Introduction

Erythema multiforme is a type of hypersensitivity reaction (also known as an allergic reaction) that causes multiple red patches on the skin that are termed target lesions. This condition can be caused by either drugs, such as antibiotics (e.g. penicillin) or infectious causes. Infectious causes of erythema multiforme can either be viral, bacterial or fungal. 

In this article, we will dive deeper into the mechanisms of this condition, how it presents and its diagnosis. Additionally, we will look into the different types of infectious causes.

Pathophysiology overview

The pathophysiology of erythema multiforme is still being studied; however, what is clear is that the mechanism that causes the distinct rash is immunological. 

Cell-mediated immunity

The specific type of immunological reaction is termed cell-mediated immunity. This is one of the body's defence systems against infections. T-lymphocytes (a special type of white blood cell) can recognise specific antigens on viruses or bacteria that attack the body through their T-cell receptors. Once this recognition happens, an immune response begins by releasing cytokines.¹ In the presence of a trigger such as an infection, these T-cells release cytokines, which in people with erythema multiforme result in damage to the epithelial cells (skin cells).² 

There are several conditions which occur due to cell-mediated immunity, which can be easily mistaken for erythema multiforme. Stevens-Johnson syndrome is a condition that occurs due to a hypersensitive reaction to a drug. Unlike erythema multiforme, this condition can cover about 10% of the body surface. Additionally, the target lesions that are synonymous with erythema multiforme are absent in Stevens-Johnson syndrome.³

Viral causes

Herpes simplex virus (HSV-1, HSV-2)

The most common cause of erythema is the herpes simplex virus (HSV), aka herpes. Studies have shown that HSV DNA has been found in over 60% of patients diagnosed with erythema multiforme.⁴ It is a common infection that often causes ulcers and blisters, which tend to be quite painful. There are two main types of HSV:⁵

• HSV-1: This is the most common type, which causes blisters on the mouth and can sometimes cause genital herpes. It is transmitted via oral contact
• HSV-2: This is the type that is typically responsible for genital herpes. It is transmitted via sexual contact

Other viruses

Although HSV is the commonest cause, there are other viruses that have been known to cause erythema multiforme. These include:⁶ 

• Varicella zoster virus- this is the virus that is responsible for chickenpox
• Adenovirus- this virus is usually responsible for respiratory tract infections, particularly in children
• Coronavirus- recently, studies have suggested that erythema multiforme could be a potential side effect of the coronavirus vaccine

Bacterial causes

Mycoplasma pneumoniae

Mycoplasma pneumoniae is the most documented bacterial cause of erythema multiforme. This bacterium typically causes damage to the lining of the lungs and is known to cause respiratory tract infections like pneumonia. Although the symptoms are usually mild and can resolve on their own, some infections caused by this bacterium require antibiotics. If Mycoplasma pneumoniae is the cause of erythema multiforme, it usually causes rashes in the mouth.^7,8

Other bacteria

Less common bacterial causes of erythema multiforme include:⁷

• Hemolytic streptococci—these are a group of bacteria that can cause scarlet fever
• Corynebacterium diphtheriae—the bacterium responsible for diphtheria, a serious infection that affects the nose and throat
• Mycobacterium Tuberculosis—this is an airborne bacterium that affects the lungs 

Fungal causes

Fungal causes of erythema multiforme are extremely rare; however, there are a few fungal organisms that have been associated with this condition. Histoplasmosis is a type of fungal infection caused by the Histoplasma capsulatum that's typically found in bird and bat droppings. Typical symptoms of this infection are fevers, headaches, and muscle aches. In rare cases, it may lead to erythema multiforme.⁹

Clinical presentation

In order to differentiate erythema multiforme from other conditions, it is important to recognise the symptoms associated with it. The most typical symptoms are the target lesions. This is a type of red, patchy rash that has a purple-grey centre. This rash appears suddenly on the palms of the hands and soles of the feet and spreads to the rest of the body. In addition to this rash, some people may also have sores in the mouth and other mucosal surfaces, like the vagina. The sores in the mouth can cause severe pain and can impact one's ability to eat and drink.^10,11

Diagnosis

The diagnosis of erythema multiforme is usually clinical. This means that a detailed history from the patient is required. It is important to find out if the patient has been recently ill, if they've recently taken any medications and when exactly the lesions appeared. Additionally, a complete physical examination is required. This includes taking vitals like temperature and examining the lesions on the skin and in the mouth. If the case is too complicated, sometimes a biopsy of the skin can be taken. A biopsy is a procedure where a portion of skin is surgically removed to be viewed under the microscope and tested in the lab.¹²

Management

Erythema multiforme is a self-limiting condition, which means that it usually resolves on its own; however, sometimes doctors will treat the symptoms. It is important to stay hydrated and get enough rest as the first line of treatment. For the rash, topical corticosteroids and antihistamines can be used. This can help minimise the appearance of the rash and help with the itchiness. Additionally, painkillers can be given for the pain associated with this condition. In people who require additional treatment, it is important to find the causative agent of this infection. If it is due to a bacteria, virus, or fungus, antibiotics, antivirals, and antifungals can be used to treat the erythema multiforme.¹³

Prognosis and recurrence

As a self-limiting condition, erythema multiforme usually has a good prognosis. With proper treatment, people with this condition will not suffer any lifelong complications. In cases where people have other conditions that compromise their immune system, like HIV, they might have a poorer prognosis. Recurrence is possible, particularly with the reactivation of HSV. Rare forms of erythema multiforme, like persistent erythema multiforme, occur when the condition persists for months and is resistant to the normal treatment plans.¹³ 

Summary

Erythema multiforme is a type of allergic reaction that causes target lesions. These lesions are red, patchy rashes with a purple-grey centre. This condition can be caused by bacteria, viruses, or fungi. The most common cause is the herpes zoster virus, which can be transmitted via oral contact or sexual contact. Reactivation of this virus can cause the recurrence of erythema multiforme. The most common bacterial cause is Mycoplasma pneumoniae, which causes respiratory infections. A rash in the mouth is a typical sign of erythema multiforme caused by this bacterium. Although it is rare for a fungus to be responsible for this condition, it can happen. Histoplasmosis is a type of fungal infection that can be responsible for this condition. Erythema multiforme is usually self-resolving; typically, people are well after a few weeks. Drinking enough fluids and getting enough rest is usually enough for most people. Anti-histamines and corticosteroids can be used for the rash and itchiness associated with it. In addition to this, anti-viral medications, antibiotics, and antifungals can be used to treat the underlying cause. Typically, erythema multiforme has a good prognosis; however, rare forms of it can last for a few months and are resistant to typical forms of treatment.