Atypical erythema nodosum in a patient with COVID-19 pneumonia.

Dear Editor,

Erythema nodosum (EN) is a common acute nodular septal panniculitis. It is the most frequent type of panniculitis and affects predominately women, with a mean age around 20 to 40 years. , The typical manifestations of EN are erythematous, painful, bilateral nodules on the extender side of the extremities, especially the lower limbs, which are painful on palpation. These lesions usually self‐resolve within 8 weeks. The diagnosis is usually clinical. In certain cases, a biopsy may be required. EN is characterized by a typical histological appearance regardless of the etiology that includes inflammation of the dermohypodermic junction and the periphery of the septa, containing neutrophils and eosinophils, turning to an infiltrate of lymphocytes and histiocytes as the process evolves. Histiocytic granulomas, known as Miescher's radial granulomas, can also appear.

A 57‐year‐old woman with a personal history of arterial hypertension was admitted to the Internal Medicine Ward due to fever and cough. Testing to detect severe acute respiratory syndrome coronavirus (SARS‐CoV) 2 infection was positive and a chest X‐ray showed bilateral pneumonia. Oxygen saturation was 93% on admission and oxygen therapy through nasal prongs at 2 L was started. She was empirically treated with hydroxychloroquine 200 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 10 days. Fever remitted in the first 48 hours, and oxygen supply was withdrawn after 3 days. On day 8 of admission, she presented fever (38.5°C), with no respiratory symptoms. Upon physical examination, an increase of volume on her right lower limb was noticed, with an erythematous plaque on the posterior side of the leg and a palpable node on the proximal portion of her thigh. Blood tests showed a pronounced elevation of inflammatory markers (C‐reactive protein 30.3 mg/dL, leukocytes 14.8 × 10E3/μL, ferritin 308 μg/L, erythrocyte sedimentation rate 87 mm). Interleukin (IL)‐6 was also elevated (46.6 pg/mL).

An ultrasound of right lower limb revealed no signs of deep vein thrombosis, showing inflammation of subcutaneous cell tissue. In the following days, fever persisted despite empirical antibiotic therapy with amoxicillin/clavulanic, clindamycin, piperacillin/tazobactam, and vancomycin. Chest X‐ray showed improvement of COVID‐19 pneumonia. A computerized tomography (CT) of the chest and abdomen revealed no tumors or enlarged lymph nodes. The patient was tested for tuberculin skin test, human immunodeficiency virus, hepatitis B and hepatitis C, blood and urine cultures, antistreptolysin O, parvovirus B19, cytomegalovirus, antitransglutaminase IgA, anti‐DNA, anti‐Ro, anti‐La, anti‐Sm, and anti‐Scl70 antibodies; all studies were normal. The angiotensin‐converting enzyme, immunoglobulins, and complements C3 and C4 levels were also normal. Antinuclear antibodies were positive in a 1/320 title, with a speckled pattern.

Two weeks after the onset of fever and lower limb edema, a CT of the lower limbs was performed, unveiling inflammation of the proximal portion of the right lower limb, were the subcutaneous node was palpable (Figure 1). CT also disclosed a low‐density, heterogeneous tissue of poorly defined limits, situated between the semimembranosus, the biceps femoris, and the vastus medialis muscles (Figure 2). A biopsy of this area revealed adipose tissue with signs of panniculitis, septal, and secondarily lobular, with the presence of thickening of the septa showing edema and fibrosis and a dense inflammatory infiltrate composed mostly of histiocytes with foci of neutrophils and some eosinophils. Some small non‐necrotizing granulomas focally centered by radial slits were also observed. No images of vasculitis, thrombus formation, or emboli were observed. Ziehl‐Neelsen staining was negative. The biopsy findings were typical of EN.

FIGURE 1

CT scan showing inflammation of the proximal portion of the right lower limb, were a subcutaneous node was palpable (arrow). CT, computerized tomography

FIGURE 2

A CT scan showing asymmetry of the lower limbs. The arrow indicates a low‐density, heterogeneous tissue of poorly defined limits between the semimembranosus, the biceps femoris and the vastus medialis muscles. CT, computerized tomography

The patient was initially treated with naproxen 500 mg twice daily, with no improvement in 48 hours. She was then started on corticosteroids (prednisone 20 mg once daily), with a rapid improvement of symptoms. Fever disappeared after 24 hours, and lower limb edema markedly improved in the first 48 hours. Symptoms completely resolved after a 2‐week course of steroids.

EN was initially related to bacterial infections, mainly streptococcal. The incidence of these infections as trigger of EN has decreased over the years. EN is also associated with other entities, especially sarcoidosis, Hodgkin's lymphoma, inflammatory bowel disease, oral contraceptives and certain immunosupressants, among others. , , However, the trigger might not be found in up to 55% of the cases. , The pathogenesis of EN is unclear, but is considered a delayed hypersensitivity reaction triggered by exposure to an antigen.

Treatment of EN should be directed to the underlying associated condition, when identified. It normally self‐resolves without any specific treatments. If further management is needed, nonsteroidal anti‐inflamatory drugs.

The recent viral infection was the only potential trigger of EN in our patient. COVID‐19 infection may induce a dysregulated immune response. Several inflammatory markers have been reported to be elevated in COVID‐19, including IL‐1, ‐2, ‐6, ‐7, and ‐10. , In patients with EN, polymorphisms of IL 1 and ‐6 promoter genes have been described, , as well as high levels of IL‐6, which may result in a higher susceptibility to EN in situations of immune dysregulation, like COVID‐19, thus resulting in an excessive inflammatory reaction. This could partially explain the relationship between COVID‐19 and EN.

COVID‐19 mainly affects the lungs, but clinicians should be aware of the multiple clinical manifestations of the disease, including the skin. To the best of our knowledge, no previous association between EN and COVID‐19 has been reported.