key: cord-0811057-0giadhrs
authors: Arkin, Lisa M.; Moon, John J.; Tran, Jennifer M.; Asgari, Samira; O’Farrelly, Cliona; Casanova, Jean-Laurent; Cowen, Edward W.; Mays, Jacqueline W.; Singh, Anne Marie; Drolet, Beth A.
title: From your nose to your toes: A Review of SARS-CoV-2 Pandemic-associated Pernio
date: 2021-07-15
journal: J Invest Dermatol
DOI: 10.1016/j.jid.2021.05.024
sha: 68b72418817004b5cabbff73caf30e7c56b1e0fc
doc_id: 811057
cord_uid: 0giadhrs

Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to SARS-CoV-2. Pernio in uninfected children is associated with monogenic disorders of excessive type 1 interferon (IFN-1) immunity, while 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 pandemic-associated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets.

Abbreviations used: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), type 1 interferon (IFN-1), Plasmacytoid Dendritic Cell (pDC)

Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to SARS-CoV-2. Pernio in uninfected children is associated with monogenic disorders of excessive type 1 interferon (IFN-1) immunity, while 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 pandemicassociated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets.

In March 2020, just weeks after the onset of community spread of COVID-19 in Italy, reports of pandemic-associated pernio emerged. Shortly thereafter, dermatologists in the US were inundated with pernio referrals as the first surge of COVID-19 arrived in the US (Bouaziz et al. 2020; Cordoro et al. 2020; Duong et al. 2020; Galván Casas et al. 2020; Landa et al. 2020; López-Robles et al. 2020; Piccolo et al. 2020) . The phenotype of cool extremities with pain/swelling, followed by red-violaceous discoloration and finally vesiculation of the toes and fingers were strikingly consistent ( Figure 1a ). Whereas older age was an important risk factor for severe infection, most patients with pernio were young, with a median age of 25 years in an international dermatology registry (Castelo-Soccio et al. 2021; Freeman et al. 2020) . Many had close contact with COVID-19 infected individuals, yet nearly all were otherwise healthy and denied typical respiratory manifestations of COVID-19 (Castelo-Soccio et al. 2021; Freeman et al. 2020) . The spatial and temporal association between pernio and the COVID-19 pandemic has now been independently observed across multiple countries including Italy, Spain, Germany, the UK, France, and the U.S.

The strength of this spatial and temporal association along with its consistency across multiple countries supports a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) triggered phenomenon. Yet low rates of positive PCR testing of nasopharyngeal samples (0-20%) and antibody positivity (0-55%) across 175 publications and thousands of reported patients have led some authors to suggest that this is an epiphenomenon (Baeck and Herman 2020; Galván Casas et al. 2020) . This review will summarize and integrate the growing evidence for a causal relationship with SARS-CoV-2 and construct a mechanistic hypothesis. Pandemic-associated pernio augments knowledge regarding the spectrum of SARS-CoV-2 infection and reinforces the critical importance of type 1 interferon (IFN-1) signaling in disease outcomes. A robust IFN-1 response in patients who remain asymptomatic and antibody negative could suggest a population with intrinsic resistance to COVID-19. Because the host immune response to SARS-CoV-2 infection is a critical determinant for COVID-19 outcomes, understanding those with natural resiliency to SARS-CoV-2 exposure could produce clinically relevant therapeutic targets.

IFN-1 responses are tightly regulated to ensure protective immunity while avoiding toxicity from excessive and prolonged IFN signaling. They are largely produced in the blood by plasmacytoid Dendritic Cells (pDC) in response to viral infection via activation of Toll-like receptors 3, 7, and 9, RIG-I and MDA. IFN-1 are produced in lower amounts by > 400 discernable cell types (intrinsic immunity). Upon binding to the type I IFN receptor, the type I interferons (13 IFN-, IFN- IFN-, IFN-, IFN-) activate robust anti-viral defense programs of interferon-stimulated genes which obstruct various steps of viral replication. Monogenic variants that impair key IFN-1-related genes are associated with life-threatening infections due to influenza pneumonia, respiratory syncytial virus, rhinovirus and herpes encephalitis (Asgari et al. 2017; Ciancanelli et al. 2015; Lamborn et al. 2017; Zhang et al. 2007 ).

