July 2020, Volume XXXIV, Number 4

Dermatology

Cutaneous manifestations of COVID-19

Keeping the differential diagnosis open

utaneous manifestations of Coronavirus Disease 2019 (COVID-19) are being reported more frequently as the global pandemic unfolds. COVID-19 has been reported to have dermatologic manifestations including morbilliform exanthems, urticaria, livedoid and vesicular eruptions, and pernio-like changes in 0.2–20% of patients. The skin may also be affected in children with multisystem inflammatory syndrome (MIS-C).

The latest case series of 716 patients with associated cutaneous eruptions associated with COVID-19—based on an international registry of 31 countries and reported by Freeman et al. in the Journal of the American Academy of Dermatology (JAAD)—found associated cutaneous features in 171 COVID-19 lab-confirmed cases. The following frequency of morphologies were reported: 22% morbilliform eruptions, 18% pernio-like changes, 16% urticarial, 13% macular erythema, 11% vesicular, 9.9% papulosquamous, and 6.4% retiform purpura. Cutaneous eruptions typically occurred after other COVID-19 symptoms such as cough, headache, sore throat, and fever in 64% of patients, and simultaneously with these symptoms in 15% of patients.

The morphology of skin lesions may be a helpful marker to predict COVID-19 severity.

The emergence of COVID Toes

COVID Toes have emerged as a possible sign of a current or prior COVID-19 infection in younger patients that present with chilblain-like eruptions. Also known as pernio, chilblains is an inflammatory condition that commonly occurs on acral surfaces such as the feet and hands, typically after cold exposure, and especially in winter climates. Cutaneous signs include erythematous or violaceous macules or patches that may evolve into vesicles or bullae. This eruption can be asymptomatic but is often associated with a burning quality. When case reports from Europe were noted in patients developing these lesions despite ambient mild temperatures, clinicians and public health officials became concerned that pernio-like eruptions may be associated with COVID-19.

Many [MIS-C] patients require hospitalization in intensive care.

Preliminary evidence suggests the pathophysiology of pernio-like lesions associated with COVID-19 is secondary to the immune system’s response to viral infection. The immune system increases interferon to fight the viral infection, which subsequently inflames blood vessels in acral areas. The histopathology from these cases does not show evidence of an occlusive vasculopathy. Early data from the international registry cited in JAAD reported clinical features, timing, COVID-19 severity, and outcomes in 318 patients with pernio-like skin lesions. The median age of patients was 25 years, and 45% had other COVID-19 symptoms (fever, cough, headache, and sore throat). Feet-only features were present in 84% of cases, hands-only in 5.1% of cases, and a combination was present in 10% of patients.

Overall, patients with pernio-like changes have milder cases of COVID-19, since only 16% of patients were hospitalized, as reported in the most recent publication from the international registry. Lesions lasted for approximately 14 days. No known patients with pernio-like lesions presented with stroke. These lesions can be asymptomatic but are more likely to be painful or have a burning quality similar to idiopathic chilblains. This condition can be treated with high-potency topical steroids, low-dose aspirin, nifedipine, and hydroxychloroquine, depending on disease severity. The timing in which cutaneous symptoms presented is an important takeaway from the registry. Pernio-like lesions occurred before COVID-19 symptoms in 13% of patients, at the same time in 15%, and after COVID-19 symptoms in 54%. COVID-19 testing among patients in this series was highly variable. Seventy-two percent of registry cases were in suspected cases without confirmatory testing and approximately 19% of patients who received testing (PCR or antibody serology) tested negative.

This group suggests that pernio-like eruptions should be considered a COVID-19 testing criteria that should prompt PCR and antibody testing. Patients and their physicians should also consider whether or not self-isolation is necessary. It is important that clinicians keep the differential diagnosis open when evaluating patients with pernio-like lesions on the extremities because other diseases can cause similar cutaneous changes (e.g., infections, vasculitis, and thrombosis.)

Cutaneous manifestations that may be associated with COVID-19

Eruptions associated with vesicular, urticarial, morbilliform, and macular erythema are most common on the trunk and extremities and be pruritic. The recent international registry data reported that 22–45% of patients with these morphologies required hospitalization. Patients with a morbilliform exanthem morphology are more likely to have pruritus and involvement of the trunk and extremities. This morphology was detected after other COVID-19 symptoms in 76% of patients.

Drugs and other viruses can also cause morbilliform eruptions and urticaria, so it is important to keep culprits other than COVID-19 in the differential diagnosis. Vesicular eruptions were reported in 15% of patients before the onset of other COVID-19 symptoms in a Spanish case series published in the British Journal of Dermatology. Vesicular eruptions can also be seen in other dermatologic conditions such as erythema multiforme; eczema herpeticum; eczema coxsackium; and hand, foot, and mouth disease. However, an acute, widespread vesicular eruption that resembles varicella in a younger patient should prompt the clinician to consider COVID-19 as a possible underlying cause. Papulosquamous eruptions have been reported and may resemble pityriasis rosea with scaly oval-shaped papules and plaques on the trunk and extremities. These eruptions can be treated with topical steroids and antihistamines.

