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Anaphylaxis (incl. anaphylactic shock): etiology, pathophysiology, symptoms and treatment. Anaphylaxis versus anaphylactoid reactions.

Anaphylaxis is a sudden, potentially life-threatening allergic reaction that involves multiple system dysfunction. It is caused by a massive release of inflammatory mediators from mast cells and basophils into the circulation. These mediators are normally responsible for the body’s protective response against infections or injuries. They dilate blood vessels, increase their permeability, allowing immune cells to seep through to arrive at the site of infection. But when released systemically, they can lead to extensive vasodilation and smooth muscle spasms, causing blood pressure to drop and airways to narrow to a dangerous level.

Common triggers include certain medications, foods, insect stings, animal venoms, and latex. Symptoms typically begin within minutes to one hour of exposure, and may include widespread itching, hives, swelling, wheezing and difficulty breathing, nausea, abdominal cramps, diarrhea, dizziness, a fast heart rate and low blood pressure. Shock may develop within minutes, patients may have seizures or faint. There is also a late phase response, usually less severe, within several hours to one day.

Classically, anaphylaxis is defined as a type I hypersensitivity, which involves immunoglobulin E, IgE, and only occurs in presensitized individuals. Patients must have had a previous contact with the allergen, which produced no symptoms, but during which the body had produced IgE antibodies against the allergen. IgE molecules bind to their receptors on the surface of mast cells and basophils. Upon reexposure to the same allergen, or sometimes a similar allergen, the allergen binds to adjacent IgE molecules, bringing their receptors together, triggering a signaling cascade that induces the release of inflammatory chemicals.

There are also anaphylactoid reactions which are clinically indistinguishable from anaphylaxis but do not involve IgE and do not require prior sensitization. They occur via direct stimulation of mast cells or basophils, in the absence of immunoglobulins, and have different triggers. These reactions are now classified as “non-immunologic anaphylaxis”, as they are equally serious and must be treated the same way, with the same urgency.

Immediate injection of epinephrine is the cornerstone treatment for anaphylaxis. Epinephrine increases blood flow, widens airways and may help relieve all symptoms, at least temporarily. Other treatments may include antihistamines, oxygen therapy or intubation, intravenous fluids, beta-agonists, or vasopressors.

The best way to prevent anaphylaxis is to avoid the triggers. People with serious reactions to unavoidable allergens may benefit from immunotherapy. In immunotherapy, patients are injected weekly with gradually increasing doses of the allergen, starting with a tiny amount. This process desensitizes the immune system, reducing reactions to the allergen, but may take several years to complete.

All images/videos by Alila Medical Media are for information purposes ONLY and are NOT intended to replace professional medical advice, diagnosis or treatment. Always seek the advice of a qualified healthcare provider with any questions you may have regarding a medical condition.

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Antihistamines are medications that counteract the action of histamine. Histamine is most notoriously known as a mediator of allergic reactions, but it’s also involved in important physiological processes such as immune response, gastric acid secretion, sleep and wake cycle, cognitive ability and food intake.
Histamine is synthesized from the amino acid histidine. It is present in all tissues but most abundant in the skin, lungs and gastrointestinal tract. Most of histamine in tissues is stored as granules inside mast cells. In the brain, histamine also functions as a neurotransmitter. It is found in histaminergic neurons of the hypothalamus, whose axons project throughout the brain.
Histamine exerts its action by binding to histamine receptors, H-receptors, all of which are G-protein- coupled. There are four H-receptors, with different tissue expression patterns and functions. Both H1 and H4 are involved in allergic inflammation, but only H1-antihistamines are currently available for allergy treatment. The major function of H2-receptor is to stimulate gastric acid secretion, so H2-antihistamines are used to treat gastric acid disorders such as gastric reflux and peptic ulcers.
The term “antihistamine” generally refers to allergy-treating H1-antihistamines.
Most allergies occur upon a repeated exposure to an allergen. Mast cells that were previously sensitized to the allergen are activated, releasing histamine and other inflammatory chemicals. Histamine causes dilation and increased permeability of blood vessels, stimulation of sensory nerves, contraction of smooth muscle; and is responsible for most allergic symptoms, ranging from watery eyes, runny nose, sneezing, itching; to swelling, hives, and difficulty breathing due to bronchospasm. When released systemically, histamine can cause extensive vasodilation and bronchoconstriction which may lead to life-threatening anaphylaxis.
Most H1-antihistamines are not similar to histamine in structure and do not compete with it for binding to H1-receptor. Instead, they bind to a different site on the receptor and stabilize it in its inactive state. The first-generation H1-antihistamines derive from the same chemical class as muscarinic, adrenergic and serotonin antagonists, so they also have anti-cholinergic, anti-adrenergic, and anti-serotonin effects. More importantly, they can cross the blood-brain barrier and interfere with histamine functions in the brain, causing drowsiness, cognitive impairment and increased appetite. Some of these drugs are actually used for their sedative side effect, as sleeping aid medications.
Second-generation antihistamines are less able to cross the blood-brain barrier, and are therefore minimally or non-sedating. They are also highly selective for H1-receptor and have no anti-cholinergic effects.

