| How is pathophysiology of type I HS? | The “classic” allergies are Type I HS reactions.
➢ Type I (Anaphylactic, Atopic or Immediate) HS can be
caused by the body’s response to a foreign substance.
➢ It involves immunoglobulin E (IgE) mediated release of
antibodies against a soluble antigen
Divided into 3 phases; Phase 1 (Sensitisation), Phase 2 (Activation), Phase 3 (Effector)
➢ The allergens that result in a type I HS may be harmless
(i.e., pollen, mites, or foods, drugs, etc.) or more hazardous such as insect venoms
➢ Regardless of the allergen, the first exposure activates a
primary IgE antibody response that sensitizes an individual to type I HS reaction upon subsequent exposure |
| How is allergen sensitization in HS type I? | Mast cells and basophils coated by IgE antibodies are
"sensitised. |
| How do S&S of immediate HS reaction occur? | ➢ On subsequent exposure, allergens bind to multiple IgE molecules on mast cells, cross-linking the IgE molecules.
➢ Within minutes, this cross-linking of IgE activates the mast cells and triggers degranulation; a reaction in which the contents of the granules in the mast cell are released into the extracellular environment.
➢ The chemical mediators released by mast cells collectively cause the inflammation and signs and symptoms associated with type I HS reactions |
| How is effector phase of T1HS? | Effector phase includes all the body’s complex reactions
to the potent chemicals from the granules
Preformed components that are released from granules
include histamine, serotonin, and bradykinin.
Selected Preformed Components of Mast Cell Granules include:
Heparin (stimulated bradykinin: increased vascular permeability, vasodilation, bronchiole constriction, mucus)
Histamine (smooth muscle contraction, vascular permeability, mucus and tears)
Serotonin (vasodilation and smooth muscle contraction)
Also release lipid mediators (LT and PG) and cytokines (TNF) have potent local effect cause vascular leak, muscle contraction and movement of granulocytes. |
| How are S&S of Type I HS caused by different mast cell mediators? | The chemical mediators released by mast cells collectively cause the inflammation and signs and symptoms associated with type I HS reactions.
Histamine (mucus secretion and tear formation, itching and sneezing (action on nerves), vasodilation (hives, headache, angioedema, hypotension))
Bronchiole constriction (wheezing, dyspnea, coughing, and cyanosis)
vomiting (due to cerebellum stimulation by serotonin and histamine)
Smooth muscle relaxation (Intestinal)
Type I Immediate HS reactions are mediated by IgE, but
T and B cells play important roles in the development of
these antibodies. (primary cells are mast cells and eosinophils) |
| How are mast cells triggered? | ➢ Many diseases can be caused by non-specific, IgEindependent mast cell activation, which might be considered
as subtype of type I HS reaction
➢ Mast cells may be triggered by other stimuli such as
– Exercise,
– Emotional stress,
– Chemicals,
– Drugs (iodinated contrast media, biologic medicines,
opiates,…)
– Anaphylotoxins (e.g., C4a, C3a, C5a, etc.).
➢ These reactions are not HS reactions although they
produce the same symptoms. |
| How is presentation of allergic reactions? | Allergic reactions (IgE-mediated reactions ) can occur as;
Immediate reactions,
late-phase reactions,
or chronic allergic inflammation
➢ Type I is first and fast. Once the mast cells and/or basophils have released their chemicals, the allergic reaction occurs rather quickly. This part of the reaction is called the immediate reaction.
➢ Responses usually occur within 15-30’ from the time of
exposure to the antigen but can be extremely quick
(within minutes) and dramatic as in anaphylaxis |
| How is type I HS based on location? | ➢ Type I HS reactions can be either localized or systemic. Localized type I HS reactions include hay fever rhinitis, hives, and asthma.
Systemic type I HS reactions are referred to as anaphylactic shock.
➢ Although anaphylaxis shares many symptoms common
with the localized type I HS reactions, the swelling of the
tongue and trachea , blockage of airways, dangerous
drop in blood pressure, and development of shock can
make anaphylaxis especially severe and life-threatening.
➢ In fact, death can occur within minutes of onset of signs
and symptoms |
| How is late onset Type I HS? | ➢ In some cases, a late onset reaction may occur after
allergen exposure and the acute response. The immediate allergic reaction caused by mast-cell degranulation is followed by a more sustained inflammation, known as the Late-phase reaction (LPR).
