Enanthem in Patients With COVID-19 and Skin Rash

Abstract

This case series describes the appearance of enanthem (oral cavity lesions) in patients with COVID-19.

Recalcati¹ recently reported skin manifestations in 18 patients in Italy with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, or coronavirus disease 2019 (COVID-19), describing “erythematous rash,” “widespread urticaria,” and “chickenpox-like vesicles.” Additional reports have described other rashes, including petechial and purpuric changes,² transient livedo reticularis,³ and acro-ischemic lesions.⁴ Whether these manifestations are directly related to COVID-19 remains unclear, since both viral infections and adverse drug reactions are frequent causes of exanthems. An important clue to distinguish between both entities is the presence of enanthem (oral cavity lesions).⁵ However, owing to safety concerns, many patients with suspected or confirmed COVID-19 do not have their oral cavity examined. Herein we describe variants of enanthem in a series of patients with COVID-19.

Methods

We included 21 consecutive patients from a tertiary care hospital who had skin rash and COVID-19, confirmed by real-time reverse transcriptase–polymerase chain reaction from a nasopharyngeal swab, and who required dermatology consultation from March 30 to April 8, 2020. The oral cavities of patients presenting with skin rash were systematically examined. Enanthems were classified into 4 categories: petechial, macular, macular with petechiae, or erythematovesicular.⁵ This study was approved by the institutional review board of Ramon y Cajal University Hospital in Madrid. Accordingly, informed consent was obtained verbally from all patients before examination, and they have been deidentified through omission of individual age and sex.

Results

Of 21 patients with COVID-19 and skin rash, 6 patients (29%) had enanthem. The age range of these patients was between 40 and 69 years, and 4 of the 6 (66%) were women. The morphology of the skin rash was papulovesicular, purpuric periflexural, and erythema multiforme–like in 1, 2, and 3 patients, respectively. The clinical and histologic findings of the erythema multiforme–like exanthem have been reported elsewhere.⁶ No enanthem was observed in patients with urticarial or typical maculopapular rashes. The enanthem was macular in 1 patient, petechial in 2 patients, and macular with petechiae in 3 patients, and was located in the palate in all patients (Figure). No patient presented with an erythemato-vesicular enanthem. The mean (range) time between the onset of COVID-19 symptoms and the appearance of mucocutaneous lesions was 12.3 days (range, −2 to 24 days). Interestingly, this latency was shorter in patients with petechial enanthem compared with those with a macular lesion with petechiae appearance. Drug intake and laboratory findings were not associated with any enanthem type (Table).

Figure. Clinical Presentation of Exanthem and Enanthem in a Patient With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

This patient presented with coalescing purpuric macules distributed in a periflexural pattern, mainly around the buttocks and inguinal area (A), and enanthem on hard and soft palate consisting of millimetric petechiae without erythema (B).

Table. Clinical and Laboratory Findings of 6 Patients With COVID-19 and Enanthem.

Patient, No.	Age, y	Exanthem type	Enanthem type	Time latency, da	Drug intake	Platelet count	D-dimer level
1	40s	Purpuric	M	12	LP, H,	Low	High
2	60s	Papulovesicular	P	−2	LP, H, A	Normal	High
3	60s	EM-like	MP	19	LP, H, A	Normal	High
4	50s	EM-like	MP	24	LP, H, A, T, C	Normal	High
5	40s	Purpuric	P	2	LP, H, A, T, C	Low	High
6	60s	EM-like	MP	19	LP, H, A,	Normal	Normal

Abbreviations: A, azithromycin; C, corticosteroids; EM, erythema multiforme; H, hydroxychloroquine; LP, lopinavir/ritonavir; M, macular; MP, macular with petechiae; P, petechial; T, tocilizumab.

^aTime latency is defined as days from the onset of coronavirus disease 2019 (COVID-19) symptoms to the appearance of mucocutaneous lesions. According to our center reference values, platelet count <140 × 10³/μL was considered low, D-dimer level >0.5 μg/mL was considered high.

Discussion

The etiological diagnosis of exanthems can be challenging for dermatologists. Some useful clues are the rash morphology, the associated symptoms, and the presence of enanthem.⁵ Pustular morphology and dusky lesions are suggestive of drug etiology, while petechial or vesicular pattern, involvement of buttocks or acral sites, and enanthem suggest an infectious etiology, especially viral.⁵ In a large series of patients with atypical exanthems,⁵ only 9% of patients with enanthem had a drug reaction, whereas 88% had an infectious etiology, most frequently viral. Enanthems may present with petechiae, macules, papules, or vesicles in the mouth. Erythemato-vesicular and petechial patterns were most commonly associated with viral infections, the latter being more frequent in adults.⁵ This is consistent with the present series, in which 5 patients (83%) had petechiae as a main component of the enanthem. Furthermore, the 2 patients with a pure petechial enanthem developed these lesions 2 days before and 2 days after the onset of COVID-19 symptoms, making association with the drug intake unlikely.

This work describes preliminary observations and is limited by the small number of cases and the absence of a control group. Despite the increasing reports of skin rashes in patients with COVID-19, establishing an etiological diagnosis is challenging. However, the presence of enanthem is a strong clue that suggests a viral etiology rather than a drug reaction, especially when a petechial pattern is observed.