What is Type IV Hypersensitivity Reaction?
Our immune system is vital in defending our body from harmful substances, but sometimes it can overreact. This overreaction happens when our immune system interacts with a substance (allergen) that causes allergies and is known as hypersensitivity. There are four different types of hypersensitivity reactions, which are ranked by two researchers, Coombs and Gell. The first three types happen quickly, within 24 hours, while the fourth type takes longer to develop – typically more than 12 hours after being exposed to an allergen. This reaction is at its peak between 48 and 72 hours.
The four types of hypersensitivity reactions are:
* Type I: reaction driven by IgE antibodies (a type of protein the immune system makes when it overreacts to an allergen)
* Type II: cell-damaging reaction driven by IgG or IgM antibodies (other types of proteins produced by the immune system)
* Type III: reaction caused by immune system complexes (a combination of an antigen and an antibody)
* Type IV: delayed reaction driven by cells’ responses
With Type IV hypersensitivity, T cells (a type of white blood cell) cause an inflammation in response to allergens. Other white blood cells like monocytes, eosinophils, and neutrophils can also be involved. After being exposed to the allergen, the body mounts an early immune response that draws white blood cells to locations in the body, where the allergens are being detected. The allergens are then engulfed by monocytes and macrophages (two other types of white blood cells), and presented to the T cells. The T cells then get activated and release certain chemicals that lead to tissue damage and can cause diseases. Examples of ailments that result from type IV hypersensitivity reactions are contact dermatitis (a type of skin inflammation) and drug hypersensitivity (an adverse reaction to drugs). This Type IV reaction is also classified into other subtypes (IVa, IVb, IVc, and IVd) based on the specific type of T cell involved and the chemicals they produce.
This delayed hypersensitivity helps our body fight certain infections, like bacteria and fungi. It also plays a key part in tumor immunity (our body’s response to cancer cells) and transplant rejection (when the body’s immune system rejects a transplanted organ or tissue). In people with AIDS (a disease that weakens the immune system), the number of CD4 cells (another type of white blood cell) gradually reduces, and as a result, their Type IV hypersensitivity reaction is impaired.
What Causes Type IV Hypersensitivity Reaction?
Type IV hypersensitivity reactions are a natural part of the body’s defense system that helps fight off infections. When this system doesn’t work as it should, it can make a person more likely to catch various infections. Sometimes, these reactions can cause problems when the immune system reacts to something it should not, like an allergen.
One common example of this can be seen when someone is exposed to poison ivy and they end up with an itchy skin condition known as contact dermatitis. Certain medications, such as antibiotics and antiseizure drugs, can also cause type IV hypersensitivity reactions, leading to drug allergies and other health issues.
When people who are infected with certain viruses take certain medications, their bodies may react negatively. For example, taking antibiotics while infected with cytomegalovirus, or taking amoxicillin while infected with Epstein Barr virus, or taking antiseizure medications while infected with herpesvirus 6 can all trigger such reactions. Two drugs, allopurinol (used to treat gout) and lamotrigine (used to treat bipolar disorder and epilepsy), have been known to cause type IV hypersensitivity reactions.
Exposure to latex can also cause both type I and type IV hypersensitivity reactions in those who are sensitive to it.
Risk Factors and Frequency for Type IV Hypersensitivity Reaction
Type four hypersensitivity is a fairly common health issue that affects certain people. There are different subtypes of this condition, such as contact hypersensitivity, which affects about 1-6% of people, and drug allergy. A drug allergy can sometimes be viewed as a separate condition and causes about one-seventh of drug side effects. Hospitalized patients occasionally show allergic reactions on their skin, with 2-3% having these reactions.
In Western Europe, studies have found a connection between ‘atopy’ (a tendency to develop allergic conditions) in healthy individuals and responses to a test for tuberculosis exposure (called the purified protein derivative or PPD test).
A large study in Sweden showed that PPD reactions of more than 3 millimeters in size were slightly more common in people with atopy compared to the general population (15.1% vs 14.7%). However, larger PPD reactions of more than 10 millimeters were very rare and similar in frequency between the general and allergic populations (1.4% and 1.2%, respectively).
