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Type IV: Cell-Mediated Hypersensitivity: What is it?

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Type IV: Cell-Mediated Hypersensitivity: What is it?

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Type IV hypersensitivity is an immune response mediated by T cells instead of antibodies. It has a delayed onset of roughly 24-72 hours. It's characterized by the recruitment of inflammatory cells, particularly T cells and macrophages, to the site of antigen exposure, leading to tissue damage and inflammation. Common examples include contact dermatitis, certain autoimmune disease, and reactions to some medications. The video above gives a brief overview of type IV hypersensitivity.

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Previous exposure to specific antigens

Contact allergy (poison ivy, nickel, soaps)

Medications

Chemicals

Immunocompromised individuals

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Clinical Manifestations of Type IV Hypersensitivity

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Clinical Manifestations of Type IV Hypersensitivity

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Contact dermatitis (redness, edema, itching)

TB skin test reaction (hardening at injection site)

Autoimmune disease (multiple sclerosis, rheumatoid arthritis, type I diabetes, psoriasis)

Delayed hypersensitivity reaction (rash, eczema, inflammation)

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The therapeutic management of Type IV hypersensitivity typically involves controlling inflammation and immune response. Management of contact dermatitis involves typical corticosteroids, emollients and moisturizes, oral antihistamines, avoidance of allergens, barrier creams, and cool compresses. First, try to avoid possible allergens such as poison ivy. Some other drug therapies include steroids. Steroids are used in late phases of allergic reaction. It is essential for individuals with contact dermatitis to work closely with a healthcare professional to determine the most appropriate treatment plan based on the severity of the condition.

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Type 4 is not dependent on antibodies.

T cells cause an inflammatory reaction against exogenous or endogenous reactions. Once there is an antigen exposure an immune and inflammation response is activated that calls for leukocytes. Macrophages and monocytes engulf the antigen which is presented to the T cell, which then becomes activated. These cells can result in illness because of what they release.

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Cleveland Clinic. (2023, March 30). Contact Dermatitis. https://my.clevelandclinic.org/health/diseases/6173-contact-dermatitis.

Guo, L. (n.d). Contact Dermatitis What Is It, Causes, Signs, Symptoms, and More. Osmosis. https://www.osmosis.org/answers/contact-dermatitis

Marwa , K., & Kondamudi , N. P. (2023, August 12). Type IV hypersensitivity reaction. National Center for Biotechnology Information. https://pubmed.ncbi.nlm.nih.gov/32965899/#:~:text=A%20Type%20IV%20hypersensitivity%20reaction,and%20neutrophils%2C%20can%20be%20involved.

Mayo Clinic Staff. (2023, April 25). Contact dermatitis. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/contact-dermatitis/symptoms-causes/syc-20352742

Novak-Bilić, G., et al. (2018, Dec). IRRITANT AND ALLERGIC CONTACT DERMATITIS - SKIN LESION CHARACTERISTICS. Acta clinica Croatica, 57(4), 713–720. https://doi.org/10.20471/acc.2018.57.04.13

Patel, K., Nixon, R. (2022) Irritant Contact Dermatitis — a Review. Curr Derm Rep 11, 41–51 . https://doi.org/10.1007/s13671-021-00351-4

Rogers, J.L,(2023). McCance & Huether’s Pathophysiology: The Biologic Basis for Disease in Adults and Children, Ninth Edition. Elsevier.

Vmc. (2005, October 11). Type IV hypersensitivity reaction information: Myvmc. HealthEngine Blog. https://healthinfo.healthengine.com.au/hypersensitivity-reaction-type-iv

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Those who have occupations or hobbies that regularly expose them to plants and harsh chemicals are at a higher risk of getting contact dermatitis. Fields like healthcare, construction, agriculture, and cosmetology have higher rates of occupational contact dermatitis.

Young people are at higher risk for contact dermatitis due to their high skin turnover rate. Women are also more susceptible. Genetics may play a small role in predisposing one to contact dermatitis.

Irritants and allergens cause immune responses that damage the epidermis. Common irritants include solvents, rubber gloves, detergents, fertilizers, pesticides. Common allergens include nickel, antibiotic creams, poison ivy, insecticides, and cosmetics.

To prevent contact dermatitis, avoid touching irritants, wear protective gloves, wash your skin, use barrier cream, and apply moisturizer. Outdoor pets may also carry allergens from plants on their fur.

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Overview

Contact dermatitis is an itchy rash caused by direct contact with a substance or an allergic reaction to it. The rash isn't contagious, but it can be very uncomfortable.

Many substances can cause this reaction, such as cosmetics, fragrances, jewelry and plants. The rash often shows up within days of exposure.

To treat contact dermatitis successfully, you need to identify and avoid the cause of your reaction. If you avoid the substance causing the reaction, the rash often clears up in 2 to 4 weeks. You can try soothing your skin with a cool, wet cloth and other self-care steps.

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Symptoms

Contact dermatitis shows up on skin that has been directly exposed to the substance causing the reaction. For example, the rash may show up along a leg that brushed against poison ivy. The rash can develop within minutes to hours of exposure, and it can last 2 to 4 weeks.

