Hypersensitivity

Hypersensitivity is an abnormal immune response where the body overreacts to substances that are usually harmless, affecting about 15% of the population and causing conditions ranging from mild allergies to life-threatening reactions.

Table of contents

• What is Hypersensitivity?
• Classification of Hypersensitivity Reactions
• Type I Hypersensitivity
• Type II Hypersensitivity
• Type III Hypersensitivity
• Type IV Hypersensitivity
• Symptoms and Signs
• Diagnosis
• Treatment

What is Hypersensitivity?

Hypersensitivity is an abnormal condition in which the immune system reacts in an undesirable and excessive way to a substance called an antigen (a substance that the immune system recognizes as foreign)^[1]. This overreaction can lead to various immune diseases, including allergies and autoimmune conditions^[1].

The immune system normally protects the body from harmful invaders like bacteria and viruses. However, in hypersensitivity reactions, the immune system mistakenly identifies harmless substances as dangerous threats. These substances can come from the external environment or from within the body itself^[1]. The resulting immune reactions are often damaging and uncomfortable^[1].

Hypersensitivity is a common occurrence. It is estimated that about 15% of humans experience at least one type during their lives, and the condition has increased since the latter half of the 20th century^[1].

It is important to understand that hypersensitivity differs from toxic and adverse effects that may result from medications, as well as from problems due to drug interactions. Hypersensitivity is specifically an immune-mediated reaction^[10].

Classification of Hypersensitivity Reactions

In 1963, scientists Philip George Houthem Gell and Robin Coombs introduced a systematic way to classify different types of hypersensitivity based on the types of antigens and immune responses involved^[1]. This system, known as the Gell and Coombs classification, is the most widely used method for understanding these complex immune reactions^[1].

According to this classification system, there are four main types of hypersensitivity^[1]:

• Type I: An Immunoglobulin E (IgE) mediated immediate reaction (IgE is an antibody that causes allergic reactions)
• Type II: An antibody-mediated reaction mainly involving IgG or IgM antibodies
• Type III: An immune complex-mediated reaction involving IgG, the complement system, and phagocytes (cells that engulf and destroy foreign particles)
• Type IV: A cytotoxic, cell-mediated, delayed hypersensitivity reaction involving T cells

The first three types are considered immediate hypersensitivity reactions because they occur within 24 hours. The fourth type is considered a delayed hypersensitivity reaction because it usually occurs more than 12 hours after exposure to the allergen, with a maximal reaction time between 48 and 72 hours^[1].

Type I Hypersensitivity

Type I hypersensitivity, also known as immediate hypersensitivity, is an exaggerated immune response to allergens such as pollen, dust mites, foods, medications, or insect venom^[2]. This type of reaction affects nearly one-third of the global population^[2].

The reaction occurs when antigen-specific IgE binds to mast cells (cells that release substances during allergic reactions) and basophils (a type of white blood cell), triggering the release of inflammatory substances including histamine, tryptase, and proteases^[2]. This is why Type I reactions are often referred to as IgE-mediated reactions^[6].

There are two stages to Type I hypersensitivity. During the first stage, called the sensitization stage, a person encounters the antigen but does not experience any symptoms. During the second stage, called the effect stage, the person is exposed to the antigen again. Since the body now recognizes the antigen, it produces a response that results in the typical symptoms of an allergic reaction^[3].

Reactions may be immediate, delayed, or the cause of chronic allergic inflammation, as observed in sensitized individuals with ongoing exposure, such as pet owners with animal allergies^[2].

Common substances that trigger Type I hypersensitivity include^[3]:

• Food products, such as nuts, shellfish, and soy
• Animal sources, such as cats, rats, or bee stings
• Environmental sources, such as mold, latex, and dust

Examples of Type I hypersensitivity conditions include atopy, anaphylaxis, asthma, and eosinophilic granulomatosis with polyangiitis^[1].

Type II Hypersensitivity

Type II hypersensitivity reactions, also called cytotoxic hypersensitivity, often destroy healthy cells and tissue^[6]. In most Type II reactions, an antibody recognizes something on the surface of your cells that it thinks is harmful. This could be part of your body or something foreign, like part of a medication, that has attached to your cells^[6].

In Type II reactions, antibodies (IgM or IgG) bind to antigens on a target cell, which is actually a host cell that is perceived by the immune system as foreign. This leads to cellular destruction through a process involving the membrane attack complex (MAC)^[1].

In some cases, cells are not destroyed. Instead, antibodies cause problems by attaching to cells when they should not. This can block the cells from receiving signals they need to work properly or activate cells when they should not be activated^[6].

Examples of Type II hypersensitivity reactions include autoimmune hemolytic anemia, rheumatic heart disease, thrombocytopenia, erythroblastosis fetalis, Goodpasture’s syndrome, Graves’ disease, myasthenia gravis, and pemphigus vulgaris^[1].

Type III Hypersensitivity

Type III hypersensitivity reactions happen when antibodies attach to antigens that are floating freely in the blood, rather than attached to a cell. This creates antigen-antibody complexes, also called immune complexes^[6].