Recent investigation of host-specific responses to SARS-CoV-2 have confirmed the central role of IFN-1 signaling in COVID-19 outcomes. An attenuated IFN-1 response was found in critically ill patients with SARS-CoV-1 (Channappanavar et al. 2016) . In an international cohort, our team found that 3% of patients with life-threatening COVID-19 harbor loss-of-function variants involved in IFN-1 signaling, with pDCs that did not produce IFN-1 in response to SARS-CoV-2 ). An accompanying study found that 10% of patients with critical COVID-19 infection had circulating neutralizing autoantibodies against IFN-1. These autoantibodies were pre-existing and were a cause of severe disease rather than a consequence of infection. Remarkably, 94% of these patients were men, half of whom were over age 65, and more than a third died from COVID-19 ).

Exceptional innate immunity may provide resistance to viral infection without engaging the adaptive immune system. In theory, robust innate and intrinsic immune responses may be sufficient to clear a viral exposure without triggering antibody production. This is a difficult phenomenon to study, as most patients with viral clearance are identified by their post-infectious seroconversion. However, potential resistance to hepatitis C infection (HCV) has been described in high-risk injection drug users who lack HCV specific T-cell responses and seroconversion despite a long history of HCV exposure, suggesting that innate immune activity may provide anti-viral defense without seroconversion (Shawa et al. 2017) . The pandemic provides an opportunity to investigate anti-viral resistance through the study of close contacts of critical COVID-19 patients who remain asymptomatic and seronegative. Patients with pandemicassociated pernio may also serve as a model for a mild or resistant SARS-CoV-2 phenotype and are readily identifiable by their skin findings.

Association of pernio/chilblains with monogenic disorders of constitutively active type 1 IFN production. Both clinically and histologically, pandemic-associated pernio mimics the skin lesions of familial chilblain lupus and Aicardi-Goutières syndrome, which are characterized by IFN-1 excess. These monogenic disorders, referred to as type 1 Interferonopathies, are caused by mutations associated with impaired nucleic acid sensing that lead to sustained and upregulated IFN-1 signaling (Rice et al. 2007; Uggenti et al. 2019; Zimmermann et al. 2019 ). In affected patients, pernio develops in early infancy followed by systemic vasculopathy due to auto-inflammation. IFN-1 is profoundly increased in affected skin and blood. Like pandemicassociated pernio, cold is a critical precipitant. In familial chilblain lupus, 5-day cold exposure of primary fibroblasts followed by rewarming enhanced reactive oxidative species, a known trigger of DNA damage, and increased IFN-1 activation, switching cells from a quiescent to a proinflammatory state (Günther et al. 2015) .

autopsy studies have demonstrated a SARS-CoV-2 tropism for the skin. ACE2, the SARS-CoV-2 receptor, is expressed on dermal blood vessels, the basal layer of the epidermis and unexpectedly on eccrine glands (Hamming et al. 2004) (Figure 1b) . We hypothesize that this expression may explain the localization of inflammation to hands and feet as these sites harbor the highest concentration of eccrine glands. This is further supported by the recent demonstration of SARS-

CoV-2 associated spike protein in cutaneous vascular endothelium and eccrine glands in biopsies from patients with COVID toes (Colmenero et al. 2020; Ko et al. 2020; Magro et al. 2020a; Moon et al. 2021; Santonja et al. 2020) . It should be noted that not all biopsy specimens detected spike protein, which could reflect the timing and depth of skin biopsy. Importantly, nucleocapsid antibody staining has been negative.