Signs and symptoms of contact dermatitis vary widely and may include:

An itchy rash

Leathery patches that are darker than usual (hyperpigmented), typically on brown or Black skin

Dry, cracked, scaly skin, typically on white skin

Bumps and blisters, sometimes with oozing and crusting

Swelling, burning or tenderness

When to see a doctor

See your health care provider if:

The rash is so itchy that you can't sleep or go about your day

The rash is severe or widespread

You're worried about how your rash looks

The rash doesn't get better within three weeks

The rash involves the eyes, mouth, face or genitals

Seek immediate medical care in the following situations:

You think your skin is infected. Clues include fever and pus oozing from blisters.

It's hard to breathe after inhaling burning weeds.

Your eyes or nasal passages hurt after inhaling smoke from burning poison ivy.

You think an ingested substance has damaged the lining of your mouth or digestive tract.

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Causes

Contact dermatitis is caused by exposure to a substance that irritates your skin or triggers an allergic reaction. The substance could be one of thousands of known allergens and irritants. Often people have irritant and allergic reactions at the same time.

Irritant contact dermatitis is the most common type. This nonallergic skin reaction occurs when an irritant damages your skin's outer protective layer.

Some people react to strong irritants after a single exposure. Others may develop a rash after repeated exposures to even mild irritants, such as soap and water. And some people develop a tolerance to the substance over time.

Common irritants include:

Solvents

Rubber gloves

Bleach and detergents

Hair products

Soap

Airborne substances

Plants

Fertilizers and pesticides

Allergic contact dermatitis occurs when a substance to which you're sensitive (allergen) triggers an immune reaction in your skin. It often affects only the area that came into contact with the allergen. But it may be triggered by something that enters your body through foods, flavorings, medicine, or medical or dental procedures (systemic contact dermatitis).

People often become sensitized to allergens after many contacts with it over years. Once you develop an allergy to a substance, even a small amount of it can cause a reaction.

Common allergens include:

Nickel, which is used in jewelry, buckles and many other items

Medications, such as antibiotic creams

Balsam of Peru, which is used in many products, such as perfumes, toothpastes, mouth rinses and flavorings

Formaldehyde, which is in preservatives, cosmetics and other products

Personal care products, such as body washes, hair dyes and cosmetics

Plants such as poison ivy and mango, which contain a highly allergenic substance called urushiol

Airborne allergens, such as ragweed pollen and spray insecticides

Products that cause a reaction when you're in the sun (photoallergic contact dermatitis), such as some sunscreens and cosmetics

Children develop allergic contact dermatitis from the usual offenders and also from exposure to diapers, baby wipes, jewelry used in ear piercing, clothing with snaps or dyes, and so on.

Risk factors

The risk of contact dermatitis may be higher in people who have certain jobs and hobbies. Examples include:

Agricultural workers

Cleaners

Construction workers

Cooks and others who work with food

Florists

Hair stylists and cosmetologists

Health care workers, including dental workers

Machinists

Mechanics

Scuba divers or swimmers, due to the rubber in face masks or goggles

Complications

Contact dermatitis can lead to an infection if you repeatedly scratch the affected area, causing it to become wet and oozing. This creates a good place for bacteria or fungi to grow and may cause an infection.

Prevention

You can take the following steps to help prevent contact dermatitis:

Avoid irritants and allergens. Try to identify and avoid the cause of your rash. For ear and body piercings, use jewelry made of hypoallergenic material, such as surgical steel or gold.

Wash your skin. For poison ivy, poison oak or poison sumac, you might be able to remove most of the rash-causing substance if you wash your skin right away after coming into contact with it. Use a mild, fragrance-free soap and warm water. Rinse completely. Also wash any clothing or other items that may have come into contact with a plant allergen, such as poison ivy.

Wear protective clothing or gloves. Face masks, goggles, gloves and other protective items can shield you from irritating substances, including household cleansers.

Apply an iron-on patch to cover metal fasteners next to your skin. This can help you avoid a reaction to jean snaps, for example.

Apply a barrier cream or gel. These products can provide a protective layer for your skin. For example, a nonprescription skin cream containing bentoquatam (Ivy Block) may prevent or lessen your skin's reaction to poison ivy.

Use moisturizer. Regularly applying moisturizing lotions can help restore your skin's outermost layer and keep your skin supple.

Take care around pets. Allergens from plants, such as poison ivy, can cling to pets and then be spread to people. Bathe your pet if you think it got into poison ivy or something similar.

Video: Allergy or irritant: The truth about your rash

Vivien Williams: Hand-washing is essential for preventing the spread of germs. But, sometimes, all this scrubbing can cause a rash. Does this mean you're allergic to the soap?

Dawn Davis, M.D., Dermatology, Mayo Clinic: One important thing to differentiate from allergic contact dermatitis is irritant contact dermatitis.

Vivien Williams: Dr. Dawn Davis says allergic contact dermatitis means a substance is causing an allergic reaction on your skin. But irritant contact dermatitis means your skin is inflamed from repeated exposure to something.

Dr. Davis: If I used lye soap on my skin, and I used it over and over again, I would develop an irritant contact dermatitis simply from eroding away the natural barrier of my skin with repetitive washing.