These immune complexes involve IgG antibodies, the complement system, and neutrophils (a type of white blood cell)^[1]. The immune complexes can deposit in various tissues throughout the body, leading to inflammation and tissue damage^[6].

A well-known example of Type III hypersensitivity is serum sickness. Serum sickness typically occurs 7 to 10 days after exposure and causes fever, joint pain, and rash^[10].

Type IV Hypersensitivity

Type IV hypersensitivity reactions, also called delayed hypersensitivity reactions or cell-mediated immunity, are mediated by T cells (a type of immune cell) rather than by antibodies^[5]. This distinguishes them from the other three types of hypersensitivity reactions.

These reactions are called “delayed” because they usually occur 12 to 72 hours after exposure to the allergen^[4]. The reaction develops more slowly because it takes time for T cells to recognize the antigen, multiply, and cause inflammation.

Examples of Type IV reactions include contact dermatitis (such as from poison ivy or nickel allergy), some lung conditions, type I diabetes, and organ transplant rejection^[4].

Symptoms and Signs

Symptoms of hypersensitivity depend on the type and severity of the reaction. They can range from mild to life-threatening^[4].

Physical symptoms of Type I hypersensitivity can include^[3]:

• Rash
• Flushing
• Hives
• Itching
• Edema (swelling)
• Wheezing
• Rhinitis (inflammation of the nose)
• Stomach cramps

More serious responses can cause^[3]:

• Nausea and vomiting
• Shortness of breath
• Cardiac symptoms
• Loss of consciousness

Symptoms or conditions caused by various types of hypersensitivity include^[4]:

• Hay fever (runny nose, itchy and watery eyes)
• Eczema (dry, red, itchy skin)
• Hives (a bumpy skin rash)
• Asthma (wheezing, coughing and difficulty breathing)

A severe type of allergic reaction called anaphylaxis is a medical emergency. It can cause^[4]:

• Breathing problems
• Swollen tongue, lips and face
• Swelling or tightness in the throat
• Difficulty talking or a hoarse voice
• Wheezing and coughing
• Abdominal pain and vomiting
• Dizziness and possible collapse

If you or someone near you has symptoms of anaphylaxis, give adrenaline using an autoinjector (such as an EpiPen) if you have one, then call for emergency medical help immediately^[4].

Diagnosis

Hypersensitivity is primarily a clinical diagnosis based on available information^[9]. The first step a doctor may take to diagnose hypersensitivity is assessing the person’s history, including taking information on signs and symptoms and reviewing their medical records^[3].

Laboratory testing may be useful in diagnosing hypersensitivity reactions. Skin testing provides the greatest specificity for certain types of reactions^[9]. For Type I hypersensitivity, testing can be done via skin test for specific IgE antibodies^[1].

For Type II reactions, testing includes both the direct and indirect Coombs test, which help identify antibodies attached to red blood cells^[1].

Blood tests can also be used to determine whether a person was exposed to and might have gained immunity against a pathogen. These are called antibody tests^[5].

Treatment

Treatment of hypersensitivity reactions varies depending on the type and severity of the reaction. The goals of treatment are to alleviate symptoms, prevent future reactions, and address potentially life-threatening complications^[2].

Effective management of hypersensitivity centers on allergen avoidance, prompt recognition, and appropriate treatment^[2]. You can reduce the chance of experiencing an allergic reaction by avoiding the substance you are allergic to^[4].

Treatment for Immediate Hypersensitivity Reactions

For anaphylaxis, epinephrine remains the first-line treatment. This is the most important medication and the only medication that has been shown to decrease mortality due to anaphylaxis^[7]. Patients are advised to carry and know how to use auto-injectors^[2].

The following steps should be taken when treating anaphylaxis^[7]:

• Withdraw the offending agent if applicable (for example, stop drug infusion)
• Check the airway and secure if needed. Patients with respiratory compromise may need to be intubated
• Administer epinephrine immediately
• Place the patient in the supine position with legs elevated
• Start intravenous fluids

Antihistamines, corticosteroids, bronchodilators, and other adjunctive medications help manage additional symptoms, such as urticaria (hives), pruritus (itching), and bronchospasm (constriction of the airways)^[2].

H1- and H2-receptor blockers can be helpful in alleviating itching, hives, runny nose, and other symptoms^[7]. Albuterol nebulizers can be used if needed for breathing difficulties. Corticosteroids are believed to help prevent or control the late-phase reaction that can occur hours after the initial reaction^[7].

Prevention

Prevention of hypersensitivity reactions includes^[7]:

• Avoid the triggering allergen as much as possible
• Patients should be given a prescription for at least 2 autoinjectable epinephrine devices and instructed in their proper use
• Patients must carry epinephrine devices at all times
• Patients should wear a medical alert bracelet to alert emergency responders to the possibility of anaphylaxis
• Patients should be taught what measures to take in case of a future anaphylactic reaction

Long-term Management

Clinicians may consider immunotherapy for long-term desensitization in select patients^[2]. There are medicines available to treat some types of allergies^[4].

Patients should be transferred to the hospital for further observation and care after a severe reaction. Late phase reactions can occur 4 to 6 hours after the initial reaction and can be as severe as or worse than the original reaction. In some cases, late phase reactions can occur up to 72 hours later^[7].