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Enanthem in Patients with COVID-19 and Skin Rash Unrelated, and the Other 3 Were from 1 Family

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Enanthem in Patients with COVID-19 and Skin Rash Unrelated, and the Other 3 Were from 1 Family Letters (Figure 1). Their HAP scores gradually increased, and the hy- Additional Contributions: We thank the patients and/or the patients’ family potrichosis in the patient with TRPS1 did not improve members for granting permission to publish this information. (Figure 2A). Hair shaft diameters were increased in every par- 1. Tanahashi K, Sugiura K, Akiyama M. Topical minoxidil improves congenital hypotrichosis caused by LIPH mutations. Br J Dermatol. 2015;173(3):865-866. ticipant with LIPH pathogenic variants (Figure 2B and C). There doi:10.1111/bjd.13790 were no serious adverse events, but some mild adverse events 2. Tanahashi K, Sugiura K, Takeichi T, et al. Prevalent founder mutation were reported (dry skin on the scalp, trichiasis, and mild hy- c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to pertrichosis on the entire body). variable severity of hypotrichosis in adulthood. J Eur Acad Dermatol Venereol. 2013;27(9):1182-1184. doi:10.1111/j.1468-3083.2012.04526.x Discussion | Lysophosphatidic acids bind the P2Y5 receptor in 3. Kinoshita-Ise M, Kubo A, Sasaki T, Umegaki-Arao N, Amagai M, Ohyama M. Identification of factors contributing to phenotypic divergence via quantitative the hair follicle epithelium and activate hair growth.5 In ARWH image analyses of autosomal recessive woolly hair/hypotrichosis with due to LIPH pathogenic variants, loss-of-function variants in homozygous c.736T>A LIPH mutation. Br J Dermatol. 2017;176(1):138-144. LIPH lead to a deficiency of lysophosphatidic acids and insuf- doi:10.1111/bjd.14836 ficient activation of P2Y5. The present prospective interven- 4. Shibata A, Tanahashi K, Sugiura K, Akiyama M. TRPS1 haploinsufficiency tional study suggests that minoxidil could be associated with results in increased STAT3 and SOX9 mRNA expression in hair follicles in trichorhinophalangeal syndrome. Acta Derm Venereol. 2015;95(5):620-621. improvements in hypotrichosis in ARWH owing to LIPH patho- doi:10.2340/00015555-1948 genic variants. There appears to be a binary response to min- 5. Shinkuma S, Akiyama M, Inoue A, et al. Prevalent LIPH founder mutations oxidil, with one group responding better than the other. The lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive data on causative pathogenic variants suggest that it is unre- hypotrichosis. Hum Mutat. 2010;31(5):602-610. doi:10.1002/humu.21235 lated to the LIPH pathogenic variants. Among the 8 patients with ARWH due to LIPH pathogenic variants, 5 patients were Enanthem in Patients With COVID-19 and Skin Rash unrelated, and the other 3 were from 1 family. All 3 members Recalcati1 recently reported skin manifestations in 18 pa- of the family were in the group responding better. Thus, we tients in Italy with severe acute respiratory syndrome coro- cannot exclude the possibility that the family had an un- navirus 2 (SARS-CoV-2) infection, or coronavirus disease 2019 known genetic modifying factor affecting the efficacy of mi- (COVID-19), describing “erythematous rash,”“widespread ur- noxidil. We need to know more about the follicular pathology ticaria,”and “chickenpox-like vesicles.”Additional reports have to understand the pharmacologic response to minoxidil. described other rashes, including petechial and purpuric changes,2 transient livedo reticularis,3 and acro-ischemic 4 Tomoki Taki, MD, PhD lesions. Whether these manifestations are directly related to Kana Tanahashi, MD, PhD COVID-19 remains unclear, since both viral infections and ad- Takuya Takeichi, MD, PhD verse drug reactions are frequent causes of exanthems. An im- Takenori Yoshikawa, MD portant clue to distinguish between both entities is the pres- 5 Yuya Murase, MD ence of enanthem (oral cavity lesions). However, owing to Kazumitsu Sugiura, MD, PhD safety concerns, many patients with suspected or confirmed Masashi Akiyama, MD, PhD COVID-19 do not have their oral cavity examined. Herein we describe variants of enanthem in a series of patients with Author Affiliations: Department of Dermatology, Nagoya University Graduate COVID-19. School of Medicine, Nagoya, Aichi, Japan (Taki, Tanahashi, Takeichi, Yoshikawa, Murase, Akiyama); Department of Dermatology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan (Sugiura). Methods | We included 21 consecutive