Vivien Williams: Dr. Davis says it's not always easy to tell the difference between an allergy or irritant.

Dr. Davis: So it's very helpful to go to a health provider, especially a dermatologist, to help differentiate between irritant contact dermatitis

Vivien Williams: and an allergy. That way you can properly treat the rash and prevent it from happening again.

For the Mayo Clinic News Network, I'm Vivien Williams.

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Contact dermatitis - Symptoms and causes

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Contact with certain substances, such as poison ivy, skin lotions and detergents, can cause an itchy rash. Here's how to manage this common form of dermatitis.

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Contact dermatitis conforms to the traditional definition of type IV hypersensitivity. It involves the activation of T cells in response to an allergen or irritant. A material such as nickel can lead to redness, edema, or itching caused by a T cell mediated response. When the skin comes into contact with the triggering substance, antigen presenting cells process the antigen and present it to T cells leading to their activation. This video discusses type IV hypersensitivity but also includes the example of contact dermatitis and how it relates.

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Type IV Hypersensitivity (Described Concisely)

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Depending on the duration and severity of exposure, contact dermatitis may progress from acute to chronic. The tissue and organ-level pathophysiology of contact dermatitis involves several key steps:

Initial exposure to an allergen or irritant triggers the sensitization phase. The allergen or irritant penetrates the skin barrier and interacts with antigen-presenting cells, such as Langerhans cells in the epidermis, which process and present the antigen to T cells.

Upon recognition of the antigen, naive T cells differentiate into effector T cells, mainly T helper 2 (Th2) cells. Th2 cells release pro-inflammatory cytokines, such as interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), which promote the recruitment and activation of other immune cells.

Effector T cells and recruited inflammatory cells, including eosinophils, mast cells, and neutrophils, release cytokines and chemokines, leading to local inflammation. Mast cells play a crucial role by releasing histamine, which contributes to vasodilation and increased vascular permeability, resulting in erythema, edema, and pruritus.

Persistent exposure to the allergen or irritant and the release of inflammatory mediators cause tissue damage and disruption of the skin barrier. This leads to further infiltration of immune cells and exacerbates inflammation.

In most cases, removal of the offending substance and supportive care lead to resolution of contact dermatitis. However, sensitized memory T cells may persist in the skin, leading to a faster and more vigorous immune response upon re-exposure to the allergen or irritant, resulting in a more rapid onset of symptoms.

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Overview

Dermatitis is the medical term for skin inflammation (irritation). Contact dermatitis is an allergic or irritant reaction that causes a painful or itchy skin rash. As the name suggests, you get contact dermatitis from coming into contact with an allergen (like poison ivy) or an irritant (like a chemical).

The condition is common. We are surrounded by irritants and potential allergens. You might experience contact dermatitis more often if you have sensitive skin or other chronic skin problems like atopic dermatitis.

Irritant reactions can occur after a single exposure or after repeated exposures over time, whereas it takes multiple exposures to the same chemical to develop an allergy. People who work in certain professions have a higher risk of developing contact dermatitis. You might repeatedly encounter irritating chemicals or allergens in these professions:

Construction workers.

Florists.

Food handlers.

Hairstylists.

Healthcare providers.

Janitors and plumbers.

Mechanics.

Artists.

The two main types of contact dermatitis are:

Allergic contact dermatitis: Your body has an allergic reaction to a substance (allergen) that it doesn't like. Common allergens include jewelry metals (like nickel), cosmetic products, fragrances and preservatives. It can take several days after exposure for an itchy, red rash to develop.

Irritant contact dermatitis: This painful rash tends to come on quickly in response to an irritating substance. Common irritants include detergents, soap, cleaners and acid.

Symptoms and Causes

Every time your skin comes into contact with an allergen that it doesn't like, your body's immune system responds. White blood cells are recruited into the skin, releasing chemical mediators of inflammation. This response causes the itchy rash. The rash may appear minutes, hours or several days after exposure.

Poison ivy is a top cause of allergic contact dermatitis. Other causes include:

Fragrances.

Metals, such as nickel.

Botanicals.

Medications, including antibiotics.

Preservatives.

Irritant contact dermatitis occurs more often than allergic contact dermatitis. You develop a rash when a chemical substance irritates the skin's outer layers. The rash is more painful than itchy.

Common causes of irritant contact dermatitis include:

Acids.

Alkalis like drain cleaners.

Body fluids, including urine and saliva.

Certain plants, such as poinsettias and peppers.

Hair dyes.

Nail polish remover or other solvents.

Paints and varnishes.

Harsh soaps or detergents.

Resins, plastics and epoxies.

Signs of contact dermatitis include a skin rash that is:

If you're regularly exposed to irritating chemicals or allergens at work and develop contact dermatitis, ask your employer for a chemical Safety Data Sheet. You can take this information to your healthcare provider to help determine what's causing the rash.

Diagnosis and Tests

Clinical examination can reveal clues to the underlying diagnosis of irritant or allergic contact dermatitis. A careful history can uncover clues as to the offending agent.

With either type of contact dermatitis, you can avoid the substance for a while to see if the rash goes away. If avoidance is not possible or not sustainable, further diagnostic testing may be indicated.