The immunohistochemistry patterns in published studies, coupled with lack of detection of viral RNA by in situ hybridization or PCR from tissue, suggests that pandemic-associated pernio may result from hematogenous spread of viral material, and may not require viral replication in skin. Ko et al. 2020) . Emerging reports of pernio following mRNA vaccination also raise speculation that this could be an immune response to viral proteins or RNA without viral replication (Davido et al. 2021; McMahon et al. 2021 ). In unaffected skin of patients with critical COVID-19 infection, Magro et al found microvascular complement deposition (an endterminal event driving thrombosis) strongly co-localized with spike protein and the ACE2 receptor, but without in situ evidence of viral RNA (Magro et al. 2020b ). The co-localization of the ACE2 receptor and viral capsid proteins suggests that circulating viral debris may dock onto the endothelium/eccrine ducts. This would be consistent with the hypothesis that patients with pandemic-associated pernio clear the SARS-CoV-2 virus via a robust IFN-1 response, but shower viral debris that binds ACE2 receptors in skin. Finally, the renin-angiotensin system (RAS) is expressed locally in skin and may be indirectly activated by ACE2 binding from SARS-CoV-2 (Silva et al. 2020; Moon et al. 2021; Steckelings et al. 2004) . We hypothesize that persistent vasoconstriction, poor capillary refill, and the chronicity of the response in some patients could also be linked to local cutaneous RAS activation (Figure 2 ).

Pandemic-associated pernio exhibits a lymphocytic infiltrate in a perivascular and peri-eccrine distribution (Figure 1b) , which is composed predominantly of lymphocytes and pDCs. pDCs are responsible for initiation of IFN-1 signaling in response to recognition of viral RNA. Immunohistochemistry studies have revealed robust human myxovirus resistance protein 1 (MxA) staining (a downstream product of IFN-1 activation) in affected specimens in a perivascular and peri-eccrine distribution (Aschoff et al. 2020) . A recent paper suggested a viral-induced interferonopathy in affected patients, demonstrating a significant increase of in-vitro IFN- production after stimulation compared with patients with mild or severe acute COVID-19 infection (Hubiche et al. 2020 ).

A cold environment is crucial to induction of COVID toes. Humans maintain a narrow range of core body temperatures through neural, vascular, and biochemical mechanisms. Increases in body temperature through fever enhance immune function and pathogen killing. Colder ambient temperatures are known to diminish the efficiency of the innate immune response, facilitating viral replication in other infections (Foxman et al. 2015) . Indeed, in vitro SARS-CoV-2 replication significantly increases with colder temperatures, demonstrating 10 fold higher infectious titers when incubated at 33 ˚C vs. 37 ˚C (V'kovski et al. 2021) . Importantly, attenuated IFN-1 expression is responsible for the increased viral replication efficiency at 33 ˚C. In pandemic-associated pernio, one could hypothesize that following clearance from the warmer respiratory tract, dispersed viral material settles at these colder acral sites due to skin tropism via ACE2 expression, evading immune clearance. With rewarming of the toes, a local IFN-1 response could be initiated by pDCs following migration into the skin.

The striking spatial and temporal association with the pandemic, accumulating evidence of both viral material and MxA in affected skin, and the biologic plausibility of pernio linked to the critical role of IFN-1 signaling in COVID-19, all suggest a causal linkage with J o u r n a l P r e -p r o o f SARS-CoV-2. This evidence implicates a robust IFN-1 response in affected patients. The absence of antibody production supports rather than undermines this hypothesis, as an exceptional innate and intrinsic immune activity may be enough to clear viral infection without seroconversion. These findings further intimate IFN-I signaling in host outcomes to COVID-19.

In cooperation with the NIH-funded Human Genome Effort and the International CHGE, the "COVID toes" biobank at the UW-Madison seeks to identify the genetic and immunologic basis to provide clinically relevant insights into SARS CoV-2 associated pernio, and could provide a framework for considering preventative approaches to SARS-CoV-2 infection utilizing early administration of IFNs.

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Dalgard 15 , Cliona O'Farrelly 16 , Colobran Roger 17 , Davoud Mansouri 18 , Diederik van de Beek 19

18 Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, The Clinical Tuberculosis and Epidemiology Research Center

42 Department of Biosciences and Nutrition

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