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Vaccines prepare the immune system, getting it ready to fight disease-causing organisms, called pathogens. To understand how vaccines work, we must first learn how our immune system responds to invading pathogens.
When a new pathogen enters the body, it meets with the body’s first-line defense, the innate division of the immune system. The innate response is immediate, but non-specific, meaning it destroys all foreign invaders without discrimination. Fever is one of the signs that the body is fighting the disease at this stage. If this fails to contain the infection, the adaptive immune system comes into play. The adaptive response is more effective, but it may take many days to activate, during which time the person is being sick. The adaptive response produces the so-called antibodies, which specifically bind to a component on the surface of the pathogen, labeling it for destruction. This component is called an antigen and is the one that has triggered the production of antibodies against it.
Remarkably, the adaptive response also leaves the body with a “memory” of the pathogen, so it can react faster the next time the same pathogen attacks. In fact, pathogen-specific antibodies are produced so fast upon reexposure to the pathogen, that no signs of illness are visible. This is called immunity, and it explains why most people get diseases such as chickenpox only once, even though they may be exposed multiple times in their lifetime.
A vaccine is basically an altered form of a pathogen, or part of it that acts like an antigen. It is introduced to the body to trigger production of antibodies, mimicking the first infection, but without causing the illness. The immune system now has the antibodies, and is ready for a fast response whenever it is exposed to the real pathogen.
When enough people in a community are vaccinated, the whole community, including the individuals that were not vaccinated, is protected against the disease. This phenomenon is known as herd immunity. Herd immunity is possible because a pathogen cannot spread without a sufficient number of vulnerable hosts. An analogy is the spread of wildfires. A wildfire only spreads where there is vegetation, or fuel, for it to burn; it would stop at a river, or a large open space. These are called firebreaks. Vaccinated individuals essentially serve as firebreaks, preventing spread of infections caused by pathogens. Herd immunity is important because not everyone can be vaccinated. Often, the very young, very old, and immunocompromised people must rely on vaccinated individuals to stop disease outbreaks. To note, however, that the number of vaccinated individuals must be great enough for community protection to occur, just like a firebreak must be large enough to stop a fire.
There are several types of vaccines:
– Live, attenuated vaccines are live pathogens that have been weakened so they don’t cause disease in people with healthy immune systems. Being the closest thing to a natural infection, they are most effective and can provide life-long immunity with a single dose. However, weakened pathogens can still be strong enough to cause illness in people with compromised immune systems, and therefore cannot be used for this group of people.
– Inactivated vaccines are pathogens that have been completely inactivated by heat or chemicals. They are safer than attenuated vaccines but less effective, and multiple doses may be required to achieve and maintain immunity.
– Subunit vaccines use only part of a pathogen, usually a peptide. These vaccines are very safe as they cannot cause disease, but to make such a vaccine, scientists must first identify the part of the pathogen that can elicit a good immune response, and this can be a difficult task.
– Toxoid vaccines: Some bacteria cause illness by releasing toxins. These toxins are inactivated and used as vaccines. Inactivated toxins do not cause disease, but can induce production of antibodies against the natural toxins.
– Conjugate vaccines: Some bacteria have a protective coat that helps them evade the immune system. This is because the coat is a weak antigen, it does not provoke a strong production of antibodies. Vaccines based on weak antigens will not protect the person effectively. To overcome this problem, the weak antigen is combined with a strong antigen from another source as a carrier, in a conjugate vaccine, to boost the immune response.