For suspected cases of allergic contact dermatitis, a series of tests called patch testing can identify the underlying cause of allergic contact dermatitis.

With a patch test, you wear adhesive patches on your skin. The patches contain chemicals known to commonly trigger allergic reactions. After 48 hours, your healthcare provider checks your skin for reactions. You'll see your provider again in another 48-96 hours for one last skin check.

There isn't a test for irritant contact dermatitis. Your healthcare provider may be able to determine what's causing the rash based on the types of irritants or chemicals you're exposed to regularly.

Management and Treatment

Treatment for both types of contact dermatitis is the same. Even with treatment, it can take several weeks for the rash to go away. Treatments include:

Avoidance: If you can figure out what's causing the rash, take steps to avoid it or minimize exposure.

Anti-itch creams: Corticosteroid creams can ease inflammation and itching.

Oral steroids: Prednisone, a type of steroid, can relieve rash symptoms that don't respond to antihistamines or other treatments.

Immunosuppressive medications: In severe cases, where repeated bouts of oral steroids are needed.

Allergic contact dermatitis is a Type IV hypersensitivity reaction, caused by a different immunologic mechanism than hives, angioedema, or anaphylaxis. However, very rarely, patients may have immunologic dysfunction which results in multiple types of concurrent hypersensitivity reactions. Thus, it is possible that people with contact dermatitis can develop hives (urticaria) and swelling (angioedema) after coming into contact with an allergen. Hives are red, raised, itchy skin welts. Angioedema is swelling deep under the skin.

Extremely rare, allergic contact dermatitis can overlap with a severe, life-threatening allergic reaction called anaphylaxis that can swell airways and close them. If you think you are experiencing anaphylaxis, call 911. You'll need an immediate epinephrine injection to counteract this allergic response. People with known allergies can carry an EpiPen®, a brand of injectable epinephrine.

Prevention

Avoiding known allergens and irritants is the best way to prevent contact dermatitis. But you can't always stay away from every possible irritant. These steps can help:

Choose fragrance-free moisturizers.

Use mild, fragrance and dye-free soaps and cleansers.

Wash immediately after coming into contact with a known allergen or irritant.

Outlook / Prognosis

If you've reacted to an allergen or irritant, you will continue to do so every time you're exposed to it again. You can prevent flare-ups by avoiding that substance.

Most people who have occupational contact dermatitis can find ways to reduce exposure so they can continue their work without breaking out in a rash.

Living With

When should I call the doctor?

You should call your healthcare provider if the skin rash:

Blisters.

Goes away for a while and then returns.

Looks infected (red, warm or swollen).

Hurts.

Itches constantly.

Doesn't go away in a week with treatment.

What questions should I ask my doctor?

If you're experiencing signs of contact dermatitis, talk to your healthcare provider. You may want to ask:

Why do I have a skin rash (contact dermatitis)?

Should I get an allergy test?

What steps can I take to prevent contact dermatitis?

What are the best treatments for contact dermatitis?

What are the best treatments for a painful or itchy skin rash?

What over-the-counter cleansers and moisturizers do you recommend?

What signs of complications should I look out for?

Contact dermatitis is uncomfortable and can be painful or itchy. Talk to your healthcare provider about how you can find out what's causing it, reduce your exposure and prevent reactions. You might develop contact dermatitis from working with irritants or chemicals. Ask your employer about how you can minimize rashes while remaining on the job.

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Contact Dermatitis: Irritants, Allergies, Symptoms & Treatment

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Dermatitis is the medical term for skin inflammation (irritation). Contact dermatitis is an allergic or irritant reaction that causes a painful or itchy skin rash. As the name suggests, you get contact dermatitis from coming into contact with an allergen (like poison ivy) or an irritant (like a chemical).

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Contact Dermatitis: What is it, Causes, Signs, Symptoms, and More

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Contact Dermatitis: What is it, Causes, Signs, Symptoms, and More

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Contact dermatitis is caused by direct contact with an irritating substance or an allergen, triggering an inflammatory skin reaction. Contact dermatitis can be acute, the cause of which is typically a strong irritant, or chronic, caused by recurring exposure to a weaker irritant.

Signs and symptoms of contact dermatitis include redness, itching, swelling, and sometimes blisters or rash formation at the site of contact with the irritating substance or allergen.

Contact dermatitis is typically treated with topical corticosteroids to reduce inflammation and relieve symptoms. Using emollients to soothe the skin, and in severe cases, oral antihistamines may be prescribed for itching.

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Contact Dermatitis: What Is It, Causes, Signs, Symptoms, and More | Osmosis

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Contact dermatitis is an inflammatory skin condition that occurs after exposure to an allergen or irritant

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Irritant vs. Allergic Contact Dermatitis

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Irritant vs. Allergic Contact Dermatitis

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Contact dermatitis can be divided into two types: irritant contact dermatitis and allergic contact dermatitis. Patch testing is used to differentiate between these diagnoses.

Irritant contact dermatitis is the most common occupational skin disease. In this form of contact dermatitis, keratinocytes trigger an inflammatory response. Being young, female, and having a Filaggrin loss-of-function mutation increase one's susceptibility to irritant contact dermatitis (Patel, 2022). You can avoid irritant contact dermatitis by using appropriate PPE and regularly applying barrier cream.

