A 9-year-old boy presented to the office with a 2-day history of fever and sore throat. At the time of presentation, he and his mother noted some painful bumps on his lower legs, and denied trauma (Figure 152-1). No history of recent cough or change in bowel habits was reported. The patient had no chronic medical problems, took no medications and had no known drug allergies. On examination, his oropharynx revealed tonsillar erythema and exudates. Bilateral lower extremities were spotted with multiple slightly-raised, tender, erythematous nodules that varied in size from 2 to 6 cm. Rapid strep test was positive and he was diagnosed clinically with erythema nodosum (EN) secondary to group A β-hemolytic Streptococcus. He was treated with penicillin and NSAIDs. He experienced complete resolution of the EN within 6 weeks.

EN is a common inflammatory panniculitis characterized by ill-defined, erythematous patches with underlying tender, subcutaneous nodules. It is a reactive process caused by chronic inflammatory states, infections, medications, malignancies, and unknown factors.

Lofgren syndrome (with hilar adenopathy).

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  Erythema nodosum occurs in approximately 1 to 5 per 100,000 persons.¹ It is the most frequent type of septal panniculitis (inflammation of the septa of fat lobules in the subcutaneous tissue).²

  
  
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  In the childhood form, the sexes are equally represented. In adults EN tends to occur more often in women, with a male-to-female ratio of 1:4.5.³

  
  
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  In 1 study, an overall incidence of 54 million people worldwide was cited in patients older than 14 years of age.⁴

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  Most EN is idiopathic (Figures 152-2). Although the exact percentage is unknown, 1 study estimated that 55 percent of EN is idiopathic.⁵ This may be influenced by the fact that EN may precede the underlying illness. The distribution of etiologic causes may be seasonal.⁶ Identifiable causes can be infectious, reactive, pharmacologic, or neoplastic.

  
  
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  Histologic examination is most useful in defining EN. Defining characteristics of EN are a septal panniculitis without presence of vasculitis. That this pattern develops in certain areas of skin may be linked to local variations in temperature and efficient blood drainage.

  
  
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  Septal panniculitis begins with polymorphonuclear cells infiltrating the septa of fat lobules in the subcutaneous tissue. It is thought that this is in response to existing immune complex deposition in these areas.⁷  This inflammatory change consists of edema and hemorrhage which is responsible for the nodularity, warmth, and erythema.

  
  
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  The infiltrate progresses from predominantly polymorphonuclear cells, to lymphocytes, and then histiocytes where fibrosis occurs around the lobules. There may be some necrosis though minimal as complete resolution without scarring is the typical course.

  
  
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  The histopathologic hallmark of EN is the Miescher radial granuloma. This is a small, well-defined nodular aggregate of small histiocytes around a central stellate or banana-shaped cleft.

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  Group A β-hemolytic streptococcal pharyngitis has been linked to EN (Figure 152-1). A retrospective study of 129 cases of EN over several decades reports 28 percent had streptococcal infection.⁵

  
  
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  Nonstreptococcal upper respiratory tract infections may also play a role.¹

  
  
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  Historically, tuberculosis (TB) was a common underlying illness with EN, but TB is now a rare cause of EN in developed countries. There are reports of EN occurring in patients receiving the bacille Calmette-Guérin vaccination.⁸

  
  
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  EN is less frequently associated with other infections agents, including Yersinia gastroenteritis, Salmonella Campylobacter, toxoplasmosis, syphilis, amebiasis, giardiasis, brucellosis, leprosy, Chlamydia Mycoplasma Brucella, hepatitis B (infection and vaccine), Epstein-Barr virus, and Bartonella.^4,9,10

  
  
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  The literature reports that EN is seen in patients with inflammatory bowel diseases. It is usually prominent around the time of GI flare-ups, but may occur before a flare (Figure 152-3). Most sources report a greater association between Crohn disease and EN than between ulcerative colitis and EN. Other chronic diseases associated with EN include Behçet disease, sarcoidosis, and Sweet syndrome.^10,11

  
  
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  EN may be seen as a hypersensitivity reaction to a fungal infection, such as Histoplasmosis and Coccidioidomycosis.¹²

  
  
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  Some debate exists over causality from pregnancy and oral contraceptives in the occurrence of EN.

  
  
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  Besides oral contraceptives, medications implicated as causing EN are antibiotics including sulfonamides, penicillins, and bromides. However, the antibiotics may have been prescribed for the underlying infection that had caused EN.¹⁰

  
  
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  Lymphomas, acute myelogenous leukemia, carcinoid tumor, and pancreatic carcinoma are associated with EN and should be considered in cases of persistent or recurrent EN.^10,13