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Gluten is not a single protein, but a complex mixture of related proteins that constitute the bulk of protein stores in many grains. These proteins belong to 2 main classes: prolamins and glutelins.
Gluten has unique viscosity properties that give the dough its elasticity. Because of its low costs, wheat gluten is widely used as a thickening or binding agent, and to fortify low-protein food products. For this reason, apart from obvious sources, gluten can also be found in a variety of processed foods, including meat and meat substitutes, as well as medications and nutrition supplements.
Prolamins are of most clinical significance when it comes to gluten-related disorders. In wheat they are called gliadin. Proteins similar to gliadin exist in rye, barley, oat, and their derivatives. These proteins are highly polymorphic, meaning there exist many variations of the same protein. Thus, not only different grains, but also different varieties or even different genotypes of the same grain can produce different gluten compounds. Composition of a particular gluten also varies depending on growing conditions and processing technologies.
Prolamins are the main causative agent of celiac disease. Prolamins are rich in the amino acids proline and glutamine, and are therefore highly resistant to digestion by enzymes of the gastrointestinal tract. Partial digestion of prolamins produces a family of small peptides, that can trigger inappropriate immune response in people with celiac disease. These peptides are known as epitopes. A given patient may react only to a few of these peptides. Different patients may react to different peptides. The most toxic epitope, responsible for strongest reactions in most patients, is a 33-amino acids peptide from wheat alpha-2-gliadin.
While it also contains gluten, oat is safe for most people with celiac disease. This is because the prolamin content in oat is significantly lower than that in the other 3 grains, and the number of people reacting to oat epitopes is relatively smaller.
People with celiac disease usually inherit a genetic predisposition to the disease. They have certain receptors that bind strongly to the epitopes and alert the immune system, specifically T-helper cells, to their presence. Activated T-helper cells release inflammatory cytokines, and attract cytotoxic T-cells to the small intestine. This results in inflammation of the mucosa, villous atrophy, and increased gut permeability. Common gastrointestinal symptoms include bloating and abnormal bowel habits.
Wheat gluten is also involved in wheat allergy. Allergy is an immediate abnormal immune response, usually within minutes of ingestion. The mechanism is similar to other food allergies and involves IgE-mediated release of histamine and other inflammatory chemicals from mast cells. Symptoms include itching, swelling, rash, vomiting, diarrhea, and in some cases, life‐threatening anaphylaxis. Gluten, however, is not always the culprit in wheat allergy. Some people react not to gluten, but to other wheat proteins and pollen proteins.
The most common gluten-related disorder is the so-called non-celiac gluten sensitivity. This term includes all reactions to gluten-containing grains that are not celiac disease or wheat allergy. Pathology is not yet understood, and the terminology maybe a misnomer, because other proteins and carbohydrates present in the grains may also be responsible for the symptoms.