In allergic contact dermatitis, skin lesions are caused by a T cell mediated immune reaction. Research suggests that abnormalities in the skin's microbiome can contribute to the development of allergic contact dermatitis.

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Irritant Contact Dermatitis - a Review

Abstract

Purpose of Review

Irritant contact dermatitis is the most common form of contact dermatitis and the most common occupational skin disease. This review provides a comprehensive summary of the endogenous and exogenous factors that play a role in the pathogenesis of irritant contact dermatitis.

Recent Findings

In conjunction with avoidance of irritants, barrier protection, and regular application of moisturizers, management now emphasizes the importance of primary prevention through educational initiatives in high-risk workplaces.

Summary

The diagnosis of irritant contact dermatitis is often difficult, as there is no confirmatory test, and it is often a default diagnosis after allergic contact dermatitis has been excluded. Early recognition, prevention, and treatment are vital in management, especially in the occupational setting.

Similar content being viewed by others

Seta Vannina & Crepy Marie-Noëlle

Introduction

The purpose of this review is to provide a comprehensive update with regard to the pathogenesis, risk factors, clinical features, and management of ICD.

Contributing Factors in the Development of ICD

Both exogenous and endogenous factors play a vital role in the pathogenesis of ICD [ 5].

Exogenous

Skin Irritants

The most common skin irritant is wet work [ 6] followed by soaps, detergents, solvents, and oils [ 7]. Wet work has been defined as:

1. 1.
Exposure of skin to liquid for > 2 h per day

2. 2.
Use of occlusive gloves for > 2 h per day or change of gloves > 20 times per day

3. 3.
Frequent hand washing > 20 times per day or use of hand disinfectants > 20 times per day [ 8]

Exposure to wet work can occur both at work as well as at home. High-risk occupations involving wet work include cleaners, butchers, cooks, beauticians, and health care workers [ 9*]. The only regulations regarding exposure to wet work are found in Germany, the Technical Standards for Hazardous Substances (TRGS) 401[ 10], a guideline for employers, providing information on occupational hazardous skin exposure and prevention of OSD.

The potency of a chemical irritant and its ability to penetrate the skin are denoted by its properties including molecular size, ionization state, and fat solubility. Different irritants target different structures in the epidermis. For example, sodium lauryl sulfate targets lipid synthesis [ 14] whereas acetone targets the proliferation of basal keratinocytes [ 15].

Factors such as concentration, volume, and duration of irritant exposure will all contribute to an irritant's ability to penetrate the skin. Increasing the volume and duration of exposure will enhance the ability of an irritant to penetrate the skin [ 16]. Increasing intervals between exposures will usually reduce the chance of irritation. Recurrent irritant exposure may result in an additive effect, with repeated exposures initially inducing an increase, then a reduction in trans-epidermal water loss (TEWL) [ 17], indicating functional adaptation or skin hardening.

Physical, Mechanical, and Environmental Factors

The role of physical, mechanical, and environmental factors in the development of ICD is often ignored. Mechanical factors include occlusion, friction, pressure, and vibration. The use of gloves or clothing can create an occlusive, humid environment, which increases irritation caused by heat and sweating.

Environmental factors include heat, cold, humidity, and UV irradiation. Exposure of skin to heat often results in sweating. The retention of sweat can contribute to skin irritation, as sweat is more irritating than water [ 18]. Heat, especially in combination with occlusion, can precipitate ICD.

Exposure to low ambient humidity and cold temperatures are contributing factors to reduced water content in the stratum corneum (SC) and as a result increase the permeability of irritants in the skin. Cold temperatures have also been associated with reducing the plasticity of the horny layer with subsequent cracking of the SC; however, a study has shown that exposure to cold averted the development of ICD [ 19].

Endogenous

Age

Susceptibility of the skin to irritants decreases with age. It is postulated that differences in microcirculatory efficiency, percutaneous penetration, SC turnover time, and loss of corneocyte cohesion [ 20] associated with increasing age cause a slower and less intense response to irritants. This is reflected in the decrease of TEWL in aged skin [ 21].

Sex

Race

Atopy

Genetic Factors

Single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) class I, II, and III are significantly associated with skin response to irritants [ 33, 34]. MHC SNPs have been demonstrated to contribute to chemical irritancy thresholds, with different MHC variants being associated with different chemical irritants. At present, the exact mechanism is unknown.

A link has been recognized between a tumor necrosis factor (TNF)-α gene polymorphism and susceptibility to ICD. At the position P308 within the promoter region of the TNF-α gene, a G to A transition polymorphism has been detected. A study of genotypes showed an association between the A allele and a low irritant threshold [ 35], which has also been significantly linked to contact sensitization to allergens such as p-phenylenediamine (PPD) [ 36] and chromium [ 37]. Another G to A transition polymorphism at the position of P238 has been identified. A study found a potential protective effect of the A allele with carriers being less susceptible to developing ICD [ 38]. This has been speculated to result from increased transcriptional repression of TNF α [ 39, 40].

