushing, and breathlessness, may indicate anaphylaxis.1,2 Acute urticaria also may co-occur with angioedema.1

Diagnosis of urticaria typically is made based on history and physical examination.5 It is important to gather information about the timing, frequency, size, and pattern of the wheals, as well as medication and supplement use, recent travel, infections, and other potential causes.2,5 Physical examination also should include vital signs as well as a test for dermographism. An examination of the ears, nose, throat, eyes, abdomen, lymph nodes, and musculoskeletal system can help reveal etiology.2

Individual wheals are transient, usually coming and going within 24 hours, and resolve without blisters or skin changes. The transient nature of the lesions distinguishes acute urticaria from many skin conditions. Conditions to consider in the differential diagnosis include erythema multiforme, arthropod bites, acute contact dermatitis, cellulitis, prodromal lesions of autoimmune bullous diseases, polymorphic eruption of pregnancy, progesterone-induced dermatosis, and systemic lupus erythematosus.1,2 Acute urticaria also commonly is confused with systemic mastocytosis, which features additional organ involvement, and urticarial vasculitis, which features painful lesions lasting more than 48 hours that result in discoloration or skin bruising.5 Finally, the presence of wheezing or stridor, gastrointestinal symptoms, and dizziness may indicate anaphylaxis. A complete review of systems can help identify systemic illnesses.2

Biopsy of a urticarial wheal should demonstrate dermal edema with mixed inflammatory perivascular infiltrate consisting of lymphocytes, eosinophils, and neutrophils.4 Additional tests to consider include complete blood count, which may support an infectious etiology; erythrocyte sedimentation rate; and C-reactive protein levels, which can indicate infection, inflammation, or NSAID-induced urticaria.1

Treatment is not necessary in mild cases of acute urticaria. If treatment is warranted, the mainstays are H1 antihistamines and topical (1%-2%) menthol aqueous cream to help relieve itching. Underlying causes of urticaria, including infections and aggravating drug, allergens, or other triggers, should be identified and addressed. Severe cases may warrant oral corticosteroids, especially if the acute urticaria presents with angioedema or systemic symptoms.1

The patient in this case was started on a daily H1 antihistamine, which resolved his lesions after several days, and the rash has not recurred.

CASE #2 Serum Sickness–Like Reaction

Serum sickness-like reaction (SSLR) is a syndrome named for its clinical resemblance to serum sickness (SS); it was described originally by von Pirquet and Schick in 1905.9-12 SS is associated with the injection of equine antitoxin, streptokinase, antilymphocyte globulin, and spider and snake antivenom; it is a type III hypersensitivity reaction resulting from deposition of circulating immune complexes that also features inflammation and complement activation.9,13 In contrast, SSLR lacks circulating immune complexes and hypocomplementemia.9 Although SSLR was common among patients treated with horse serum for diphtheria and tetanus in the early to mid-1800s, the condition now is less common because of modernized immunization techniques.11

Approximately 7% of the population will experience SSLR, with hospitalized patients having an increased risk (10%-20%).14 Among children, cefaclor use is a risk factor for SSLR, with estimates of cefaclor-associated SSLR ranging from 0.024% to 0.5%.13,14 A cefaclor metabolite is thought to bind to tissue proteins, resulting in an SSLR inflammatory response in genetically susceptible patients.13 A study of hospitalized children with SSLR in Turkey found an average patient age of 101 months and a mean hospital stay of 5 days.15

SSLR generally occurs as a reaction to a drug and, in contrast to SS, is not associated with internal organ involvement, hypocomplementemia, circulating immune complexes, vasculitis, or renal involvement.10,13 Beta-lactam antibiotics, particularly cefaclor, as well as sulfonamide antibiotics and minocycline are major etiologic agents.9,13 Additional potentially causative classes include but are not limited to antineoplastic, psychiatric, anti-inflammatory (eg, NSAIDs and antirheumatic agents), antithymocyte globulin, antiepileptic, antiarrhythmic, and antihypertensive drugs.11,14 Recent reports have linked SSLR with bupropion, mirabegron, monoclonal antibodies (omalizumab and rituximab), elexacaftor/ tezacaftor/ivacaftor, drotaverine, and ixekizumab.13,16-20

