key: cord-0683176-7nreqmqy
authors: Khalil, Shadi; Hinds, Brian R.; Manalo, Iviensan F.; Vargas, Iris Monica; Mallela, Sudhakar; Jacobs, Randy
title: Livedo Reticularis as a Presenting Sign of Severe Acute Respiratory Syndrome Coronavirus 2 Infection
date: 2020-07-17
journal: JAAD Case Rep
DOI: 10.1016/j.jdcr.2020.07.014
sha: 02306755f2379a212b0290ab9981fe02fb301c47
doc_id: 683176
cord_uid: 7nreqmqy

nan

Over three million cases of Severe Acute Respiratory Syndrome Coronavirus-2 infection (SARS-CoV-2) have been documented in the USA. 1 The prevalence of skin findings in Coronavirus disease 2019 (COVID-19) infections has been reported as high as 20%. 2 Two COVID-19 patients with associated transient unilateral livedo reticularis (LR) were previously described. 3 We present a case of transient LR as the initial presenting sign in a case of COVID-19.

A previously-healthy 34-year-old female healthcare worker with no past medical history and known recent workplace exposures to SARS-CoV-2 developed erythema of the left hand. Over two days, the rash progressed, and she developed congestion, fever, and 

This is one of few reports of cutaneous changes preceding systemic signs/symptoms of COVID-19 infection. [3] [4] [5] [6] This patient was healthy, with outpatient disease-management, negative laboratory workup, and lack of newly-initiated pharmacotherapy, arguing against other confounding LR triggers such as coagulopathy/vasculopathy and strengthening the association between LR and SARS-CoV-2. Of note, this patient was young, a demographic over-represented in a high-rash-prevalence COVID-19 study. 2 Similar to previous COVID-19-associated LR, the trunk was spared, as opposed to trunk-predilection noted with other COVID-19 cutaneous findings. 2

Histology identified viral exanthem, with other notable changes, including superficial deposition of mucin. Mucin is a pathologic feature of multiple skin lesions, including granuloma annulare, acute lupus erythematosus, dermatomyositis, pseudomyxoma cutis, and reactive skin conditions. 7, 8 It is unclear whether the observation of mucin in this biopsy was associated with subclinical disease that may have been unmasked with infection, or whether it was directly associated with the exanthem.

While histologic findings were consistent with viral exanthem, the gross morphologic feature of her rash was transient progressive LR, suggesting underlying vascular phenomena. Even in pathogenic LR, microscopic vascular changes are notoriously difficult to detect as inflammation can be distributed in a segmental fashion, or more simply, there can be low-grade inflammation, whereby patent vessels remain without discernible vasculitis or vasculopathy. An incisional wedge biopsy can certainly increase the potential diagnostic yield, permitting a more thorough assessment of cutaneous vessels, but this was not feasible in our patient's case.

The pathophysiology of livedo reticularis involves hyper-congestion of the cutaneous venous vasculature by restricted arterial inflow, exaggerated venous dilation, or impaired venous outflow. 9,10 Endotheliitis, increasingly accepted as a disease-feature of COVID-19, 11-13 may have contributed to the etiopathogenesis of our patient's LR. SARS-CoV-2 is increasingly recognized to have wide-reaching tropism, with capacity to infect and replicate in various tissues and cell types, including lung, gut, kidney and brain. 14, 15 There is increasing suspicion for direct endothelial cell infection by SARS-CoV-2 16 and one study has observed SARS-CoV-2 spike protein directly within the endothelial cell cytoplasm in COVID-19-associated chilblains lesions. 17 Endotheliitis, possibly through such direct endothelial cell infection, may in turn result in vascular changes that drive altered coagulation and vascular homeostasis. 11, 18 This may ultimately result in dilated venous vasculature and the manifestation of livedo reticularis, as was observed in this patient.

In this case, laboratory coagulation tests were normal and did not demonstrate classical COVID-19-associated coagulopathy (increased fibrinogen and d-dimer with minimal changes in the prothrombin and partial thromboblastin times). 15 Importantly, COVID-19associated coagulopathy is a laboratory finding associated with advanced and significant infection. In this patient with appropriate vitals and underwhelming clinical picture, the identification of vascular-associated skin findings argues in defense of direct viral influence on blood vessel behavior. Of note, it is not recommended to routinely evaluate for coagulation profiles in COVID-19 patients not admitted to the hospital.

Of interest, this patient was a healthcare worker, as were three previous COVID-19 patients who demonstrated isolated cutaneous changes at onset of disease course. 3, 4, 6 It remains to be determined whether healthcare providers are at greater risk in the development of cutaneous changes, possibly due to differences in exposure, inoculation dose, or route of infection.

It is important for clinicians to be aware of dermatologic manifestations, including exanthems, with SARS-CoV-2 infections. As the pandemic continues and rapid identification of disease remains important, the observation of COVID-19 associated skin rashes such as COVID-19 LR may serve as an early sign of developing disease. The association between COVID-19 LR and disease severity remains to be 

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