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Allergy refers to abnormal reactions of the immune system to otherwise harmless substances. Normally, the immune system raises immune response to protect the body from foreign invaders, such as bacteria or viruses, but does not react to non-infectious environmental antigens. In people with allergies, however, the immune system also reacts to these substances, producing allergic reactions. Such substances, called allergens, can come from the patient’s natural environment, foods, medications, latex products, or insect bites.
Most allergies are mediated by a class of antibody called immunoglobulin E, IgE. IgE is produced when the body is first exposed to an allergen. Production of IgE is activated by a subtype of T-lymphocytes, known as type 2 helper T-cells, TH2. IgE molecules then bind to their receptors on the surface of mast cells and basophils. The first exposure is usually asymptomatic, but the body is now sensitized. Upon reexposure to the same antigen, the antigen binds to adjacent IgE molecules, bringing their receptors together, triggering a signaling cascade that induces the release of histamine and other inflammatory chemicals. These chemicals cause dilation and increased permeability of blood vessels, mucus secretion, stimulation of sensory nerves, smooth muscle spasms, and are responsible for allergic symptoms, which can range from mild to severe. Mild symptoms usually consist of watery eyes, runny nose, sneezing and a mild rash; while severe reactions may include swelling, hives, difficulty breathing due to bronchospasm, and digestive problems due to increased gastrointestinal motility. When released systemically, these chemicals can cause extensive vasodilation and smooth muscle spasms which may lead to anaphylaxis, a life-threatening condition in which blood pressure drops and airways narrow to a dangerous level.
The reactions are immediate, within minutes of contact with the allergen. There is also a late phase response, due to subsequent tissue infiltration with eosinophils and other inflammatory cells.
People who are sensitized to a specific allergen may also react to other substances that contain similar antigens. This is called cross-reactivity. For example, people who are allergic to birch pollen may also have reactions to certain fruits and vegetables such as apples or potatoes, consumption of which can cause itching and swelling of the lips and oral cavity.
Both genetic and environmental factors contribute to the development of allergic diseases.
Allergies tend to run in families. What is inherited is the susceptibility to allergic reactions, due to irregularities in the makeup of the immune system.
Early childhood exposures to bacterial and viral infections are thought to suppress TH2 cells and are therefore protective against allergic diseases. This theory, known as hygiene hypothesis, implies that living in too sterile an environment is a risk factor for allergic diseases. While still a hypothesis, it does partly explain the higher prevalence of allergies in developed countries. Other risks factors include exposure to allergens and stress.
Diagnosis is usually based on symptoms and patient’s history. Potential allergens may be identified with skin prick test or intradermal test, where small amounts of common allergens are introduced into the skin and local reactions are observed. A blood test, called allergen-specific serum IgE test, can also be performed. In this case, patient’s blood sample containing IgE is tested for binding to common allergens. If binding occurs, the person is allergic to that allergen.
Antihistamines are effective for treatment of mild allergies. Other drugs include mast cell stabilizers, corticosteroids and leukotriene modifiers. Severe reactions require immediate injection of epinephrine.
The best way to prevent allergies is to avoid the offending allergens. People with serious reactions to unavoidable allergens may benefit from immunotherapy. In immunotherapy, patients are injected weekly with gradually increasing doses of the allergen, starting with a tiny amount. This process desensitizes the immune system, reducing reactions to the allergen, but may take several years to complete.

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Hypersensitivity refers to abnormal reactions of the immune system against certain antigens. It includes exaggerated reactions to otherwise harmless environmental antigens, commonly known as allergies; and inappropriate reactions against the body’s own antigens, or autoimmune diseases.
Reactions can range from a mild rash, to damaged organs, to fatal anaphylactic shock.
There are 2 principal groups of factors contributing to hypersensitivity:
– Imbalance between effectors and regulators of immune response: in some people, mechanisms that normally moderate the immune system are compromised, causing it to overreact to harmless, non-infectious antigens.
– Self-reactivity of immune cells: during their development in the thymus and bone marrow, T-cells and B-cells learn to not react to the body’s own antigens; self-reactive cells are normally eliminated; but in some people, some of these cells escape and may attack their own tissues once activated.
Hypersensitivity reactions only occur in pre-sensitized individuals. Patients must have had a previous contact with the antigen, which produced no symptoms, but during which the body had started making antibodies or activated immune cells that may cause symptoms in subsequent exposures to the same antigen.
Hypersensitivity is classified into 4 types based on mechanisms of action:
In type I hypersensitivity, a previous exposure to the antigen results in production of a class of antibodies called IgE. IgE molecules bind to their receptors on the surface of mast cells and basophils. Upon re-exposure to the same antigen, or sometimes a similar antigen, the antigen binds to adjacent IgE molecules, bringing their receptors together, triggering a signaling cascade that induces the release of histamine and other inflammatory chemicals. These chemicals cause dilation of blood vessels, smooth muscle spasms, and are responsible for symptoms such as edema, rash, difficulty breathing due to bronchospasm, abdominal cramping, vomiting and diarrhea. The reactions are immediate, within minutes of contact with the antigen, and can range from mild to severe. Severe reactions may lead to anaphylactic shock, a life-threatening condition in which blood pressure drops and airways narrow to a dangerous level. Most allergies are type I hypersensitivity reactions.
In type II hypersensitivity, previously formed IgG or IgM antibodies bind to antigens on the surface of a particular cell type. Antibody binding marks the cells for destruction, either by the complement system or phagocytosis. The antibodies may also interfere with normal functions of the cells without killing them. Type II is at the basis of many autoimmune diseases, where the body produces antibodies to destroy its own cells. Another example is hemolytic disease of the newborn, where maternal antibodies bind to D-antigen on the surface of fetal red blood cells and destroy them.
Type III hypersensitivity reactions are also mediated by IgM or IgG, but in this case, the antibodies bind to free-floating antigens, forming antibody-antigen complexes. The complement system is activated and inflammation results, causing damage to the affected tissue. A typical example is serum sickness, induced by a large amount of antigens in the blood. Immune complexes are deposited in the walls of blood vessels, triggering their inflammation, or vasculitis.
Type IV hypersensitivity is a delayed reaction, mediated by T-cells. Pre-sensitized T-cells are produced during a previous contact with the antigen. Upon re-exposure to the same antigen, T-helper cells release inflammatory cytokines, while T-killers induce cytotoxic reactions. Typical examples are allergic reactions to substances that come into direct contact with the skin, known as contact dermatitis. Type IV is also the basis of the tuberculosis skin test.

