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Caution in the time of rashes and COVID-19

      To the Editor: We applaud the authors of a recent report in JAAD
      • Jia J.L.
      • Kamceva M.
      • Rao S.A.
      • Linos E.
      Cutaneous manifestations of COVID-19: a preliminary review.
      who performed a systematic literature review of the highly variable cutaneous manifestations of coronavirus disease 2019 (COVID-19). Since the global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), dermatologists have mobilized to identify, catalog, and disseminate potential cutaneous manifestations of SARS-CoV-2 infection. Lack of widespread testing and potential limitations in assays that detect acute and previous infections underscore the utility of identifying skin manifestations of COVID-19.
      These limitations, however, make it difficult to definitively conclude that skin manifestations of COVID-19 are due to SARS-CoV-2. In fact, the most commonly reported cutaneous manifestation, pernio-like lesions (so-called COVID toes),
      • Jia J.L.
      • Kamceva M.
      • Rao S.A.
      • Linos E.
      Cutaneous manifestations of COVID-19: a preliminary review.
      seem to generally occur in patients who test negative for viral infection by polymerase chain reaction and subsequent serologic testing.
      • Galvan Casas C.
      • Catala A.
      • Carretero Hernandez G.
      • et al.
      Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases.
      However, detection of SARS-CoV-2 in endothelial cells of these lesions suggests direct viral invasion.
      • Colmenero I.
      • Santonja C.
      • Alonso-Riano M.
      • et al.
      SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases [e-pub ahead of print].
      On the other hand, patients who have confirmed SARS-CoV-2 infection have been reported to develop a wide variety of cutaneous manifestations, including morbilliform eruption, urticaria, petechiae, retiform purpura, periorbital erythema, vesicular, livedo reticularis, digitate papulosquamous, erythema multiforme, pernio-like lesions, and androgenic alopecia
      • Jia J.L.
      • Kamceva M.
      • Rao S.A.
      • Linos E.
      Cutaneous manifestations of COVID-19: a preliminary review.
      • Galvan Casas C.
      • Catala A.
      • Carretero Hernandez G.
      • et al.
      Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases.
      • Colmenero I.
      • Santonja C.
      • Alonso-Riano M.
      • et al.
      SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases [e-pub ahead of print].
      (Fig 1). It remains to be determined which skin manifestations are a sign of SARS-CoV-2 infection due to direct tissue injury from viral tropism or to sequela of infection such as coagulopathy and immune injury.
      • Colmenero I.
      • Santonja C.
      • Alonso-Riano M.
      • et al.
      SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases [e-pub ahead of print].
      Figure thumbnail gr1
      Fig 1Reported cutaneous manifestations of coronavirus disease (COVID-19). These skin findings have been reported by clinicians as potential signs of COVID-19. Most of these highly variable and rare findings reported in case reports and small case series may not be specific to severe acute respiratory syndrome coronavirus 2 infection. We urge caution and continued scholarship moving forward to decipher what impact COVID-19 has on skin.
      We recommend caution when concluding that cutaneous findings are specifically due to SARS-CoV-2. Without question, SARS-CoV-2 is a unique and devastating virus with multiple tissue tropism and heterogeneous immune activation. With further clinical studies, more widespread testing, and a better understanding of the natural course of the virus, these skin manifestations will likely settle into 2 types: virus-specific and nonspecific. To determine virus-specific mechanisms, direct detection of viral particles within cutaneous lesions is needed.
      • Colmenero I.
      • Santonja C.
      • Alonso-Riano M.
      • et al.
      SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases [e-pub ahead of print].
      Furthermore, these studies should use control tissue of similar lesions (eg, perniosis) that occurred before the pandemic.
      In the absence of direct viral detection, unique immune signatures identified within patients with COVID-19 should be investigated in patients who develop skin manifestations. Cutaneous lesions that are nonspecific should be grouped into those that are suggestive of COVID-19 vs those that are not. The COVID-19 Dermatology Registry will be critical to identifying which cutaneous manifestations are most suggestive of COVID-19.
      The difficulty in classifying the cutaneous manifestations of a systemic, complex, and heterogenous immune-mediated disease is reminiscent of systemic lupus erythematosus (SLE). Although distinct in etiology, disease course, and treatment, the lessons learned from studying SLE may be applied to understanding the cutaneous manifestations of COVID-19. In 1992, Dr Robert A. Greenwald commented that “anything happening to a patient with SLE which is not immediately otherwise explicable will automatically be blamed on the lupus, regardless of pathophysiologic validity.”
      • Greenwald R.A.
      Greenwald's law of lupus.
      This became known as Greenwald's law of lupus. Subsequently, Dr Richard Sontheimer provided a corollary to Greenwald's law that anything happening to patient with a positive anti-nuclear antibody will be blamed on lupus.
      • Sontheimer R.D.
      Greenwald's law of lupus: the Sontheimer amendment.
      Now it appears that anything happening to a patient's skin during the COVID-19 pandemic will be attributed to SARS-CoV-2 infection, rightly or wrongly.
      We thank Dr Jean Bolognia for input on the figure. Biorender.com was used to generate the figure with academic subscription.

      References

        • Jia J.L.
        • Kamceva M.
        • Rao S.A.
        • Linos E.
        Cutaneous manifestations of COVID-19: a preliminary review.
        J Am Acad Dermatol. 2020; 83: 687-690
        • Galvan Casas C.
        • Catala A.
        • Carretero Hernandez G.
        • et al.
        Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases.
        Br J Dermatol. 2020; 183: 71-77
        • Colmenero I.
        • Santonja C.
        • Alonso-Riano M.
        • et al.
        SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases [e-pub ahead of print].
        Br J Dermatol. 2020; https://doi.org/10.1111/bjd.19327
        Date accessed: July 1, 2020
        • Greenwald R.A.
        Greenwald's law of lupus.
        J Rheumatol. 1992; 19: 1490
        • Sontheimer R.D.
        Greenwald's law of lupus: the Sontheimer amendment.
        J Rheumatol. 1993; 20: 1258-1259

      Linked Article

      • Absence of specific cutaneous manifestations of severe acute respiratory syndrome coronavirus 2 in a reference center in Brazil
        Journal of the American Academy of DermatologyVol. 84Issue 1
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          To the Editor: We read with interest the letters from the New York City report regarding the absence of COVID toe lesions on their patients and the recommendation of caution when concluding that cutaneous findings are specifically due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2 Since the global pandemic of SARS-CoV-2, the University of São Paulo Medical School Hospital—a reference center and one of the largest university hospitals in Latin America—reorganized its structure, offering about 300 intensive care units and 500 nursery beds fully dedicated to SARS-CoV-2.
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