Clinical symptoms of SSLR typically arise 1 to 3 weeks after initial administration of the causative medication.9 Skin eruptions are one of the most common manifestations of SSLR, appearing in 90% of cases.14 Cutaneous eruptions usually involve erythema and well-demarcated urticarial lesions, often with a lavender hue in the center. These urticarial plaques are sharply marginated and frequently coalesce.14,21 Patients also may present with acral erythema and/or edema as well as arthritis and/or arthralgia. Polyarticular joints, such as the knees, hips, wrists, and ankles, generally are painful and swollen, often leading to the inability to walk. Additional symptoms include fever and lymphadenopathy.9,13,21 Rashes of SSLR tend to be milder than those of SS.9,10

Diagnosis of SSLR is made via physical examination and history, particularly recent medication usage.14 Laboratory

TABLE. Acute Urticaria vs Serum Sickness-Like Reaction

Acute Urticaria1–8 Serum Sickness-Like Reaction9-21

Dermatologic presentation • Well-circumscribed, pruritic wheals • Can co-occur with angioedema

Epidemiology • Average presenting age in the early 20s • More common than chronic urticaria in children • Female preponderance, except in young children

Potential risk factors • Atopic diseases • Urticarial plaques, often with a central lavender hue • Arthralgia and/or arthritis in polyarticular joints

• More prevalent among hospitalized patients • Increased prevalence in children

• Cefaclor use in children

Etiology • Immunoglobulin E-mediated mast cell histamine release • Food, medication, or infections (viruses, bacteria, and parasites) • Rarely caused by systemic conditions • Drug reaction • Most common etiology is beta-lactam and sulfonamide antibiotics (cefaclor in children)

Histology • Dermal edema with mixed inflammatory perivascular infiltrate • Superficial, mid-dermal, interstitial, and perivascular infiltrate consisting of eosinophils and neutrophils

Diagnosis • Clinical via history and physical examination • Clinical via history and physical examination

Treatment • Topical 1%-2% menthol aqueous cream • H1 antihistamines • Treat underlying cause • Oral corticosteroids in severe cases • Self-limiting • Causative drug should be withdrawn and avoided • Severe cases may warrant hospitalization, oral corticosteroids

Dermatologic Look-Alikes

results can show mild hematuria or proteinuria, eosinophilia, leukocytosis, and elevated erythrocyte sedimentation rate.13,14 In cases where biopsy is obtained, histopathology features include superficial, mid-dermal, interstitial, and perivascular infiltrates consisting of eosinophils and neutrophils.14

Differential diagnosis for SSLR includes hypersensitivity vasculitis, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, toxic epidermal necrolysis, and StevensJohnson syndrome. Hypersensitivity vasculitis, which often is triggered by beta-lactam administration, causes cutaneous eruptions and joint involvement, but it appears clinically more similar to leukocytoclastic vasculitis, presenting with erythematous to violaceous papules on the lower extremities, potentially with blisters and small ulcers. DRESS syndrome results in facial edema and exanthema leading to secondary desquamation and does not involve joints. Toxic epidermal necrolysis and early Stevens-Johnson syndrome can be differentiated from SSLR by their mucosal involvement and rapid desquamation.14

SSLR characteristically is benign and self-limited and can be treated symptomatically, with treatment depending on the severity of the case.9-11 The offending drug should be discontinued and avoided in the future. Symptoms can be treated with topical corticosteroids, NSAIDs, and antihistamines.13,14 Patients with severe joint involvement or extensive rash may require oral corticosteroid therapy or hospitalization.9,13,21 After withdrawal of the aggravating drug, SSLR generally resolves within 1 to 2 weeks.14 In cases of cefaclor-induced SSLR, some clinicians avoid subsequent use of beta-lactam antibiotics, but administration of a different cephalosporin typically is well-tolerated.13 Patients who have had SSLR induced by minocycline should consider avoiding other tetracyclines because little is known about cross-reactivity.13

The patient in this case was treated in the ED with antihistamines and topical steroids. He showed significant improvement in his rash overnight and then resolution over the next week. He has experienced neither sequelae from the rash nor recurrence. ■

Cefaclor use is a risk factor for SSLR, with estimates of cefaclor-associated SSLR ranging from 0.024% to 0.5%.

