COVID-19-related cutaneous manifestations associated with multiple drug sensitization as shown by lymphocyte transformation test.

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Patients with novel coronavirus disease 2019 (COVID‐19) can present with a wide variety of cutaneous manifestations. , Drug‐induced eruptions, however, are often indistinguishable from the COVID‐19‐related rash. Because many patients (~20%) with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection have been shown to develop cutaneous manifestations, the rash may have been reported as COVID‐19‐related rash without excluding the possibility of drug eruptions. Here, we report a case suspected of COVID‐19‐related rash, in which lymphocyte transformation tests (LTTs) to the culprit drugs were positive.

A 44‐year‐old man presented with fever (38.5°C). He denied cough, sore throat or shortness of breath, and had no history of drug eruptions. On the 17th day of symptoms, he developed erythematous macules and petechiae on his both legs; erythematous macules suddenly appeared in the knee, flexural thigh and popliteal fossae (Fig. 1). Significant laboratory findings are as follows: white blood cell count, 5300/mm3; lymphocyte count, 715/mm3; platelets, 118 000/mm3; and C‐reactive protein (CRP), 4.95 mg/dL. CT images displayed ground‐glass opacification patterns and bilateral lung involvement. His COVID‐19 reverse transcription–polymerase chain reaction test result was positive. About 6 days before the eruption appeared, he had received loxoprofen sodium hydrate, acetaminophen and favipiravir. He recalled that he had used loxoprofen and acetaminophen in the past but only on few occasions. Loxoprofen was withdrawn, and despite the use of acetaminophen and favipiravir, the eruption spontaneously involuted over 4 days without a trace (Fig. 2). LTTs were performed and showed positive reactions to all drugs used. He was discharged 7 days later and has no long‐term sequelae.

Figure 1

The patient developed symmetrically distributed erythematous macules on the flexural thigh.

Figure 2

Clinical course of drug‐induced rash in a patient with SARS‐CoV‐2 infection and relationship between WBC, platelet count, AST, ALT, γ‐GTP and CRP levels, and SARS‐CoV‐2 RNA positivity.

The main difficulty in assigning a pathogenic role to SARS‐CoV‐2 infection in any cutaneous manifestation is that there were no or few standard laboratory methods to distinguish between virally induced rash and drug‐induced rash. The identification of the causative drug appears to rely on the time interval between the beginning of drug use and onset of rash. In our patient, loxoprofen was the most likely causative drug for cutaneous manifestations. In view of our observation that positive LTT reactions were detected not only to loxoprofen but also to other two drugs (Stimulation Index to each drug, 2.03–2.10), it is likely that our patient was sensitized to all the drugs. Such 'multiple drug hypersensitivity' can be most efficiently proven by LTTs. Interestingly, such 'multiple drug hypersensitivity' was often observed associated with mycoplasma pneumoniae infection. No previous reports, however, described the occurrence of multiple drug hypersensitivity in patients with SARS‐CoV‐2 infection. A straightforward interpretation is that our patient could be immunologically sensitized to multiple medications probably due to preceding or underlying SARS‐CoV‐2 infection, although it remains unknown whether SARS‐CoV‐2 infection could serve to enhance the activation of drug‐specific T cells with cross‐reactive reactivity. Nevertheless, we cannot totally exclude the possibility that multiple drug sensitization proven solely by LTTs may be a mere epiphenomenon of the underlying SARS‐CoV‐2 infection.

In conclusion, we recommend that LTT tests be utilized in any patient with cutaneous manifestations of SARS‐CoV‐2 to exclude the possibility of drug sensitization. Multiple drug hypersensitivity is apparently under‐reported because the diagnosis of SARS‐CoV‐2‐induced rash is usually made without performing LTTs. If cutaneous symptoms were viewed as a mere manifestation of SARS‐CoV‐2 infection with no further search to identify drug hypersensitivity, then the disease would remain regarded as SARS‐CoV‐2‐induced rash. Indeed, the presentation of our patient was consistent with symmetrical drug‐related intertriginous and flexural exanthema (SDRIFE). Although SDRIFE‐like skin lesions have been reported as a cutaneous manifestation of COVID‐19, a drug aetiology could have caused SDRIFE‐like skin lesions in patients with SARS‐CoV‐2 infection.

Conflict of interest

The authors have no conflict of interest to declare.

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