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The major players of humoral immunity are B-cells. They develop in the bone marrow and complete their maturation in the spleen. Similar to T-cells, B-cells are formed in billions of variations, each carrying a unique surface protein, called B-cell receptor, BCR. Just like T-cells, they also learn to not react to the body’s own antigens; those that react to self-molecules are eliminated or ignored. The majority of mature B-cells, namely the follicular B-cells, circulate to secondary lymphoid organs – the same locations as mature T-cells, where they expect encounters with pathogens. T-cells and B-cells are usually separated into defined T-cell and B-cell zones within these organs.
Here again, specific immunity relies on the invading pathogen finding a match among these many variations of B-cells. Only cells that can bind to the pathogen, can be activated to produce antibodies. B-cell surface receptors, BCRs, are actually membrane-bound antibodies. The existence of BCR variations means that the body already has all the antibodies it can possible make right from the start. For resource management purposes, it makes sense not to produce all of them in large quantities. Instead, presence of an invading pathogen selectively activates the binding B-cell, which then multiplies and produces huge amounts of that particular antibody to combat the pathogen.
An antibody is basically a protein whose structure consists of variable and constant regions. The variable regions give the antibody its uniqueness, much like the bit, or blade, of a key. This is where it binds to a specific antigen, which is the lock.
There are several classes of antibodies, differing in their constant regions. Different antibody classes engage different mechanisms to neutralize the antigen. The surface receptors on B-cells are IgM and IgD molecules.
Each B-cell has thousands of identical copies of BCR on its surface. When a pathogen binds, it usually binds to several of these receptors, linking them together, triggering endocytosis of the pathogen. B-cells then cut the pathogen into pieces and display them on MHC-II molecules on their surface. Thus, B-cells now become antigen-presenting cells, but are not yet activated. In most cases, activation of antigen-primed B-cells does not happen until they are stimulated by antigen-specific T-helper cells.
Nearby, in the T-cell zone, T-helper cells are activated by dendritic cells carrying antigens of the same pathogen, and become effector T-helper cells. Some of these effector cells leave lymph nodes for the site of infection, while other, namely the follicular helper cells, migrate to T-cell B-cell borders, and bind to the antigens presented by B-cells. This interaction triggers T-cells to produce helper factors, which activate B-cells.
Activated B-cells undergo first rounds of proliferation and differentiation, giving rise to the first batch of plasma cells producing antibodies, mainly of IgM class; and a group of cells that are committed to become memory B-cells. The latter undergo antibody class switching; and form a so-called germinal center, where they go through cycles of multiplication and hypermutation in the immunoglobulin gene. This process produces slightly different variations of the same antibody, which are then subject to a binding test to the same antigen. Those that no longer bind are discarded, while the remaining compete for binding to antigen-specific T-helper cells. B-cells with the highest affinity to the antigen win the interaction with T-helpers and exit the germinal center. They can either become long-lived memory B-cells, or differentiate into antibody-producing plasma cells. This second batch of plasma cells produces better antibodies and lives longer than the first batch. They also make antibodies of different classes (predominantly IgG), which neutralize the pathogen in many different ways.
Upon reexposure to the same pathogen, memory B-cells mount a much faster immune response. Plasma cells form within hours, producing huge amounts of the best possible antibody within days, destroying the pathogen so quickly that no signs of illness are noticeable.