These advancements represent a novel potential approach in the detection of ICD susceptibility.

Pathogenesis

Previously, the pathogenesis of ICD was thought to be a non-immunological reaction; however, it is now recognized that the immune system plays a vital role in causing ICD [ 41].

Irritation occurs by either damaging epidermal cells [ 42], disruption of the epidermal barrier, or a combination of both [ 43]. Disruption of the epithelial barrier allows for increased permeability of irritants [ 44]. Keratinocytes act as "signal transducers" responsible for instigating cutaneous inflammation via the conversion of exogenous stimuli into the secretion of cytokines, adhesion molecules, and chemotactic factors [ 45]. Upon damage to the keratinocyte, upregulation of primary cytokines IL-1α, IL-1β, and TNF-α occurs [ 46] which triggers the proliferation of keratinocytes and formation of lipids [ 47] playing a role in restoring the epidermal barrier. Additional cytokines IL-6, IL-8, and GM-SCF are subsequently secreted, activating Langerhans cells, dermal dendritic cells, and endothelial cells [ 44] which further recruits inflammatory cells to the site of chemical trauma [ 48].

Irritants can also trigger pattern recognition receptors such as toll-like receptors (TLRs) and NOD-like receptors, which result in activation of the innate immune response via inflammasome and NFĸB pathways [ 44, 52].

There is growing evidence that oxidative stress with the formation of reactive oxygen species plays a role in the pathogenesis of ICD [ 53]. It has been postulated that targeting oxidative stress could be beneficial in the treatment of ICD, with clinical studies demonstrating the therapeutic benefits of antioxidants [ 54].

Clinical Types

Acute Irritant Contact Dermatitis

Acute ICD occurs when the skin is exposed to a potent irritant often in a single exposure, such as concentrated acids, strong alkalis, and solvents such acrylonitrile. In severe cases, this may present as burns, such as from kneeling in wet concrete.

Complete healing can take weeks in acute ICD, generally with a good prognosis [ 57].

Delayed Acute Irritant Contact Dermatitis

Delayed acute ICD represents the most common form of ICD. Chemicals such as benzalkonium chloride, anthralin, calcipotriol, and tretinoin may cause a delayed inflammatory response, not visible until 8-24 h after primary exposure [ 58]. This may lead to misdiagnosis as ACD. Clinical symptoms are similar to acute ICD with the skin becoming sensitive to touch and water [ 59].

Irritant Reaction

Irritant reaction is a subclinical type of ICD that typically affects individuals exposed to wet work. Clinical features are monomorphic, characterized by erythema, scaling, vesicles, pustules, and erosions [ 59]. It often begins on fingers under occlusive jewelry such as rings and spreads to involve the hands and forearms.

This condition may spontaneously resolve with cessation of exposure, or can also progress to cumulative ICD [ 60].

Subjective/Sensorial Irritation

Subjective or sensorial irritation is characterized as sensory discomfort in the form of stinging, burning, or a sensation of itch, in the absence of clinical or histological evidence of skin irritation. Neural pathways are believed to be responsible [ 61]. Irritants identified include propylene glycol, hydroxy acids, ethanol, lactic acid, azelaic acids, benzoic acid, benzoyl peroxide, mequinol, and tretinoin.

Non-Erythematous Irritation

Non-erythematous ICD refers to early skin irritation without clinical signs of inflammation. Associated SC barrier changes can be demonstrated using assays that are usually available only in research settings [ 62]. Symptoms are comparable to subjective irritation. Prognosis is variable.

Cumulative (Chronic) ICD

Cumulative ICD is a result of multiple subthreshold insults to the skin, if the interval between skin exposures is too short to allow complete recovery of the skin barrier function [ 63]. It develops slowly and is linked to exposures to weak irritants [ 64].

Clinical features include erythema, vesicles, and dryness with progression to lichenification, hyperkeratosis, and chapping. Clinical features develop when the damage goes beyond the elicitation threshold. The threshold is dependent on the individual and may decrease as the disease progresses.

Given that exposure to weak irritants often occurs both at home and in the workplace, cumulative ICD may result from exposure to multiple irritants, rather than a single agent. The impact of combined multiple irritants produces an increased skin inflammatory response; however, the extent of interactive effect is unpredictable [ 65].

Frictional Dermatitis

Frictional dermatitis results from repeated frictional trauma, specifically shearing forces acting horizontally to the skin surface [ 66]. It is characterized by hyperkeratosis, acanthosis, and lichenification. Frictional ICD is recognized to contribute to ACD by enhancing percutaneous penetration of allergens [ 66].

Traumatic ICD

Traumatic ICD occurs after acute trauma to the skin such as burns, lacerations, or exposure to a potent irritant. The hands are the most commonly involved; however, there are reported cases of nail involvement [ 67]. Usually, there is delayed healing of the original trauma followed by the development of eczematous lesions [ 64]. It is usually a chronic condition and may be resistant to treatment.

Pustular and Acneiform Dermatitis

Exposure to oils, naphthalene, chlorinated aromatic hydrocarbons, and fluorinated compounds may result in pustular and acneiform dermatitis. Patients most affected are those with seborrheic dermatitis, prior acne vulgaris, and atopy. The prognosis is variable.

