key: cord-0751889-x42dxchw
authors: Schwartz, Robert A.; Lambert, W. Clark
title: COVID-19 Specific skin changes related to SARS-CoV-2 Visualizing a Monumental Public Health Challenge
date: 2021-02-01
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2021.01.009
sha: 28b48b35f873d1dadab8f04253c6a17eaa50c68c
doc_id: 751889
cord_uid: x42dxchw

The novel coronavirus SARS-CoV-2 has caused coronavirus disease-2019, known as COVID-19, now a pandemic stressing millions of individuals worldwide. COVID-19 is a systemic respiratory infection that may have dermatologic signs and systemic sequelae, a devastating public health challenge with parallels to the two great influenza pandemics of the last century. Skin lesions linked with COVID-19 have been grouped into 6 categories with three distinct indicative patterns: vesicular (varicella-like), vasculopathic, and chilblains-like (including “COVID toes” and “COVID fingers”) plus three less suggestive ones: dermatitic, maculopapular, and urticarial morphologies. Vasculopathic changes are the most concerning, in some patients reflecting a devastating blood clotting dysfunction. Ways to detect, prevent, and treat COVID-19 will be discussed keeping in mind the context of possible cutaneous markers of COVID-19 to enhance detection.

Coronavirus disease 2019 (COVID- 19) , a viral infection caused by severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2), was first reported from Wuhan in central China in December 2019 (1) (2) (3) (4) (5) . Within a few months it disseminated globally, capturing international attention with an early huge outbreak in northern Italy (4) , creating the current pandemic (6) . The World Health

Concern on January 30, 2020 (7) and as a pandemic on March 11, 2020 (6) . So far, as of August 26, 2020 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the seventh coronavirus known to infect humans with SARS-CoV, MERS-CoV and SARS-CoV-2 capable of causing severe disease (9, 10) . The four others produce only mild symptoms. SARS-CoV-2 is a novel coronavirus, an RNA virus closely related to the original SARS-CoV, but far more deadly.

This flu-like syndrome is also noteworthy for neurological findings, especially loss or reduced sense of smell (1, 9, 10) . Smell dysfunction has been delineated as a biomarker for early COVID-19 (9) . While most COVID-19 patients reported mild 4 symptoms, many other are not so fortunate. This flu-like syndrome spreads through close contact with infected individuals and by droplets released into the air during coughing, sneezing and talking with fomite spread a salient factor, as it was in the SARS 2003 epidemic (11) . In addition, other respiratory infections may coexist, whether viral, bacterial or fungal, providing further challenges, with particular concern centered on the ongoing global epidemic of iatrogenic Candida cruris pulmonary infection in intensive care units (12) . The number of affected individuals diagnosed, often utilizing real-time reverse transcription polymerase chain reaction (rRT-PCR) from a nasal swab, understandably rises as more people become tested, causing public consternation, as, concurrently, systemic extrapulmonary involvement and possible sequelae are being highlighted (11, 13, 14) , including cutaneous findings reflecting clinically salient vascular thromboses (11, 13) .

Skin lesions linked with COVID-19 are noteworthy . Cutaneous findings with the infection itself may produce skin changes which have been classified into 6 categories with three distinct indicative patterns: vesicular (varicella-like), vasculopathic, and chilblains-like (including "COVID fingers" or "COVID toes") (Figs. 1-3) plus three less suggestive ones: dermatitic, maculopapular, and urticarial morphologies (Fig. 4) (1) ( Table 1 ). In addition, separating those from a variety of similar but non-COVID-19 associated cutaneous changes may be challenging (11, 13, 15) . A Spanish study classified the cutaneous manifestations associated with COVID-19 five clinical patterns: acral erythema with vesicles or pustules (pseudo-chilblain), other vesicular eruptions (9%), urticarial lesions (19%), maculopapular eruptions (47%) and livedo or necrosis (6%) (19) . From these maculopapular eruptions seven maculopapular patterns were delineated: 1) were short-lived, either mildly or not pruritic, and did not usually correlate with disease severity. It was speculated that the above cutaneous findings are similar to those occurring during common viral infections. Others suggested the varicellalike exanthem as a rare but specific cutaneous sign of COVID-19 (26) .