Signs and Symptoms of Type IV Hypersensitivity Reaction
Type IV hypersensitivity is a type of immune response that has different forms, each with their own unique features. This can result in several types of conditions, which I will outline below:
- Contact dermatitis: This is a skin rash that happens after exposure to an allergen. The skin becomes red, itchy, and swollen and may blister and form crusts. Long-term exposure can lead to chronic contact dermatitis, which features longer lasting or recurring rashes. Everyday items like gloves, clothes, and common industrial chemicals can cause this.
- Granulomatous-type hypersensitivity: This can be seen in conditions like tuberculosis and sarcoidosis. The latter disease can affect any organ, forming granulomas, or clusters of inflamed cells. Symptoms can vary, but it often affects the lymph nodes, lungs, eyes, and skin. It can also cause general symptoms like fatigue, weight loss, or fever.
- Acute generalized exanthematous pustulosis (AGEP): This is a rare reaction to drugs that causes a pustular rash all over the body within 24 hours of exposure to the offending drug.
- Drug fever: Some drugs, like trimethoprim-sulfamethoxazole or tetracyclines, can cause fever as the only symptom. Some conditions, such as acute HIV infection, can increase susceptibility to drug fever when treated with antiretroviral therapy.
- Stevens-Johnson syndrome/toxic epidermal necrolysis: These are life-threatening conditions that cause severe skin and mucus membrane damage, leading to blistering. This condition can resemble a third-degree burn. Painkillers, anticonvulsants, and sulfa drugs often trigger these reactions.
- Drug-induced hypersensitivity syndrome (DiHS): Another severe drug-induced reaction characterized by rash, fever, and damage to multiple organs, particularly the heart, lungs, liver, and kidneys.
Testing for Type IV Hypersensitivity Reaction
Contact dermatitis, a type of skin inflammation, is usually diagnosed based on its physical appearance. However, in some rare cases, a small sample of skin might be needed for examination under a microscope, a procedure known as a skin biopsy.
If your doctor suspects that a specific substance might be causing your skin reaction, she or he may recommend a skin patch test. This test involves applying small amounts of various potential allergens (substances that cause allergies) to your skin using adhesive patches. By observing how your skin reacts to these different substances, your doctor can identify the allergen causing your symptoms.
On some occasions, your doctor might suggest blood tests to help with the diagnosis. These tests measure different types of cells in your blood and can help understand if your immune system is reacting to an allergen.
In case your doctor suspects you have tuberculosis, a skin test (where a small amount of tuberculin is injected under your skin) might be performed. The reaction to this test can indicate whether you have tuberculosis. If the test suggests tuberculosis, you will likely need a chest X-ray for further confirmation.
If a disease called sarcoidosis, which involves growth of tiny collections of inflammatory cells, is suspected, there are a few tests your doctor might consider. These include a chest X-ray, a lymph node biopsy (a small sample is taken from your lymph nodes), a blood test for the angiotensin-converting enzyme (this enzyme level may be elevated in sarcoidosis but it’s not a definitive test), or tests on your salivary glands or the area in your chest between your lungs.
Treatment Options for Type IV Hypersensitivity Reaction
Type IV hypersensitivity treatment differs based on the specific illness stemming from this allergic reaction.
Contact dermatitis is a type of skin inflammation triggered by direct contact with a particular substance. The first step in managing it is to identify and avoid the substance causing the allergic reaction. The severity of the skin condition will guide the treatment, which typically involves creams or ointments that contain steroids. The stronger the steroid in the ointment, the more severe the dermatitis.
In contrast, the treatment for Stevens-Johnson syndrome/toxic epidermolysis is far more intensive. This is a serious condition where the skin and mucous membranes react severely to a medication or infection, often causing the skin to blister and peel. Here, immediate medical attention is needed. This may include treatment in an intensive care unit, fluid therapy to prevent dehydration, antibiotics for any secondary infections, and steroids to control inflammation.
Granulomatous diseases refer to a wide variety of conditions marked by the formation of granulomas–small areas of inflammation in tissue. The treatment for these conditions varies depending on the specific disease. For conditions like systemic and ocular sarcoidosis (forms of inflammation in various organs and the eyes), the typical treatment involves steroids. In cases of pulmonary sarcoidosis, a lung disorder, methotrexate, a medication to control the body’s immune response, may be used.
