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]
Synonyms and Keywords * COVID-19-associated exanthematous rash; COVID-19-associated livedo reticularis; COVID-19-associated livedoid lesions; COVID-19-associated multisystem inflammatory syndrome in children; COVID-19-associated retiform purpura; COVID-19-associated urticaria; COVID-19-associated vasculitis; COVID-19-associated vesicular eruptions

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.

Disease	Epidemiology	Predisposing factors	Clinical features					Lab abnormalities
			Signs				Symptoms
Toxic shock syndrome	Occurs in both adults and children (9:1 female predominance)	Occurs in association with vaginitis during menstruation following tampon use (S. aureus); As a complication of soft tissue infections (S. pyogenes or GAS) In females undergoing medical abortion (C. sordellii)	Fever	Hypotension	Diffuse Rash	Other signs	Diarrhea Vomiting Rash: Diffuse scarlantiform rash (red sunburn-like rash. It is flat and turns white if pressed) Thick skin desquamation appears on the hands and feet at around 1-2 weeks of disease progression, and might be followed by hair desquamation or shedding of fingernails and toenails after 2-3 months	Hyponatremia Uremia Hepatic dysfunction (total bilirubin, serum asparate aminotransferase or serum alanine aminotransferase levels >2 times upper normal limit) Leukocytosis with a polymorphonuclear shift to the left Platelets < 100,000 per mm3(thrombocytopenia) Pyuria of renal origin.
			+	+	+	Nonpitting systemic edema Tachycardia Mucous membrane hyperemia (vaginal, oral, conjunctival)
Meningococcemia	Occurs in young adults living in close proximity (college dorms, military recruits)	Close contact with a carrier Intimate kissing and cigarette smoking are associated with increased risk of meningococcal carriage	+	+	+	Positive Kernig's sign Positive Brudzinski's sign Photophobia	Vomiting Nausea Headache Cool extremities Seizures Rash: petechiae and purpura (star-shaped rash, which can develop into purple bruising. Meningococcal rash can usually be confirmed by a glass test in which the rash does not fade away under pressure.	Positive blood cultures (Neisseria meningitidis) CSF findings typical of bacterial meningitis:[24] Cells >300/uL Predominantly granulocytes Total protein 100-500mg/dl Glucose ratio (CSF/plasma) <0.3 Lactate >2.1 mmol/L CSF gram stain and culture may be positive
Stevens Johnson syndrome (SJS)	HLA-B*1502 gene leads to increased susceptibility	Triggered by certain medications, most commonly: Anticonvulsants Non-steroidal anti-inflammatory drugs Antibiotics Mycoplasma pneumoniae Herpes simplex virus	+	+	+	Positive Nikolsky sign (exerting mechanical pressure on several erythematous zones resluts in peeling of skin) Skin macules which rapidly coalescence.	Ocular involvement: eyelid edema, erythema, crusts, and ocular discharge, to conjunctival membrane or pseduomembrane formation or corneal erosion Rash: Purpuric macules and targetoid lesions; full-thickness epidermal necrosis,  presenting as blisters and areas of denuded skin; and mucous membrane involvement	Serum levels of the following are typically elevated in patients with Stevens-Johnson syndrome: Tumor necrosis factor (TNF)-alpha Soluble interleukin 2-receptor Interleukin 6 C-reactive protein Histological work up of skin sections reveal wide spread necrotic epidermis involving all layers
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome		HHV-6 Carbamazepine Minocycline Allopurinol Abacavir Nevirapine Clindamycin	+	+	+	Multi-organ dysfunction: Pneumonitis Hepatitis Renal failure Encephalitis Cardiac failure Hemophagocytosis	Lymphadenopathy Rash: Urticarial, maculopapular eruption and, in some instances, vesicles, bullae, pustules, purpura, target lesions, facial edema, cheilitis, and erythroderma	Eosinophilia Leukocytosis Uremia Increased ALT and AST
Red man syndrome	Patients in whom the offending drug infusion is given over less than 1 hour and who are not pre-treated with diphenhydramine	Hypersensitivity to: Vancomycin Ciprofloxacin Amphotericin B Rifampicin Teicoplanin Cefepime	+	+	+	Local infusion site erythema Angioedema (rare)	Headache Chills Diziness Chest pain Dyspnea Pruritis Rash: An erythematous rash that involves the face, neck, and upper torso	No elevation in tryptase levels indicating that it is an anaphylactoid reaction
Kawasaki disease	Occurs in children, usually age 1-4 years	Interaction of genetic and environmental factors Infection in combination with genetic predisposition to an autoimmune mechanism (autoimmune vasculitis)	+	+	+	Non-suppurative, painless bilateral conjunctival inflammation (conjunctivitis) Strawberry tongue (marked redness with prominent gustative papillae), Deep transverse grooves across the nails may develop (Beau’s lines), lymphadenopathy present(acute, non-purulent, cervical), Coronary artery aneurysms.	High and persistent fever that is not very responsive to normal treatment with acetaminophen or NSAIDs, Rash: diffuse macular-papular erythematous rash	Liver function tests may show evidence of hepatic inflammation and low serum albumin levels Low hemoglobulin and age-adjusted hemoglobulin concentrations thrombocytosis anemia. Echocardiographic abnormalities, such as valvulitis (mitral or tricuspid regurgitation) and coronary artery lesions, are significantly more common in Kawasaki disease Pyuria of uretheral origin.
Scarlet fever	Distributed equally among both genders. Most commonly affects children between five and fifteen years of age.	Occurs after streptococcal pharyngitis/tonsillitis	+	+/-	+	Pastia's sign (puncta and skin crease accentuation of the erythema) Strawberry tongue Cervical lymphadenopathy may be present. Scarlet fever appears similar to Kawasaki's disease in some aspects, but lacks the eye signs or the swollen, red fingers and toes	Rash: Characteristic sandpaper-like rash which appears days after the illness begins (although the rash can appear before illness or up to 7 days later), rash may first appear on the neck, underarm, and groin	Leukocytosis with left shift and possibly eosinophilia a few weeks after convalescence. Anti-deoxyribonuclease B antibody positive Antistreptolysin-O titers (antibodies to streptococcal extracellular products) Antihyaluronidase, and antifibrinolysin may be positive.

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.
• Disseminated intravascular coagulation.
• 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.
• Histopathological studies and PCR investigation on skin biopsies are necessary to confirm infection of skin with SARS-CoV-2 infection.

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.