➢ This late response involves the recruitment of other
effector cells, notably TH2 lymphocytes, eosinophils, and
basophils, which contribute significantly to the immunopathology of an allergic response
➢ LPR occurs hours after immediate reaction. It generally peaks at about 6–12 h and subsides at about 24 h. The LPR can last hours to days (24-72 hours).
➢ Signs and symptoms of delayed or late-phase allergic
reactions are generally the same as those for immediate
allergic reaction |
| How is combination of immediate and Late phase HS? | The immediate and late phase reactions together combine to form a severe allergic response. Activation of the recruited cells leads to the release of more chemical mediators that cause tissue damage and late-phase symptoms of swelling and redness of the skin, coughing, wheezing, and nasal discharge.
➢ Continuous or repeated exposure to an allergen can
result in chronic allergic inflammation.
➢ Tissue from sites of chronic allergic inflammation
contains eosinophils and T cells (particularly TH2 cells)
➢ Eosinophils can release many mediators, which can cause tissue damage and thus increase inflammation.
➢ Collectively, this results in structural and functional
changes to the affected tissue.
➢ When a pre sensitized individual is exposed to
an allergen, it can lead to a rapid immune response that
occurs almost immediately |
| How is manifestation of type I HS? | The reaction may be manifested in different areas of the body
– Skin (urticaria, eczema),
– Mucosa of mouth/throat/tongue (angioedema),
– Eyes (conjunctivitis),
– Nasopharynx (rhinorrhea, rhinitis),
– Bronchopulmonary tissues (asthma),
– Gastrointestinal tract (gastroenteritis) food allergy and
– or multiple organs (anaphylaxis)
causing symptoms ranging from minor itching and
inflammation to death |
| How is skin and mucosal allergies? | Urticaria is characterised by weals (hives) ==> pale central area surrounded by redness and swelling or angioedema (swellings in 10%) or both in 40%
Weals (wheals) or hives are generally raised, circumscribed, erythematous papules and plaques (that blanch with pressure), involving the dermis and epidermis, and classically have a central area of pallor, often round in shape and of variable size, Outbreaks that may occur anywhere on the skin are usually very itchy (it may have a burning sensation) and transient; It lasts from a few minutes to 24 hours.
Urticaria/angioedema:
According to level of mast cell degranulation clinical signs
are superficial (Urticaria) or deep swelling
(Angioedema) |
| What are the types of urticaria? | There are classically 2 main types of urticaria:
– Immunological urticaria which essentially depend on the
synthesis of IgE antibodies (Type I reactions in
immunological urticaria are by far the most common), and
– Non-immunological urticaria, the most frequent, totally
independent of a specific humoral or cellular immune
response.
Causes: IgE mediated [allergens], Non-IgE mediated [diseases], Non-immunological [temperature, light, meds] |
| How is history of urticaria? | Information regarding history of previous urticaria and
duration of rash and itching is useful for categorizing
urticaria (with or without angioedema) as acute or
chronic;
Acute urticaria– Urticaria that recurs within a period of
less than six weeks is acute (can be allergic) or
Chronic urticaria –in rarer cases, where the rash comes
and goes or persists for more than 6 weeks, often over
many years |
| What are causes of acute urticaria? | Acute urticaria that is more common in children, may
appear early after exposure (perhaps minutes) and can
last several weeks.
For acute urticaria, ask about possible precipitants, such
as the following:
Foods, drugs, IV radiocontrast, travel, infection, perfumes, detergents, pets, Fire and stings, pregnancy, contact with latex, sun/cold exposure, exercise, alcohol (most common is food, meds, infections and latex)
NOTE food could cause IgE mediated true allergy or non immunoliogical (pseudoallergens) should occur directly after eating (questionable after 3-6 hours
Meds rarely cause IgE mediated (usually non-immuno) some do both mechanisms (Abx) |
| How is presentation of urticaria? | ➢ Acute urticaria is most often a single episode and quickly resolving. No further examination is necessary.
➢ It is necessary to look for a triggering element in the hours preceding the eruption.
➢ Allergic urticaria and/or angioedema are rare, and always arise on a mode acute (rare cause of acute urticaria) and not chronic.
➢ All urticarias are acute initially. Some will become
chronic after a period of time that is usually defined as
6 weeks or more. The condition is considered chronic
hives (more common in adults) and recur frequently over
months or years.