Dina Zamil, BS, is a medical student at Baylor College of Medicine, in Houston, Texas; Tara L. Braun, MD, is a resident in the Department of Dermatology at Baylor College of Medicine; and Christopher Rizk, MD, is a dermatologist affiliated with Baylor College of Medicine.

References

1. Sabroe RA. Acute urticaria. Immunol Allergy Clin North Am. 2014;34(1):11-21. 2. Schaefer P. Acute and chronic urticaria: evaluation and treatment. Am Fam Physician. 2017;95(11):717-724. 3. Czarnetzki B. The history of urticaria. Int J Dermatol. 1989;28(1):52-57. 4. Zuberbier T. Urticaria. Allergy. 2003;58(12):1224-1234. 5. Kanani A, Betschel SD, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol. 2018;14(suppl 2):59. 6. Falkenhain-López D, Sánchez-Velázquez A, López-Valle A, Ortiz-Frutos FJ. SARS-coronavirus-2 and acute urticaria. Int J Dermatol. 2020;59(7):867-868. 7. Adeliño R, Andrés-Cordón JF, Aracelis De La Cruz Martínez C. Acute urticaria with angioedema in the setting of coronavirus disease 2019. J Allergy Clin Immunol Pract. 2020;8(7):2386-2387. 8. Abuelgasim E, Dona ACM, Sondh RS, Harky A. Management of urticaria in COVID-19 patients: a systematic review. Dermatol Ther. 2021;34(1):e14328. 9. Katta R, Anusuri V. Serum sickness-like reaction to cefuroxime: a case report and review of the literature. J Drugs Dermatol. 2007;6(7):747-748. 10. Peter JG, Lehloenya R, Dlamini S, et al. Severe delayed cutaneous and systemic reactions to drugs: a global perspective on the science and art of current practice. J Allergy Clin Immunol Pract. 2017;5(3):547-563. 11. Wolf R, Orion E, Marcos B, Matz H. Life-threatening acute adverse cutaneous drug reactions. Clin Dermatol. 2005;23(2):171-181. 12. von Cesanatico P, Freiherr CP, Schick B. Die Serumkrankheit. Franz Deuticke; 1905. 13. Knowles SR, Shear NH. Recognition and management of severe cutaneous drug reactions. Dermatol Clin. 2007;25(2):245-253, viii. 14. McNamara K, Hughes OB, Strowd LC. Cutaneous drug eruptions including serum sickness-like reaction, symmetrical drug-related intertriginous and flexural exanthema, and drug-induced lupus. Clin Dermatol. 2020;38(6):641-647. 15. Yorulmaz A, Akın F, Sert A, Ag˘ır MA, Yılmaz R, Arslan S¸. Demographic and clinical characteristics of patients with serum sickness-like reaction. Clin Rheumatol. 2018;37(5):1389-1394. 16. Tan MG, Burns BF, Glassman SJ. Serum sickness-like reaction associated with mirabegron. JAAD Case Rep. 2019;5(6):537-539. 17. Weiss SL, Smith DM. A case of serum sickness-like reaction in an adult treated with omalizumab. Mil Med. 2020;185(5-6):e912-e913. 18. Brennan S, Marmor I, Schafer C, et al. Serum sickness-like reaction following initiation of elexacaftor/tezacaftor/ivacaftor therapy. Pediatr Pulmonol. 2020;55(11):2846-2847. 19. Ali S, Corcea SL, Cristian RM, Bumbacea RS. A rapid desensitization protocol in a case of drotaverine-induced serum sickness-like reaction in a pregnant woman: a case report. Exp Ther Med. 2019;18(6):5105-5107. 20. Lindberg MR, Todd SP, Bunker DR, DeKlotz CMC. Ixekizumab-induced serum sickness (like reaction): an unusual adverse effect. J Clin Rheumatol. Published online December 3, 2019. 21. Bender NR, Chiu YE. Dermatologic evaluation of the patient. In: Nelson Textbook of Pediatrics. 21st ed. Elsevier. 2019:3441-3451.