Introduction 

Coronavirus disease-2019 (COVID-19) is a virus that causes a severe respiratory illness in those affected. The virus was first identified in Wuhan, China. The global spread of this virus will lead to a pandemic in 2019.¹ This virus is part of a large family of viruses. These viruses tend to cause upper respiratory tract infections in humans. The severity of the illness can vary however, three main types can lead to death. Severe acute respiratory syndrome (SARS) coronavirus, which causes severe respiratory symptoms. Middle East respiratory syndrome (MERS) coronavirus, which originates from the Middle East and is known to cause respiratory symptoms and Severe acute respiratory syndrome (SARS-CoV-2) coronavirus-2, which led to the 2019 pandemic.²

A major key in containing this pandemic was the introduction of vaccines to the virus. One type of vaccine works by introducing a weakened form of the virus into the body’s immune system, eliciting a mild immune response. This allows the immune system to take effect to kill the virus and create a biological memory of the virus. Thus, when the virus is reintroduced to the body through infection, a quick and effective immune response takes place. This kills the virus before it is able to lead to a severe illness.³ 

Although COVID-19 is predominantly a respiratory condition, there have been growing reports of dermatological manifestations related to the virus. This has been reported in viral infection and vaccination against the virus.^4,5

What is erythema multiforme?

The research shows erythema multiforme as the main dermatological manifestation of the virus. Erythema mutiforme is a skin reaction thought to be caused by a hypersensitivity of the body's immune system. It commonly presents on hands and feet however, it can spread to other parts of the body, like the torso or chest. It usually shows up on the skin as circular patterns with a central blister known as target lesions. This presentation is usually self-resolved without treatment. Rashes can be itchy and cause sensation changes like burning.^7,8

Erythema multiforme can present following an infection; however, it can also be triggered by medications, vaccines, or allergies.

There are many reported causes of erythema multiforme in the following infections:⁹

• Herpes simplex virus
• Mycoplasma pneumoniae
• Measles
• Mumps
• Rubella
• Meningococca

Erythema multiforme can also present as a side effect of the following medications:⁷

• Non-steroidal anti-inflammatory drugs (NSAIDs)
•  Antibiotics
• Statins 
• Anti-epileptics

The literature shows a link between some vaccines and erythema multiforme:¹⁰

Erythema multiforme following COVID-19 infection 

There are multiple case reports of erythema multiforme following COVID-19 infections. Studies show that at the onset of the pandemic, it was often misdiagnosed. Erythema multiforme presentation was being mistaken for allergies, dermatitis and other infectious rashes; which led to repeated re-presentation to medical professionals, before clinicians around the world researched this link. 

Case studies showed erythema multiforme would commonly present on the limbs. Commonly affecting the very young or older adults. The presentation of erythema multiforme also varied greatly. You may present with a skin rash prior to any other symptoms of COVID-19. This early presentation often led to mistreatment. The later development of a fever and respiratory symptoms would confirm this diagnosis retrospectively. You could also develop a skin rash later in the progression of your COVID-19 infection.¹¹ 

Studies show the severity also varies. There are cases where you experience mild symptoms that resolve without treatment and mainly present peripherally; however, in some cases, you could experience a very severe form of the rash requiring steroid treatment. In the severe cases, the rash is present in the oral mucosa and groin region. 

Ultimately, these case reports call for further research into the link between COVID-19 and erythema multiforme. Studies show the presentation seems to vary greatly. Clinicians advise a low threshold for testing for COVID-19 with a new rash, as it can be an early presentation of the virus. They also concluded that erythema multiforme should be considered as a potential diagnosis in this presentation of rash to avoid mistreatment.¹² 

Erythema multiforme following COVID-19 vaccination 

Modern vaccines have been used for many years and tend to have very few side effects. Of those few side effects, skin changes are among the most common. Redness, swelling, and tenderness at the injection site are often reported in up to 90% of recipients.¹³

Erythema multiforme has also been reported following the COVID-19 vaccinations. The onset varies from days to weeks after vaccination. It presents in the same fashion following COID- infection. The COVID-19 vaccine contains a weakened form of the virus that produces a reduced immune response in the body. As a result of this, studies show the erythema multiforme presentation is generally much milder in comparison to the presentation following infection.¹⁴ 

Irrespective of the potential side effects of erythema multiforme following the vaccine, the overall benefits far outweigh this risk. Vaccines prevent severe reactions to infectious diseases and have eradicated some diseases. They ensure your health and the health of the wider public, creating a safe and healthy society. Vaccines protect the most vulnerable in our society, the very young and older adults. Research has proven their effectiveness and their importance in protecting the health of the public.¹⁵ 

Clinical diagnosis and differential

As discussed in this article. Erythema multiforme is considered as a potential diagnosis if it is preceded or followed by a COVID-19 viral infection or preceded by a COVID-19 vaccine. 

For erythema multiforme to be diagnosed, there are certain characteristic presentations observed by the clinician. 

Characteristic presentation include:⁸ 

• Circular rash 
• Central raised lesion or Central pale region -Target lesions
• Raised spots
• Present on dorsal surface of limbs, hands and feet 
• Red or dusky on darker skin tones 

Investigations confirmed through laboratory blood testing, imaging and a skin biopsy if needed. A significant aspect of testing would be to rule out other causes of this rash, as it can present very similarly. Ruling out any medication allergies, non-respiratory infections, or autoimmune conditions helps narrow down the diagnosis. 

Investigations: 

• Drug history
• Chest radiology
• Blood test 
• Allergy blood test 

Erythema multiforme can be mistaken for other skin conditions so an in-depth assessment is required. Differential diagnosis for Erythema multiforme will be ruled out by the appropriate investigations. 

Differential diagnosis:¹⁶ 

• Urticaria
• Fixed drug eruption
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Management and prognosis 

Erythema multiforme has a good prognosis. Without complications, it is not a fatal condition; the risk of recurrence is very low. Generally, treatment is supportive. This means the rash itself does not require treatment, however, medical input can be provided to aid with symptom relief. Medications such as topical corticosteroids, antihistamines, systemic corticosteroids aid in relieving redness, swelling, itching and over-intensity of the rash.

Erythema multiforme is usually self-limiting and commonly resolves within 7 -21 days. The rash commonly resolves however, you may experience some skin scarring. In most prior cases, erythema multiforme has no lasting effects.

Very rarely, erythema multiforme can present on the mucosal surfaces, affecting the eyes, mouth, or genitals. In this presentation, systemic steroid treatment is required. Lesions can take 4 to 6 weeks to resolve. Like the extremities, lesions heal completely without scarring. Unfortunately, you may experience some complications following mucosal erythema multiforme. 20% of people will experience eye complications, resulting in conditions like uveitis, conjunctivitis, and dry eye syndrome.⁸ Management of these complications will be needed. 

Summary 

Erythema multiforme is a skin rash characterised by raised red lesions on the limbs and dorsal aspects of the hands and feet. Though not very common, studies show numerous cases of erythema multiforme before, during, or following a COVID-19 infection. Typically, erythema multiforme resolves by itself however, medication can aid in relieving some of the symptoms.

Studies highlight the importance of correct diagnosis and treatment. Experts urge that there should be a high suspicion of erythema multiforme if you have any COVID-like symptoms around the time of rash presentation. It is key to recognise that the risk of erythema multiforme is greatly outweighed by the benefits of vaccination. 

Future research is essential to identify the exact mechanism of erythema multiforme formation and discover the reason for its presentation in COVID-19 infection or following a COVID-19 vaccination.