patients from a tertiary care hospital who had skin rash and COVID-19, confirmed by Accepted for Publication: May6,2020. real-time reverse transcriptase–polymerase chain reaction from Corresponding Author: Masashi Akiyama, MD, PhD, Department of Dermatology, Nagoya University Graduate School of Medicine, 65 a nasopharyngeal swab, and who required dermatology con- Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan (makiyama@med. sultation from March 30 to April 8, 2020. The oral cavities of nagoya-u.ac.jp). patients presenting with skin rash were systematically exam- Published Online: July 15, 2020. doi:10.1001/jamadermatol.2020.2195 ined. Enanthems were classified into 4 categories: petechial, 5 Author Contributions: Drs Taki and Akiyama had full access to all of the data in macular, macular with petechiae, or erythematovesicular. This the study and take responsibility for the integrity of the data and the accuracy study was approved by the institutional review board of Ra- of the data analysis. mon y Cajal University Hospital in Madrid. Accordingly, in- Study concept and design: Taki, Sugiura, Akiyama. Acquisition, analysis, or interpretation of data: All authors. formed consent was obtained verbally from all patients be- Drafting of the manuscript: Taki, Akiyama. fore examination, and they have been deidentified through Critical revision of the manuscript for important intellectual content: Tanahashi, omission of individual age and sex. Takeichi, Yoshikawa, Murase, Sugiura, Akiyama. Statistical analysis: Taki. Obtained funding: Takeichi. Results | Of 21 patients with COVID-19 and skin rash, 6 patients Administrative, technical, or material support: Takeichi, Yoshikawa, Murase. (29%) had enanthem. The age range of these patients was be- Study supervision: Sugiura, Akiyama. tween 40 and 69 years, and 4 of the 6 (66%) were women. The Conflict of Interest Disclosures: Dr Taki reported receiving nonfinancial morphology of the skin rash was papulovesicular, purpuric support (the 1% minoxidil solution used in the present study) from Taisho periflexural, and erythema multiforme–like in 1, 2, and 3 pa- Pharmaceutical Co., Ltd. (Tokyo, Japan) during the conduct of the study and the 2018 Nagoya University Medical Association Research Encouragement Prize tients, respectively. The clinical and histologic findings of the outside the submitted work. No other disclosures were reported. erythema multiforme–like exanthem have been reported 1134 JAMA Dermatology October 2020 Volume 156, Number 10 (Reprinted) jamadermatology.com © 2020 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Letters Figure. Clinical Presentation of Exanthem and Enanthem in a Patient With Severe Acute Respiratory Syndrome Coronavirus 2 Infection A Lateral view of the exanthem B Enanthem 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; (COVID-19) symptoms to the appearance of mucocutaneous lesions. H, hydroxychloroquine; LP, lopinavir/ritonavir; M, macular; MP, macular with According to our center reference values, platelet count <140 × 103/μL was petechiae; P, petechial; T, tocilizumab. considered low, D-dimer level >0.5 μg/mL was considered high. a Time latency is defined as days from the onset of coronavirus disease 2019 elsewhere.6 No enanthem was observed in patients with ur- them suggest an infectious etiology, especially viral.5 In a ticarial or typical maculopapular rashes. The enanthem was large series of patients with atypical exanthems,5 only 9% of macular in 1 patient, petechial in 2 patients, and macular with patients with enanthem had a drug reaction, whereas 88% petechiae in 3 patients, and was located in the palate in all pa- had an infectious etiology, most frequently viral. Enan- tients (Figure). No patient presented with an erythemato- thems may present with petechiae, macules, papules, or vesicular enanthem. The mean (range) time between the vesicles in the mouth. Erythemato-vesicular and petechial onset of COVID-19 symptoms and the appearance of mucocu- patterns were most commonly associated with viral infec- taneous lesions was 12.3 days (range, −2 to 24 days). Interest- tions, the latter being more frequent in adults.5 This is con- ingly, this latency was shorter in patients with petechial en- sistent with the present series, in which 5 patients (83%) anthem compared with those with a macular lesion with had petechiae as a main component of the enanthem. Fur- petechiae appearance. Drug intake and laboratory findings thermore, the 2 patients
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