In the case of Crohn’s disease, an inflammatory bowel disease, anti-tumor necrosis factor (anti-TNF) monoclonal antibodies are used. These drugs help reduce inflammation by targeting a protein in the body’s immune system. Schistosomiasis, a disease caused by parasitic worms, can be treated with praziquantel, a medication that kills the worms.
If a tuberculin test is positive, indicating an individual is infected with tuberculosis, treatment must begin promptly. Tuberculosis is a serious infection that primarily affects the lungs. Treatment typically involves a combination of antibiotics to kill the bacteria causing the infection.
What else can Type IV Hypersensitivity Reaction be?
Both viral skin rashes and certain bacterial infections can result in a rash that looks quite like contact dermatitis, which is an allergic skin reaction. Understanding the timeline of when exposure to a potential allergy trigger occurred can help distinguish between these conditions.
Sarcoidosis, a condition that affects multiple organs but often starts in the lungs and lymph nodes, can lead to symptoms similar to those of tuberculosis. A chest Xray can show lymph nodes in the lungs, a key sign of the condition. However, the treatment for these conditions are not the same. Tuberculosis is typically treated with antibiotics, while sarcoidosis often requires steroids.
What to expect with Type IV Hypersensitivity Reaction
The prognosis, or potential recovery outlook, tends to vary based on the individual’s specific symptoms. In the case of contact dermatitis, a condition where skin becomes red, sore, or inflamed after direct contact with a substance, most patients generally recover with no ongoing issues. Research indicates that about 40% of patients who avoid the substance that caused their reactions didn’t experience any further skin inflammation.
New cases of acute sarcoidosis, a disease involving abnormal collections of inflammatory cells, are more commonly found in white individuals compared to black individuals. There’s a higher likelihood of the disease going away on its own within two years. This happens in about two-thirds of patients. However, for the remaining group, the disease often becomes chronic, or long-lasting. This condition tends to fluctuate between periods of worsening symptoms and periods of improvement. The mortality rate in sarcoidosis, or the percentage of patients who die from the disease, is typically due to respiratory failure and can affect up to 5% of patients.
In the case of tuberculosis, a serious bacterial infection that mainly affects the lungs, the prognosis tends to be positive if it’s diagnosed early and promptly treated with antibacterial drugs.
Possible Complications When Diagnosed with Type IV Hypersensitivity Reaction
Granulomatous diseases are conditions that can affect any part of the body. However, certain types of these diseases tend to affect specific organs more often. For example, a disease called sarcoidosis often impacts the lungs, eyes, and kidneys. This can lead to serious health problems like pneumonia, lung scarring, lung failure, blurred vision from cataracts, eye pressure from glaucoma, and kidney failure. Another granulomatous disease, tuberculosis, in addition to the lungs, can commonly affect the spine and joints resulting in conditions like back pain, stiff joints, and joint inflammation known as arthritis.
In a skin condition called contact dermatitis, an individual can experience something called auto-eczematization. This is a general increase in skin inflammation following a second exposure to a specific substance that causes an allergic reaction. This inflammation interrupts the normal condition of the skin, which serves as our body’s primary barrier. When the skin is disrupted, this can lead to a higher possibility of secondary skin infection by bacteria and other infectious organisms.
Furthermore, severe cases of a skin condition known as Steven Johnson syndrome or toxic epidermal necrolysis can result in permanent scarring of the skin.
Common Consequences:
- Pneumonia, lung scarring, and lung failure
- Blurred vision, eye pressure, and kidney failure
- Back pain, stiff joints, and arthritis
- Increase in skin inflammation
- Higher chance of secondary skin infection
- Permanent scarring of the skin
Preventing Type IV Hypersensitivity Reaction
It’s important for patients to know about and notice the early symptoms of Type IV hypersensitivity reactions. Understanding these reactions can be hugely helpful in managing the condition in the best way possible. Patients should be made aware of the common triggers they’re likely to react to, as well as how to avoid them. If a reaction does take place, removing the cause quickly and starting treatment to reduce inflammation can ease the discomfort and shorten the length of the illness.
