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

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 include an erythematous exanthem (including a lacy pattern and a petechial, dengue-like rash), livedo reticularis, cutaneous vasculitis acute urticaria, chickenpox-like blisters.

Pathophysiology

• The exact mechanisms of COVID-19 induced cutaneous manifestations are not yet well known,however skin pathologies in which a virus is implicated, various types of manifestations in the cutaneous district involved. Frequently, it is indicating a hematogenous spreading of the virus through the cutaneous vascular system.
• The next step could create activation of the immune system with mobilization of lymphocytes and Langerhans cells patrolling that run through the skin-lymph node path. If the virus swarm induces the creation of immune complexes, this can lead CD4 + T helper lymphocytes to produce cytokines, like IL-1, IFN-γ, and TNF-α, and to recruit eosinophils, CD8+ cytotoxic T cells, B cells and natural killer (NK) cells leading a lymphocytic thrombophilic arteritis.
• Sepsis or severe viral infections could activate the cytokine cascade inducing a CID phenomenon. Just like we observed in the skin and in the lung and kidneys of COVID + patients. However, there are underhanded viral attacks that probably induce a modification in the structure of the keratinocyte, which is destroyed by the cytotoxic lymphocytes, almost resembling the well- known ancient trick of the "Trojan horse."
• 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.Lucchese A. From HSV infection to erythema multiforme through autoimmune crossreactivity.
• Histopathological examination of lung biopsy of COVID + pneumonia indicates a severe damage of the alveolar epithelial cell floating in the alveolar space just like in bullous severe erythema multiforme in which ballooning keratinocytes detach from the spinous layer.
• Degeneration and necrosis of parenchymal cells and formation of hyaline thrombi in small vessels were observed in lung and other organs..
• severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state.

• The viral particles present in the cutaneous blood vessels could lead to a lymphocytic vasculitis.
• Keratinocytes may be a secondary target after Langerhans cells activation.
• Immune response to infection leads to Langerhans cells activation, resulting in a state of vasodilation and spongiosis.
• Microthrombosis and DIC originating in other organs results in livedo reticularis.
  • Hypoxia-related accumulation of deoxygenated blood in blood vessels.
  • Vasculopathy with deposition of C5b-9 and C4d.

Histology

• histopathological studies and PCR investigation on skin biopsies are necessary to clarify the close relationship between skin and SARS-CoV-2 infection,however histopathological study of skin dermatoses in patients affected by COVID-19 infection in the Northern part of Italy showed:.
  • diffuse maculopapular eruption involving only the trunk, clinically suggestive for Grover disease showed, in addition to the classic dyskeratotic cells, ballooning multinucleated cells and sparse necrotic keratinocytes with lymphocytic satellitosis.
• punch biopsy showed in the upper dermis diffuse telangiectatic small blood vessels with no other peculiar features, and In a second punch nests of Langerhans cells within the epidermis was the unique clue in this stage.
  • maculo-papulo-vesicular rash histological findings showed a perivascular spongiotic dermatitis with exocytosis along with a large nest of Langerhans cells and a dense perivascular lymphocytic infiltration eosinophilic rich around the swollen blood vessels with extravasated erythrocytes.
  • papular erythematous exanthema showed edematous dermis with many eosinophils. Cuffs of lymphocytes around blood vessels in a lymphocytic vasculitis.
  • The purpuric skin lesions showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature.

Differentiating COVID-19 Dermatologic manifestations with other Diseases

• COVID-19 can present with a rash and be mistaken for Dengue..
• maculopapular eruption involving only the trunk, clinically suggestive for Grover disease.

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.
• In Spain,Most of the patients were children (median 13 years) and young adults (median 31, average 36, range 18–91 years old)..

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 as the primary presenting symptoms..
  • Urticaria.
  • Livedo reticularis lesions
    • Livedo reticularis is caused by conditions, including disseminated intravascular coagulation (DIC), that reduce blood flow through the cutaneous microvasculature system leading to deoxygenated blood accumulation in the venous plexus..
  • petechial skin rash.
  • Acral eruption of erythemato‐violaceous papules and macules, with possible bullous evolution, or digital swelling.
  • Acute acro-ischemia in the child
    • the presentations of acro-ischemia including finger/toe cyanosis, skin bulla and dry gangrene..
    • they could be the 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.

Table:1 Location and symptoms of chilblain‐like lesions in children and adults during the pandemic

Age/sex	Chilblain location/symptoms	COVID‐19 positive	Symptoms of COVID‐19,	Close contact to COVID‐19	Time in weeks during/prior/after COVID‐19
15/M	Toes, heel/ mild itchy	PCR negative Chest X‐ray: bilateral pneumonia	Asymptomatic	NO	Unknown: skin lesions led to the diagnosis of pneumonia, otherwise asymptomatic.
15/F	Finger, heel/ mildly painful when pressing	Test not done	Nasal congestion, diarrhea	Father with COVID‐19, close contact	One week prior mild symptoms and 3 weeks after visiting her father
23/F	Toes/mild itchy	Test not done	Fever, headaches, itchy	Lives in high risk area	3 weeks prior
44/M	Toe/mildly painful when pressing	Test not done	Sore throat	Unknown	Sore throat 10 days earlier
91/M	Toe	Yes (requiring hospitalization)	Recovered		After 3 weeks of COVID‐19 confirmed
24/F	Toes/painful when pressing	Yes			After infection

Laboratory Findings

Acute acro-ischemia in the child lab results:

• • 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.

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.