➢ The etiologic agent is more likely to be identified in acute
urticaria (40-60%) than in chronic urticaria (10-20%).
Cause of chronic urticaria can be similar to acute but includes also infections, hormonal disorder, autoimmune, tumors, unknown cause 90% more frequent in girl 70% |
| What is chronic spontaneous urticaria? | ➢ Chronic spontaneous urticaria (CSU) refers to urticarial
lesions arising spontaneously, occurring on most days of
the week for six weeks or more.
➢ CSU is a common condition that has a lifetime prevalence rate of around 1.8% of the general population
➢ This disorder, whose subjects need not be atopic
individuals; is typically diagnosed when chronic hives and
swelling (associated angioedema occurs in about 40
percent of patients) do not appear to be associated with
any other systemic disease process and are not due to
one of the physically induced urticaria
Workup very limited strong association with thyroid autoimmune diseases (24% have thyroid autoantibodies)
Avoid aspirin and NSAIDs (aspirin exacerbated cutaneous disease) |
| How is aspirin exacerbated cutaneous disease? | Drugs inhibit COX1 pathway resulting in overproduction of LTs, so selective COX2 inhibitors are better.
Cause angioedema alone (vasodilation, exudation of plasma into deeper tissue than simple urticaria, non pitting edema, non pruritic, occur on mucosal surfaces and respiratory tract or GI, may cause voice changes) |
| How is japanese classification of angioedema? | ز |
| How is drug angioedema classification? | . |
| What are different drugs reactions causing angioedema alone? | ➢ Aspirin and other NSAIDs are other common causes of
angioedema generally involving the face.
➢ Responses to the NSAIDs may be complex with mixed
cutaneous and respiratory symptoms.
➢ Unlike anaphylaxis, anaphylactoid reactions are most
likely related to inhibition of (cyclooxygenase) COX-l by
NSAIDS and leukotriene production
➢ ACE inhibitors cause a higher rate of angioedema in
black patients than in non-black patients.
➢ Angioedema to ACE inhibitors usually occurs within the
first week of treatment (may be within days, months, or
even years of the treatment) and the drug should be
withdrawn immediately in the patients who experience a
reaction
ARBs similar to ACEi <10% |
| What is hereditary angioedema? | ➢ Hereditary Angioedema (HAE) is a very rare and
potentially life-threatening genetic condition, autosomal
dominant disorder (AD) of C1 inhibitor (C1-INH), that
occurs in about 1 in 10,000 to 1 in 50,000 people
➢ Although named after its complement inhibitory activity,
C1-inhibitor is the most important physiological inhibitor
of plasma kallikrein
➢ People who have HAE have low levels of C1 esterase inhibitor in their body.
➢ HAE results from excessive production of bradykinin
due to deficiency of C1 esterase inhibitor
Sx (edema of body, excruciating abdominal pain, nausea, vomiting, intestinal wall swelling, airthroat swelling dangerous) |
| What are types of angioedema? | ➢ Angioedemas can be divided into two categories according to their etiology: angioedema linked to substances released by mast cell degranulation and angioedema caused mainly by bradykinin
➢ Angioedema resulting from mast cell degranulation is
typically associated with urticaria. These are angioedema
whose origin is primarily allergic or anaphylactoid and
probably a large part of idiopathic recurrent angioedema.
➢ Angioedema of which bradykinin is the main mediator are not associated with urticaria. These are angioedema linked to taking angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonists, hereditary angioedema |
| What are labs and workup for angioedema? | ➢ Laboratory studies may be helpful, as follows:
– Acute urticaria- Laboratory studies generally are not
indicated
– Chronic or recurrent urticaria (>6 wk) - Basic laboratory
studies should include complete blood count (CBC),
erythrocyte sedimentation rate (ESR), thyroid-stimulating
hormone (TSH), and antinuclear antibody (ANA)
➢ Other studies that may be considered include the
following:
– Imaging studies - Generally not indicated unless suggested
by a specific symptom or sign
– Punch biopsy - If urticarial vasculitis is suspected |
| What is allergic rhinitis? | ➢ Release of these mediators in the upper respiratory tract
can result in sneezing, itching, nasal congestion,
rhinorrhea, and itchy or watery eyes.
➢ Non allergic rhinitis doesn't usually cause itchy nose, eyes or throat — symptoms associated with allergies such as
hay fever (allergic rhinitis).