Asteatotic Irritant Dermatitis

Asteatotic irritant dermatitis, also referred to as "exsiccation eczematid," "winter eczema," and "eczema craquelé," is seen primarily during winter in cool climates. This variant is common amongst the elderly with dry skin on the lower legs, especially in low-humidity environments. Individuals report intense pruritus, dry skin, and scaling. Reduction in natural moisturizing factors and lipids in the SC is thought to contribute. Intense pruritus is usually relieved by the use of moisturizing creams, and topical corticosteroid ointments are helpful [ 68].

Airborne Dermatitis

Diagnosis

ICD is a diagnosis of exclusion, as there is no routine diagnostic test. The diagnosis is established from the history, clinical examination, and by excluding ACD with negative patch testing. A thorough history regarding occupational and domestic exposures is crucial, and relevant information includes the frequency, intensity, and duration of exposure to skin irritants, as well as the affected skin area(s) [ 44].

The pattern and distribution of dermatitis plays a key role in the diagnosis. ICD always starts at the site of skin contact with the irritant and generally does not spread. Common sites include the hands, face, and perineal areas, particularly in infants and adults experiencing incontinence.

Patch testing is recommended to exclude the differential diagnosis of ACD, which may be clinically indistinguishable from ICD. Even if the results are negative, patch testing has been shown to have a positive impact on quality of life [ 71].

Bioengineering techniques, such as the measurement of TEWL, provide a non-invasive method to measure skin irritation in ICD; however, these are not always available in a clinical setting.

The role of skin biopsy remains limited in the diagnosis of ICD, given that histopathological changes vary between irritants and relates to their mode of action and concentration [ 72]. Histological findings in chronic ICD are generally similar to those of ACD. Reflectance-mode confocal microscopy (RCM) is a non-invasive novel technique which can be used to differentiate between acute ICD and ACD in experimental settings, with superficial epidermal changes (SC disruption, parakeratosis, and separation of individual corneocytes) being more prominent in ICD compared to ACD [ 73, 74]. RCM is postulated to be more sensitive and specific than clinical examination during patch testing and could potentially play a role in distinguishing between doubtful-positive and negative reactions [ 75]. RCM allows repeated observation of the affected area in real time, which is non-invasive compared to conventional histology [ 76].

Prevention

Approaches to preventing exposure to irritants in the workplace involve standard occupational hygiene principles including elimination and/or substitution of the irritant, isolation, and engineering controls including changing the way a job is performed, administrative controls, and finally use of personal protective equipment (PPE) [ 77].

Recent studies have highlighted the importance of pre-employment screening tools in the workplace in early identification of hand dermatitis [ 78].

The use of PPE is recommended in the prevention of ICD. The choice of PPE is guided by the nature of the irritants, the areas of skin exposed, the chemical and physical properties of PPE, and its functionality in relation to the occupation [ 79].

Gloves are a frequently used form of PPE, given that ICD usually affects the hands. Selection of appropriate gloves for the management of ICD may be challenging, given that the protective capabilities of gloves are dependent on many variables.

Glove thickness plays a major role in chemical permeation. However, thin gloves provide greater user comfort and dexterity than thicker gloves made from the same material [ 83].

Given that half of the cases of occupational contact dermatitis (OCD) have been observed to appear within the first 2 years of employment [ 91], there is a role for educational strategies to promote awareness of potential irritants, appropriate use of PPE, and recognition of the early signs of OCD, specifically ICD. Interdigital dermatitis, also referred to as the "sentinel" sign, is regarded as an early stage of hand ICD in occupations involving wet work [ 92]. The impact of work-related educational programs has been shown to be effective in Danish healthcare workers [ 93], student nurses [ 94], and hairdressers [ 95].

A soap-free cleanser is preferable, as synthetic detergents are less irritating to the skin because of the neutral or slightly acidic pH [ 96]. The relatively high-free fatty acid content of soap free cleansers also provides a moisturizing effect, preventing hand irritation and dryness. The use of ABHS including moisturizers avoiding common allergens is recommended as an alternative to detergents [ 97].

Inflammasome-targeted therapies such as topical disulfiram have been shown to be effective in inhibiting ICD in a recent study on human subjects [ 102]. This is thought to be a result of the reduction in the inflammatory cytokine IL-18. This advancement provides a novel approach in the prevention of ICD.

Management

The primary treatment in ICD is avoidance, skin protection from the offending irritant(s) both in the workplace and at home [ 103], and use of topical therapy, particularly moisturizing creams.

Moisturizers are commonly used to improve dry skin symptoms and maintain healthy skin [ 104]. There is increasing evidence of their role in the treatment of ICD by preventing the absorption of exogenous substances and improving skin barrier recovery [ 105]. It is thought that using moisturizers increases skin hydration and that their lipid components modify endogenous epidermal lipids, with high lipid content moisturizers significantly preventing ICD when compared to formulations with lower lipid content [ 104]. Patients should be advised to apply moisturizers frequently, particularly before and after shifts, and after handwashing [ 106]. Evidence has also shown the protective role that moisturizers play in the long and short term, in the primary prevention of occupational ICD [ 99**, 107].

