From Your Nose to Your Toes: A Review of Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic‒Associated Pernio

Abstract

Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pernio in uninfected children is associated with monogenic disorders of excessive IFN-1 immunity, whereas severe COVID-19 pneumonia can result from insufficient IFN-1. Moreover, SARS-CoV-2 spike protein and robust IFN-1 response are seen in the skin of patients with pandemic-associated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate the host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets.

Figure 1

Pandemic-associated pernio presentation and histopathology. (a) Representative clinical photographs of COVID toes, with red‒violaceous discoloration and swelling on multiple distal digits bilaterally. (b, c) Representative histopathologic section of a patient’s punch biopsy specimen (H&E); (b) demonstrating dense perivascular and periadnexal inflammatory infiltrate; (inset) magnification demonstrating tight inflammation around eccrine structures (outlined). Bar = 100 μM. (c) Staining of eccrine structures (outlined) for ACE2 (green) and nuclei (blue). Bar = 100 μM. ACE2, angiotensin-converting enzyme 2.

Figure 2

Illustrated hypothesis of pandemic-associated pernio pathophysiology. (a) Viral exposure to SARS-CoV-2 in the environment. (b) SARS-CoV-2 is cleared by a robust innate immune response in the nasopharynx. (c) There is hematogenous showering and dissemination of viral material or virus. (d) Docking of spike protein to the ACE2 receptor on dermal capillaries results in vasoconstriction and perivascular inflammation. (e) Docking of spike protein to ACE2 receptors on eccrine glands results in periadnexal inflammation. (f) Plasmacytoid dendritic cells, the major contributor to IFN-1 response, migrate to the skin in response to viral material. ACE2, angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.