➢ Triggers of nonallergic rhinitis symptoms vary and can
include certain odors or irritants in the air, changes in the
weather, some medications, certain foods, and chronic
health conditions.
➢ A diagnosis of nonallergic rhinitis is made after an allergic cause is ruled out. |
| What is allergic asthma? | ➢ Release of these mediators in the lower respiratory tract
can cause bronchoconstriction, mucus production, and
inflammation of the airways, resulting in chest tightness,
shortness of breath, and wheezing |
| What is ASA-induced asthma? | ➢ Aspirin-Exacerbated Respiratory Disease (AERD) is a
respiratory condition consisting of three factors – asthma, recurring nasal polyps, and a sensitivity to aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, naproxen or diclofenac
➢ AERD often associated with rhinosinusitis and nasal polyps is due to cyclooxygenase inhibition and leukotriene production.
➢ The disease is not caused by taking Aspirin or NSAIDs, but sinus or asthma symptoms get worse when taking these medications
➢ It is well-established that following ingestion of aspirin or any other inhibitor of cyclooxygenase-1, patients with Samter’s disease or AERD develop the sudden onset of worsening respiratory clinical symptoms, which usually involves nasal congestion, rhinorrhea, wheezing and bronchospasm.
➢ Gastrointestinal distress, nausea, a pruritic rash and angioedema can also occasionally develop. |
| How is atopy (type I HS immediate)? | ➢ Type I HS include atopic diseases, which are an
exaggerated IgE mediated immune responses (i.e., allergic: asthma, rhinitis, conjunctivitis, and dermatitis), and allergic diseases, which are immune responses to foreign allergens (i.e., anaphylaxis, urticaria, angioedema, food, and drug allergies).
➢ Atopy is defined as “a genetic predisposition toward the development of immediate HS reactions (to make IgE) against common environmental antigens (allergen)”.
➢ There are certain risk factors that increase the risk of allergic diseases. These factors include geographical distribution, environmental risks such as pollution or socioeconomic status, genetic predisposition, or the “hygiene hypothesis”.
➢ Hygiene hypothesis proposes that childhood exposure to antigens from a diverse range of microbes leads to a better-functioning immune system later in life.
➢ The lack of early challenges to the immune system by organisms may result in failures in immune system functioning later in life |
| What does type I HS include? | ➢ Type I HS include atopic diseases, which are an exaggerated IgE mediated immune responses (i.e., allergic: asthma, rhinitis, conjunctivitis, and dermatitis), and allergic diseases, which are immune responses to foreign allergens (i.e., anaphylaxis, urticaria, angioedema, food, and drug allergies).
➢ The development of food allergy is multifactorial, and there is a complex interplay between environmental factors that may contribute to the risk of food allergy.
➢ While there is strong evidence to support the early
introduction of allergenic solids to reduce the risk of food
allergy, early introduction alone is unlikely to be sufficient to prevent all food allergy.
➢ The Dual-allergen exposure hypothesis suggests that
early life exposure to allergens through the skin causes Tcell skewing towards allergic type Th2 cells (IL-4, IL-5, IL13) and subsequent food allergy, whereas early oral
exposure causes T-cell skewing towards tolerance
(subsets of Th1 and Treg IFNg, TNFa, IL-10, TGFb) |
| How is food cross-reactivity? | ➢ Cross-reactivity
Individuals with allergies may react to substances that contain particles that are similar to the main antigen.
Examples (primary allergen – cross-reactant allergen)
• Bird dander – egg yolk [The Bird –Egg Syndrome]
• Pollen – various foods [oral allergy syndrome; OAS]
• (e.g., apple, hazelnut, carrot, kiwi, apricots, peaches)
• Mites – crustaceans
• Latex – exotic fruits (e.g., banana, avocado, kiwi)
• Cat dander – pork
➢ Food allergies make up the majority of allergies today.
➢ Food allergies occur in 1-2% of adults and in 8% of children under 6 years of age
Sx (skin, GI, RT, severe anaphylaxis 50%)
Typically IgE mediated but some are non or mixed (up to 2 hours from food ingestion, some have prolonged effect) |
| How is prevalence of food allergies? | ➢ Any food can cause allergy but overall only a few foods account for the vast majority of allergies.
➢ Despite the prevalence varying from country to country, food allergies are predominantly triggered by the “Big Eight”; referring to milk, egg, tree nut, peanut, soy, wheat, fish and shellfish.