Strontium salts have been shown to be effective in treating sensory irritation and are thought to act by selectively blocking the activation of cutaneous type C nociceptors [ 108]. However, this treatment is not commonly used worldwide.

Cool compresses are a primary treatment of acute ICD by providing an environment which reduces the inflammation and surface temperature changes associated with acute ICD [ 109, 110].

Complications of ICD include bacterial superinfections. These are usually treated aggressively with antibiotics to prevent the development of cellulitis.

Although histamine is not involved in the mechanism of ICD, in clinical practice, oral antihistamines are often prescribed for symptomatic relief. Studies on mice have shown the potential role of topical antihistamines in ICD by reducing inflammation and enhancing barrier function [ 111]. However, to date, there have been no randomized clinical trials demonstrating the efficacy of antihistamines in ICD [ 111].

The Osnabrueck tertiary intervention program (TIP) is a multidisciplinary approach intended to treat severe recalcitrant OSD, comprising a 3-week inpatient phase followed by a 3 week no-exposure outpatient phase. Therapy aims to be free of corticosteroids in order to promote long-term stabilization of the epidermal barrier. TIP intervention has been shown to significantly reduce the use of corticosteroids [ 115, 116, 117**]. Management also includes intensive patient education, health-psychological intervention, and specialized employment consultants [ 118]. Follow-up studies have shown a significant reduction in hand eczema severity and days of absence from work as well as improvement in quality of life both in short-term [ 115] and long-term follow up [ 116, 117 **].

Topical calcineurin inhibitors (TCIs) are topical immunomodulators that provide a safe alternative to corticosteroids. An association of topical TCIs with skin cancer has been suggested, but there is no strong evidence [ 119], while there may be an association with risk of lymphoma [ 120]. TCIs have been shown to be favorable in the treatment of ICD [ 121, 122]. Other systemic treatments include alitretinoin, which has been shown to be an effective treatment in study of patients with chronic hand eczema, 43.2% of whom were diagnosed with ICD [ 123].

Oral immunomodulators may be required in the treatment of chronic ICD if other first- or second-line treatments fail. Cyclosporine is reported to be beneficial in the treatment of chronic hand eczema [ 114] but is used with caution given its associated side effects.

Limited evidence has highlighted the use of dupilumab, a monoclonal antibody treatment approved for the treatment of atopic dermatitis, to be effective in the treatment of chronic recalcitrant hyperkeratotic ICD [ 124] and non-atopic hyperkeratotic hand eczema [ 125]. Further studies are required to determine the use of dupilumab as a potential therapeutic agent in ICD.

Prognosis

Severe ICD is associated with a poor prognosis despite advancements in prevention and treatment strategies. A worse prognosis is linked to history of atopy, female sex, and delayed diagnosis [ 44]. Prognosis can be improved with early detection, patch testing to clarify the diagnosis, and exclude ACD and educational interventions to increase knowledge of ICD in affected individuals [ 129].

Conclusion

ICD is a complex disease influenced by endogenous and exogenous factors. ICD remains a diagnosis of exclusion, and currently, there is no diagnostic test available. For many clinicians, the diagnosis may be difficult, especially if patch testing is not available. Delays in diagnosing ICD are associated with a poorer prognosis. Advancements into RCM as a diagnostic approach appear to be promising. The mainstay of treatment in ICD remains avoidance of skin irritants and the use of PPE, with moisturizers to maintain skin barrier function. In cases of occupationally acquired ICD, the role of health promotion and preventative strategies has been shown to be beneficial, but are often poorly implemented in workplaces. Further studies are required to more fully evaluate predisposing factors, as well as informing clinicians of therapeutic approaches to better manage ICD.

Abbreviations

ACD:

Allergic contact dermatitis

ICD:

Irritant contact dermatitis

CLA:

Cutaneous lymphocyte association

OSD:

Occupational skin disease

PPE:

Personal protective equipment

SC:

Stratum corneum

TEWL:

Trans epidermal water loss

TNF:

Tumor necrosis factor

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Occupational Dermatology Research and Education Centre, Skin Health Institute, Level 1/80 Drummond Street, Carlton, 3053, Australia

Kajal Patel & Rosemary Nixon

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Correspondence to Kajal Patel.

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Patel, K., Nixon, R. Irritant Contact Dermatitis - a Review. Curr Derm Rep 11, 41-51 (2022). https://doi.org/10.1007/s13671-021-00351-4
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# data[].attributes.attachment_link.title
Irritant Contact Dermatitis - a Review - Current Dermatology Reports

# data[].attributes.attachment_link.description
Purpose of Review Irritant contact dermatitis is the most common form of contact dermatitis and the most common occupational skin disease. This review provides a comprehensive summary of the endogenous and exogenous factors that play a role in the pathogenesis of irritant contact dermatitis.

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Different allergens follow slightly altered pathways in the development of contact dermatitis. For example, nickel salts are water soluble and pass directly through channels in the cell membrane via ion-exchange. Nickel then binds to proteins as it is incorporated into the cell. Th1 cells appear to be more dominant in the immune response to nickel compared to Th2 (Novak-Bilic, 2018).