A binational, multicenter, prospective study evaluated cutaneous involvement in COVID-19 between January 1 and March 15, 2020, collected prospectively by experienced dermatologists in Wuhan, Hubei province, China, and Lecco, Lombardy region, Italy (24) . In it 678 patients with confirmed COVID-19, of whom 53 patients (7.8%) had new dermatologic conditions detected at admission or during hospitalization, 44% evident initially and the rest detected at a mean of 11.7 days (range, 2-23 days after hospitalization). Of these 53 patients, the most common finding was a mildly pruritic short-lived spontaneously resolving erythematous rash (70%) of macular, papular, maculopapular or erythema multiforme-like morphology, followed by diffuse urticaria (26%). Two patients (4%) had scattered vesicles, characterized as varicelliform eruptions, but proven by COVID 19 and Dermatology 6 performing polymerase chain reaction not to be herpetic in origin. Thirteen had manifestations associated with clotting disorders: diffuse petechiae, purpura, or acro-ischemia evident as primarily finger/toe cyanosis.

The vasculopathic patterns are particularly concerning with regard to the possible development of disseminated intravascular coagulation (DIC) in patients with COVID-19 (11, 13, 16, 17) . Clinical patterns with DIC in COVID-19 disease range from petechial and transient livedo reticularis -like eruptions to retiform purpura and acro-ischemic findings including finger/toe cyanosis, skin bullae and dry gangrene, which in some cases resembles chilblains (11, 18, 28, 30, 31) . One should differentiate the thrombotic/coagulopathic vasculopathic acral ischemia of DIC from COVID-19 chilblain-like lesions ("blue COVID fingers or toes") ( Figure   3 ) (17, 18) . Histopathologic examination of the vasculopathic lesions shows extensive intravascular coagulation often with exaggerated demarcation of erythrocytes from surrounding vascular contents and dissipation of erythrocytes into the surrounding dermis (Fig 5) . This acral ischemia results from thrombosis and reflects a hypercoagulable state and highly elevated D-dimer levels. Chilblain or perniosis-like lesions do not appear to be directly caused by COVID-19 infection (19) , although they have been identified as one of three indicative skin patterns for COVID-19 diagnosis (11) . The COVID-19-associated chilblain and thrombotic retiform purpura have a different pathogenesis (31) . These chilblainlike lesions clinically and histologically strongly resemble idiopathic and autoimmune related chilblains (20) . Acral ischemia associated with DIC in COVID-19 patients and chilblain-like findings in COVID-19 disease patients do not reflect different degrees of involvement within the same spectrum (11, 16, 21, 22, 31) . 7 Other dermatologic finding has been considered. A high frequency of male pattern hair loss among those admitted for COVID-19 has been suggested, which was attributed to possible androgen expression as a clue to COVID-19 severity (35) . A 35-year old woman with COVID-19 and anagen effluvium was described (36) .

COVID-19 disease may be associated with adverse reactions to anti-COVID-19 disease medications (11, 34, (37) (38) (39) , particularly as there is an understandable and appropriate effort to find and explore inexpensive, safe, easy-to-use, and readily avoidable options such as azithromycin (37), some with years of clinical experience with both oral and topical administration (38, 39) . Many clinical trials are in progress. Varying degrees of enthusiasm have centered on hydroxychloroquine (40), with a specific risk of a potentially lethal cardiac arrythmia (41) , and of a potentially serious adverse cutaneous eruption delineated as generalized pustular figurate erythema (11, 42, 43) . COVID-19 has also resulted in many lifestyle changes with cutaneous consequences, including contact and irritant dermatitis to masks (11) .

The death rate in patients with COVID-19 disease varies markedly among individuals depending on age and co-morbidities. The age distribution is remarkable with young at low risk and the elderly at extremely high risk of serious COVID morbidity and mortality, resulting in proposals to protect those most vulnerable (11) . However, patients with a "Do Not Resuscitate (DNR)" notation on their medical chart are often not offered treatment with a respirator even when their COVID 19 and Dermatology 8 physicians feel that it is indicated for treatment of their COVID-19 disease. This may be a major contributor to their high mortality rate. (44) The spread of the COVID-19 virus may be reduced by frequent prolonged handwashing, sanitizer use, air cleansing, and appropriate social distancing with mask usage (11, (45) (46) (47) . Frequent handwashing may produce a dermatitis and possibly favor bacterial infections of skin and nails as exemplified by chloronychia, the Goldman-Fox syndrome associated with Pseudomonas aeruginosa, an opportunistic pathogen shown to penetrate gloves from affected nails of properly washed and gloved medical care providers to patients (47) .

Rendering spaces safer can be extremely important (48) . Special air space cleaning devises may be worthy of consideration for public facilities, buses, and airplanes.

Modifying the air and minimizing the danger within enclosed spaces can be pivotal. Room ventilation limits viral aerosol transmission. There are at least two methods of cleansing the air containing this virus: these solutions are applicable whether in a waiting room, a commercial airliner, a cruise ship or a sports arena.

