COVID-19-associated dermatologic manifestations

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nuha Al-Howthi, MD[2] Ogechukwu Hannah Nnabude, MD; Aditya Ganti M.B.B.S. [3]

Overview

COVID-19 infections is caused by the novel coronavirus or also known as SARS-2 virus. The disease is believed to incline towards respiratory organs due to the high expression of ACE receptors. However, skin rashes have been uncommonly described in patients with COVID-19 infection. Dermatologic manifestations of COVID-19 though rare include an erythematous exanthem, livedo reticularis, vasculitis, urticaria, vesicles. Common clinical features of covid-19 infection includes fever, dry cough, shortness of breath, myalgia and fatigue.

Historical Perspective

• In 1937, coronavirus was first isolated from chickens.
• In 1965, Tyrrell and Bynoe used cultures of human ciliated embryonal trachea to propagate the first human coronavirus (HCoV) in vitro.

• The etiological agent, a novel coronavirus, SARS-CoV-2, is a virus identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China.
• The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020.
• On March 12, 2020 the World Health Organization declared the COVID-19 outbreak a pandemic.

Pathophysiology

• The exact mechanisms of COVID-19 induced cutaneous manifestations are not yet well known.
• Transmission of COVID-19 takes place during the prodromal period when those infected are mildly ill and are carrying on with their usual activities.
• The virus infects epithelial cells of the lung alveoli by receptor‐mediated endocytosis via the angiotensin‐converting enzyme II (ACE-II) as an entry receptor.
• ACE-II receptors's presence in the extrapulmonary tissues (heart, kidney, endothelium, and intestine) could explain the multi-organ dysfunction.
• Following transmission, the novel coronavirus spreads hematogenously to invade the cutaneous tissue.
• This spread is believed to activate the immune system with mobilization of lymphocytes and langerhans cells resulting in immune complex depositions.

Immune Response

• Immune complexes deposition stimulate T-helper cells to initiate cytokines cascade.
• IL-1, IFN-γ, and TNF-α are produced to recruit eosinophils, CD8+ , B cells and natural killer cells resulting in lymphocytic thrombophilic arteritis.
• Keratinocytes are destroyed by the cytotoxic lymphocytes which is secondary to langherhans cell activation resulting in vasodilation and spongiosis.
• Microvascular injury occurs mediated by activation of complement pathways and an associated pro coagulant state.
• The purpuric skin lesions showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d
• In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature.

Microscopic pathology

• Histopathological studies and PCR investigation on skin biopsies are necessary to clarify the close relationship between skin and SARS-CoV-2 infection. On microscopy features
  • Classic dyskeratotic cells
  • Ballooning multinucleated cells
  • Sparse necrotic keratinocytes
  • Lymphocytic satellitosis.
  • Punch biopsy of the upper dermis demonstrated
    • Diffuse telangiectatic small blood vessels
    • Nests of Langerhans cells within the epidermis
  • Perivascular spongiotic dermatitis with exocytosis al
  • Dense perivascular lymphocytic infiltration
  • Eosinophilic rich around the swollen blood vessels
  • Extravasated erythrocytes.
  • Lymphocytic vasculitis.

Differentiating COVID-19 Dermatologic manifestations with other Diseases

• COVID-19 skin manifestations can often look similar to other diseases that can present with a rash such as toxic shock syndrome, meningococcemia, rickettsial diseases, measles, and scarlet fever.

Epidemiology and Demographics

• The incidence of dermatologic manifestations with COVID-19 infections increases with age; the median age at diagnosis is 53 years.
• Males are more commonly affected than females.
• Most of the patients were children (median 13 years) and young adults (median 31, average 36, range 18–91 years old).

Risk Factors

There are no established risk factors to determine what conditions or diseases predispose Covid-19 infection to manifest as cutaneous complications. However, similar to all viral illnesses, exposure is considered the most significant risk factor for infection with Coronavirus disease 2019 (COVID-19).

• CDC has proposed the following list of conditions that may increase the risk of a severe disease regardless of the individual's age:
  • Elderly (those aged 60+)
  • Cardiovascular disease patients
  • Diabetics
  • Chronic respiratory disease patients
  • Hypertensive patients
  • Cancer patients
  • Individuals in long term care facilities

History and Symptoms

• The timing of skin lesions depends on various factors and not really known but 3 days before diagnosis to 13 days after diagnosis.
• The most common cutaneous manifestation of COVID-19 is a maculopapular exanthem (morbilliform).
• Majority of lesions were localized on the trunk, however, some patients experienced cutaneous manifestations in the hands and feet.
• Skin lesion development occurred before the onset of respiratory symptoms or COVID-19 diagnosis in some of the patients , and lesions spontaneously healed in all patients within 10 days
• The other cutaneous manifestations included:
  • Morbilliform rash
  • Urticaria
  • Livedo reticularis
  • Petechial skin rash

Physical Examination

• • Acral eruption of erythemato‐violaceous papules and macules, with possible bullous evolution, or digital swelling.
  • Acute acro-ischemia in the child
    • Presentations of acro-ischemia including finger/toe cyanosis, skin bulla and dry gangrene..
    • Expression of secondary microthrombosis due to endothelial damage and vascular disorders..
  • Erythema multiforme-like lesions that might be another pattern of exanthem associated with COVID-19 infection.
  • Further studies are needed to evaluate whether these lesions are associated with the virus, the drug intake or any other conditions.
  • COVID-19 Toes.
    • Similar to the type of cold related changes we have seen in the feet of people for many years, but often occurring in places where the conditions are not cold and damp.
    • These seem to happen more commonly in younger patients.
  • Chilblain‐like lesions
    • The pseudo‐chilblain pattern frequently appears late in the evolution of the COVID‐19 disease.
    • The lesion was red–purple papules on the dorsal aspect of the fingers on both hands and diffused erythema in the subungual area of thumb.

Laboratory Findings

• • D-dimer, fibrinogen, and fibrinogen degradation product (FDP) were significantly elevated in most patients.
  • Prothrombin time was prolonged in 4 patients. D-dimer and FDP levels progressively elevated consistent with COVID-2019 exacerbation.
  • Four patients were diagnosed with disseminated intravascular coagulation (DIC).
  • Low molecular weight heparin (LMWH) was administrated in 6 patients, which reduced D-dimer and FDP rather than improved clinical symptoms.
  • 
    HSV is suspected of provoking stimulation of immunopathological mechanisms in erythema multiforme.
    • The herpes virus could play a role in autoimmune cross-reactivity, triggering the keratinocyte that activates IL-1, IFN-γ, and TNF-α, recruiting cytotoxic and NK cells that target the keratinocytes itself.

Diagnostic studies

Diagnosis of COVID-19 infection was successfully confirmed by RT-PCR.

Prognosis

• The skin lesions are initially reddish and papular resembling chilblains.
• Subsequently, in the span of approximately 1 week they become more purpuric and flattened.
• Finally, they seem to resolve by themselves without requiring any treatment.
• Aggravation of previous skin diseases, such as rosacea, eczema, atopic dermatitis and neurodermatitis, was also observed in some Covid‐19 patients.

Treatment

• Supportive care for patients is typically the standard protocol because no specific effective antiviral therapies have been identified.

• Currently, infection prevention and control are considered urgent and critical due to the lack of specific treatment and heightened risk of spreading during the incubation period.