Livedoid changes with retiform purpura have also been reported in COVID-19 patients. These changes, along with acral cyanosis, indicate vasculopathy, with commonly affected areas including the extremities and buttocks. These skin changes differ from pernio-like lesions and are more commonly found in older critically ill patients. This is typically a late finding after other COVID-19 symptoms have presented. Every patient was hospitalized, and 82% had acute respiratory distress syndrome in the recent JAAD case series.

This morphology was detected after other COVID-19 symptoms in 76% of patients.

Kids and MIS-C

Multisystem Inflammatory Syndrome in Children (MIS-C) can present with features of Kawasaki disease and/or Toxic Shock Syndrome. Kawasaki disease may be triggered by an infectious pathogen, but its underlying cause has not been identified. It typically affects children under the age of five and is more common in patients of Asian descent. The CDC has outlined the features of MIS-C to include:

  • Fever for more than 24 hours.
  • Laboratory evidence of inflammation.
  • Evidence of multisystemic involvement (more than two systems, including cardiac, renal, respiratory, hematological, gastrointestinal, dermatological, and neurological).
  • No evidence of other alternative diagnoses.
  • Positive SARS-CoV-2 by PCR, serology, or antigen test or COVID-19 exposure within four weeks prior to symptom onset.

Patients may fulfill full or partial criteria for Kawasaki disease. Diagnostic criteria for this disease include fever for at least five days, and at least four of the following five symptoms:

  • Oral cavity changes, including erythematous lips, lip fissuring, or strawberry tongue.
  • Polymorphic rash that can be maculopapular, targetoid or erythema multiforme-like rash, or widespread scarlatiniform erythema affecting the extremities and perianal area.
  • Bilateral non-purulent conjunctivitis.
  • Erythematous hands and feet with desquamation.
  • Unilateral cervical adenopathy that is 1.5 centimeters in size.
  • The clinical features noted above do not need to be present at the same time to make the diagnosis.

Toxic shock syndrome, often caused by Staphylococcus aureus or Streptococcus pyogenes, typically presents with fever, chills, myalgias, hypotension, nausea, vomiting, and widespread erythema that may desquamate. In a New England Journal of Medicine report involving children with MIS-C from 26 states, Feldstein et al. reported that cutaneous involvement was found in 76% of patients, and Kawasaki disease-like features in 40% of their patients in their study involving children with MIS-C. In that same report, coronary artery aneurysms were found in 8% of patients. Patients with Kawasaki disease-like symptoms were more likely to be younger than five years old in this case series.

Another case series published by Dufort et al. in the New England Journal of Medicine involving children with MIS-C from New York State reported 60% of those patients had rashes. Thirty-six percent of those patients had Kawasaki disease-like features. Similar to the prior case series, younger patients were more likely to exhibit Kawaski disease-like features (48% of children 0–5 years old, 43% 6–12 years old, and 12% 13–20 years old presented with Kawasaki disease-like features, respectively). Dermatologic features were the most common presenting sign of MIS-C in this group.

Symptoms of MIS-C are highly variable, and early recognition of this condition is important since many patients require hospitalization in intensive care. Thirteen non-fatal cases of MIS-C (average age 5) were reported in Minnesota by the state health department on July 1, 2020. However, only eight patients required intensive care. Treatment options for MIS-C include intravenous immunoglobulin, systemic steroids, anticoagulation therapy, anakinra, tocilizumab, and siltuximab.

Assessment of cutaneous manifestations of COVID-19

The heterogeneous cutaneous manifestations of COVID-19 can be challenging to assess. Pernio-like lesions may be a more specific cutaneous sign of this disease compared to eruptions with other morphologies. It is very important that new onset pernio-like eruptions prompt physicians to consider PCR and serology testing, as well as quarantining. Children with cutaneous signs of MIS-C who have other symptoms for this disorder should be referred to the hospital for immediate evaluation.

It’s important to note that the severity of COVID-19 appears to be higher in patients who have associated urticarial, vesicular, and morbilliform eruptions, compared to those with pernio-like eruptions. In fact, patients with retiform purpura have the highest associated severity of COVID-19.

Referrals

Due to the complexity of cutaneous manifestations in COVID-19, primary care doctors should not hesitate to refer patients to dermatologists for evaluation of possible COVID-associated eruptions. Telemedicine visits can be helpful for patients who have other systemic symptoms of illness and pose an infectious risk to others. This technology can also be utilized for patients in rural areas who may lack access to a board-certified dermatologist.

Phillip Keith, MD, is a board-certified dermatologist, a fellow of the American Academy of Dermatology, and a member of the Minnesota Dermatological Society. He is a physician at Dermatology Consultants and practices in St. Paul and Vadnais Heights. 

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Phillip Keith, MD, is a board-certified dermatologist, a fellow of the American Academy of Dermatology, and a member of the Minnesota Dermatological Society. He is a physician at Dermatology Consultants and practices in St. Paul and Vadnais Heights.