Air scrubbing utilizes a device that decontaminates and then recirculates the air within a room, often with high efficiency air filtration along with internal high output ultraviolet light-C (254 nanometer wavelength) irradiation. Another approach is use of a chemical mist employing devices using hydrogen peroxide or hypochloric acid. These approaches are important. However, a forceful sneeze or cough probably requires more, a mask to reduce the distance a cough or sneeze travels with viral aerosol deposition on floors and other surfaces requiring effective sanitization as well. 9 Prevention enhances the need to minimize risk beyond the recommendations detailed above. It is a good idea to discourage health care workers over 65 years old or with significant morbidities from seeing patients in-person and assist older physicians in reducing or eliminating direct patient contact, employing telemedicine to communicate with patients and others (11) .

Vaccines are under accelerated development, as efforts to find effective therapy continue with some feeling a sense of the world possibly drowning in this pandemic, exemplified by a famous sculpture made decades earlier (Fig 6) . But rather than being overwhelmed by water, we are enveloped by the air around us, from which we must eliminate the respiratory virus causing COVID-19 disease (48) . Air defense is essential. As one looks to the future, one should also evaluate of Kapila (50) , so that neuropsychiatric symptoms and sequelae will not be overlooked in favor of cutaneous and respiratory ones (11, 14, 51) .

The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health -The latest 2019 novel coronavirus outbreak in Wuhan, China

Caution Warranted: Using the Institute for Health Metrics and Evaluation Model for Predicting the Course of the COVID-19 Pandemic

NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China

Cutaneous manifestations in COVID-19: a first perspective

Interrupting COVID-19 transmission by implementing enhanced traffic control bundling: COVID 19 and Dermatology 11

Implications for global prevention and control efforts

WHO Director-General's opening remarks at the media briefing on COVID-19

Statement on the second meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV). World Health Organization (WHO)

Smell dysfunction: a biomarker for COVID-19

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

COVID-19 with dermatologic manifestations and implications: An unfolding conundrum

Cutaneous manifestations of a 21st century worldwide fungal epidemic possibly complicating the COVID-19 pandemic to jointly menace mankind

Disseminated Intravascular Coagulation: A devastating systemic disorder of special concern with COVID-19

Post-Pandemic Neuropsychiatric Complications: von Economo's Disease, the Kapila Syndrome and More: Linkages in View of the new Covid-19 Pandemic

Erythema multiforme-like lesions in children and COVID-19

Prominent changes in blood coagulations of patients with SARS-CoC-2 infection

Zhonghua Xue Ye Xue Za Zhi. [Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia

Chilblains in children in the setting of COVID-19 pandemic

Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases

Online ahead of print

COVID toes"): Histologic, immunofluorescence and immunohistochemical study of 17 cases

The skin in disseminated intravascular coagulation: Prospective analysis of thirty-six cases

Disseminated Intravascular Coagulation: A Dermatologic Disease

Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): A prospective study from China and Italy

Calzavara-Pinton P. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients

Viral exanthem in COVID-19, a clinical enigma with biological significance

Urticarial eruption in COVID-19 infection

A case of COVID-19 presenting in clinical picture resembling chilblains disease. First report from the Middle East

Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV

The differing pathophysiologies that underlie COVID-19 associated perniosis and thrombotic retiform purpura: a case series

Retiform purpura as a dermatological sign of covid-19 coagulopathy

A Dermatologic Manifestation of COVID-19: Transient Livedo Reticularis

A distinctive skin rash associated with Coronavirus Disease

Unique skin manifestations of COVID-19: Is drug eruption specific to COVID-19?

A preliminary observation: Male pattern hair loss among hospitalized COVID-19 patients in Spain -A potential clue to the role of androgens in COVID-19 severity

COVID-19 related anagen effluvium

Online ahead of print

Azithromycin and COVID-19 Prompt Early Use at First Signs of this Infection in Adults and Children An Approach Worthy of Consideration

Topical Antiviral and Antifungal Medications in Pregnancy: A Review of Safety Profiles

Systemic Medications of Dermatological Importance in COVID-19

Combination in Patients Hospitalized with COVID-19

Off-label" use of hydroxychloroquine, azithromycin, lopinavirritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers

Generalized Pustular Figurate Erythema. A Newly Delineated Severe Cutaneous Drug Reaction Linked with

Generalized pustular figurate erythema. First report in two COVID 19 and Dermatology 18

COVID-19 patients on hydroxychloroquine

Do Not Resuscitate" (DNR) Status Determines Death Rate in Many Hospitalized COVID-19 Patients

Moisturizer use due to excessive handwashing during the COVID-19 pandemic

Shifting dermatology market strategies from cosmetics to moisturizers and sanitizers treatments in COVID-19 era

Chloronychia: the Goldman-Fox syndrome: implications for patients and health care workers

COVID-19 and the