Case report :
A 58 year-old male patient, with a medical history of chronic obstructive pulmonary disease (COPD), diabetes type 2 and hypertension presented to the emergency department with shortness of breath and fever, on December 19, 2020. A SARS-CoV-2 RNA nasopharyngeal swab, followed by real-time reverse transcription polymerase chain reaction (RT-PCR) and a chest computerized tomography scan, confirmed a severe case of COVID19. The patient was admitted to a specialized department for 2 weeks and treated with different antibiotics, including cefotaxime, imipenem/cilastatin, and teicoplanin.
The patient also received dexamethasone phosphate sodium, enoxaparin sodium, famotidine, vitamin C, and supplemental oxygen. According to the latest treatment guidelines, hydroxychloroquine was not used of (it was massively used off-label for COVID19 treatment during the first wave of the pandemic).
Seven days after total recovery and withdrawal of all antibiotics, systemic steroids, and famotidine, and only 2 days after withdrawal of enoxaparin and vitamin C, the patient developed a pustular eruption on an erythematous base that began in intertriginous areas (retroauricular folds) and rapidly affected more than 50% of the body surface area (Fig 1). The patient was febrile and there was no mucous membrane involvement. Laboratory test revealed leukocytosis with marked neutrophilia. The renal and liver functions were normal. Repeated blood and pustule bacterial culture yielded negative results. Viral serology (EBV, CMV, and parvoB19) was negative, and a new SARS-CoV-2 RNA nasopharyngeal swab, followed by RT-PCR, was negative. Skin biopsy revealed acanthosis and multiple spongiform subcorneal pustules. Edema and perivascular lymphocytic infiltration were observed in the dermis (Fig 2).
Based on the EUROSCAR criteria, our patient had a score of 12, indicating a definite diagnosis of AGEP (typical pustule (+2), typical erythema (+2), typical distribution of AGEP (+2), postpustular desquamation (+1), no mucosal involvement (0), acute onset < 10 days (0), resolution < 15 days (0), no fever (+1), no polymorphonuclear neutrophils > 7000 (+1), and spongiform subcorneal pustule with papillary edema (+3)). The patient was treated with high-level topical corticosteroids, which resulted in progressive resolution of exanthema within a few days. The patient also received enoxaparin sodium without aggravation of the rash. The patient continued his chronic medication without any relapse of AGEP, one year later.
Our case raises a dilemma regarding whether such cutaneous lesions are related to COVID-19 or its treatment.
The relationship between AGEP and SARS‐CoV‐2 infection or its treatment remains poorly understood [4-14]. AGEP generally occurs within 48 hours of treatment initiation [3]. Almost all reported cases of AGEP following COVID-19 were associated with hydroxychloroquine and were characterized by a long incubation period of up to two-three weeks [4,9]. Only a few reported cases of AGEP following COVID-19 were related to other drugs such as cefepime, cefditoren, and cefrtiaxone, which occurred approximately seven7 days after starting the antibiotic [10, 11, 13]. Moreover, some authors have suggested a possible association between COVID-19 and  late-onset AGEP (up to three months after COVID-19 recovery), based on a few reports of AGEP due to viral infections [12-14]. In fact, it has been reported some degree of similarity between inflammatory cytokine profile alterations during COVID-19 and AGEP [15]. Therefore, due to COVID-19 impact on the immune system, this infection may induce AGEP-like eruptions [13, 14]. In our patient, the eruption appeared seven days after withdrawal of all antibiotics, systemic steroids, and famotidine and two days after enoxaparin withdrawal. Additionall , enoxaparin was reintroduced without clinical aggravation. Therefore, we hypothesized that patient’s vigorous immune response to COVID-19 may have triggered an unusual delay-onset reaction to one of the prescribed drugs or a late-onset skin manifestation mimicking AGEP in association with COVID-19.