LAUSR

Dear Editor, Hydroxychloroquine (HCQ) is an old drug with a new indication; it has recently been integrated into chemoprophylaxis and treatment protocols for severe acute respiratory 2 (SARS-CoV-2) infection. Acute generalized exanthematous pustulosis (AGEP) is by far, the most common serious dermatological side effect of HCQ. We have recently encountered an atypical case of AGEP triggered by HCQ in a patient treated for SARS-CoV-2 infection. The patient was a 28-year-old female, who presented with a widespread rash and a burning sensation on the skin. She had been diagnosed with SARS-CoV-2 infection and received HCQ for 5 days as the sole treatment. The rash had started 8 days after the introduction of HCQ and 6 days prior to dermatology referral. Dermatological examination revealed a symmetrical diffuse erythematous maculopapular rash on the abdomen, thighs, breasts, shoulders, and gluteal regions (Figure 1A). There were no clinically visible pustules. Histopathological examination of a punch biopsy specimen disclosed acanthosis, spongiosis, multiple intraepidermal pustules of varying sizes and hydropic degeneration of the basal layer (Figure 1B). The upper dermis displayed sparse extravasated erythrocytes, and a perivascular infiltration composed of lymphocytes, histiocytes, eosinophils, and some neutrophils. The cutaneous manifestations in COVID-19 infection are diverse and include exanthems, urticaria, purpura, and varicella-like vesicles. Late-onset cutaneous lesions have been attributed to vasculitis or thrombotic vasculopathy. A quandary faced by a dermatologist in a patient with COVID-19 infection and a cutaneous eruption is whether the clinical portrait arises from SARS-CoV-2 infection, itself, or from an agent used for its treatment. In our opinion, the possibility that a given cutaneous eruption might originate from a medication should always be considered and a cutaneous biopsy should be attempted whenever feasible. Pustular eruptions occurring in patients with COVID-19 infection are more likely to point to a drug-related cause. In the early phase of an eruption, when pustules are yet to appear clinically, it may be difficult, even impossible, to differentiate AGEP and skin rash of COVID19 infection and a skin biopsy remains as the most valuable method in verifying the ultimate diagnosis. The elapsed period between drug exposure and onset of AGEP varies according to the type of medication. Antibiotics such as amoxicillin typically have shorter latencies (24–72 h), whereas others, like HCQ, generally have longer latencies (10–12 days or longer: range 4–30 days). This comparatively longer latency of HCQ can be ascribed to the length of time (5–6 weeks) required to achieve maximal serum concentrations. The latency period of 8 days in our patient was shorter than average. Cytokine storm, because of a dysregulated Th17 pathway, might account for a comparatively brief latency period for HCQ-induced AGEP during COVID19 infection. Because HCQ has been used more frequently and extensively during COVID-19 pandemic, serious and unusual cutaneous adverse reactions liable to HCQ have been increasingly confronted in clinical practice. HCQ-induced AGEP sine pustulosis is one example of such reactions. As expected, more than 30 cases of HCQ-induced AGEP have been published during the past 2 years.