The adaptive immune response, also known as acquired or specific immunity, is the body’s defense system tailored to target a specific pathogen. It has two branches: cellular or cell-mediated immunity, and humoral, or antibody-mediated immunity.
The major players of cellular immunity are T-lymphocytes. They develop in the thymus, for which they are named. During the process of maturation, billions of variations of T-cells are formed, each carrying a unique surface protein, called T-cell receptor, TCR. In addition, a population of T-cells, called helper T-cells, also has a receptor named CD4; while a second population, of cytotoxic T-cells, carries CD8 receptor. In the process of development, T-cells also learn to not react to the body’s own antigens; those that react to self-molecules are eliminated. Mature T-cells then migrate to lymph nodes and other lymphoid tissues, where they await exposure to pathogens.
Basically, specific immunity relies on the invading pathogen finding a match among these billions of T-cell variations. Only the ones that can bind to the pathogen, are selectively activated. T-cells, however, cannot bind free-floating pathogens. They can only bind to pieces of the pathogen bound to a certain host molecule called major histocompatibility complex, or MHC, on the surface of so-called “antigen-presenting cells”. There are two classes of MHC:
– MHC class I molecules are expressed by all nucleated cells of the body. These molecules are constantly produced in the cytoplasm and, on their way to the cell membrane, pick up pieces of peptides and display them on the cell surface. If a cell is infected by a virus or is cancerous, a foreign or an abnormal antigen is displayed; and the cell can bind and activate a matching T-cell. MHC-I only binds CD8 receptor, thus activating only cytotoxic T-cells.
– MHC class II molecules occur exclusively on professional antigen-presenting cells, of which dendritic cells are most effective. Resident dendritic cells on the site of infection swallow up pathogens, cut them into pieces, and display them on MHC-II molecules on their surface. These dendritic cells then migrate to the nearest lymph node, where they present the antigens to a matching T-helper cell, whose CD4 receptor binds to MHC-II.
Activation of T-cells, however, requires a second binding between the two cells. This is the verification step, a safeguard mechanism serves to prevent the immune system from overreacting.
Once activated, T-cells undergo repeated cycles of mitosis in a process called clonal expansion. This process produces clones of identical cytotoxic and helper T-cells, both of which are specific to the pathogen. Some of these cells differentiate into effector cells, while other become memory cells.
Most effector T-cells leave the lymph node for the bloodstream and are delivered to the site of infection, where they carry out immune attack against the pathogen. Helper T-cells produce interleukins which help with the activation of cytotoxic T-cells, B cells, and other immune cells. With such diverse functions, helper T-cells are central to adaptive immunity. Cytotoxic T-cells, on the other hand, are the main actors of cellular immunity. They release toxins and directly kill infected or cancerous host cells.
While effector cells die during or shortly after the infection, memory cells live for much longer periods of time. Some of them remain in lymph nodes, while other circulate the blood or migrate to peripheral tissues. Memory T-cells are also more numerous than the original naïve T-cells. Upon reexposure to the same pathogen, they can mount a much faster immune response, destroying the pathogen so quickly that no signs of illness are noticeable.
It is important to note the role of a third T-cell population, known as regulatory, or suppressor T-cells, in dampening the immune response when it’s no longer needed. Once the pathogen is cleared, regulatory T-cells downregulate the proliferation of effector T-cells, keeping the immune reaction from running out of control. They also help differentiate between self and non-self antigens, and thus preventing autoimmune diseases.