➢ These account for 90% of all food-induced allergic reactions
➢ In children under the age 2, 90 percent of the incriminating foods are cow’s milk, eggs, legumes (such
as peanuts, which are not nuts) and soy.
➢ In adults, fish, shellfish, fruits, and tree nuts might be
added to the list. |
| How does food tolerance occur? | ➢ Clinical tolerance develops to most food allergens over
time, except for peanuts, nuts, and seafood; allergy to
peanut, tree nuts, fish, and shellfish are generally
lifelong, although 20% of individuals may outgrow
peanut allergy.
➢ Children with low levels of peanut-specific IgE should be
re-examined to determine whether they have outgrown
their allergy |
| How is dx of food allergies? | ➢ Allergy testing can help confirm or rule out allergies,
reducing adverse reactions and limiting unnecessary
avoidance and medications.
➢ For assessing the presence of allergen-specific IgE antibodies, we can use two different methods:
➢ ELISA test for IgE detect specific IgE antibodies, to determine the substances a subject is allergic to.
➢ This is different from a skin allergy test, which determines allergy by the reaction of a person's skin to different substances.
➢ Non–IgE-mediated and mixed IgE- and non–IgEmediated food allergies present with their symptoms
several hours after the ingestion of the food.
➢ Because the symptoms are usually delayed as compared to IgE mediated food allergy it is more difficult to make the association between offending food and the
symptoms |
| How is classification of non-IgE mediated food allergies? | can vary by system (GI-cutaneous) |
| What are disorders of non-IgE mediated raections to food? | . |
| What is food intolerance? | ➢ It is important to note that food intolerance is different
from food allergy.
➢ Food allergies trigger the immune system (it is
immunological hypersensitivity reaction), while food
intolerance does not.
➢ Food intolerance, also known as non-allergic food
hypersensitivity, refers to difficulty in digesting certain
foods
➢ A food intolerance response takes place in the digestive
system. It occurs when we are unable to properly
breakdown the food.
➢ This could be due to enzyme deficiencies, sensitivity to
food additives or reactions to naturally occurring
chemicals in foods |
| How are sx of food intolerance? | ➢ It can be difficult to determine whether the patient has a
food intolerance or an allergy because the signs and
symptoms often overlap
➢ The symptoms of food intolerance generally take longer
to emerge, compared to food allergies.
➢ Onset typically occurs several hours after ingesting the
offending food or compound and may persist for several
hours or days. In some cases, symptoms may take 48
hours to arrive
➢ Food intolerance symptoms are generally less serious
and often limited to digestive problems.
➢ Food intolerance may manifest with the inability to
adequately digest the Gluten in wheat, cow’s milk sugar
Lactose, Fructose found in fruit juices (gluten most common) |
| How is lactose intolerance? | A nonallergic reaction that typifies food intolerance
would be an acute gastrointestinal response in a lactoseintolerant individual.
This patient does not have the enzyme lactase and,
therefore, cannot break down sugar lactose in milk and
other foods into glucose and galactose
The lactose arrives as is in the large intestine where it is
fermented by bacteria. Profound diarrhea or vomiting
usually results without any other system involved.
Food avoidance is the treatment of choice, as it is with
food allergy, and over time, food intolerance may
resolve. |
| What are chemical causes of food intolerance? | ➢ Chemical causes
Certain chemicals in foods and drinks can cause
intolerance, including amines in some cheeses, and
caffeine in coffee, tea, and chocolates.
Some people are more susceptible to these chemicals
than others
➢ Processed meat can contain nitrates that are the source
of some people's food intolerances
➢ Exclusion diets are extremely useful in isolating the
culprit foods.
In a typical exclusion diet, the suspected food is removed
from the diet for a set period, usually between 2 weeks
and 2 months.
If during this period the adverse reactions resolve, it
becomes more likely that the culprit has been found |
| What is anaphylaxis? | ➢ Anaphylaxis is a severe allergic reaction that starts
suddenly, affects many body systems and may cause
death.
➢ The pathophysiology of anaphylaxis is clinically defined
by the physiological effects of the immediate-phase and
late-phase mediators on the target organs
➢ By definition, anaphylaxis involves the cardiovascular,
respiratory, gastrointestinal, or epidermal system; in
most cases, multiple organs are involved.
➢ These symptoms typically come on over minutes to
hours. systemic vasodilation and permeability cause hypotension (most common cause of death is anaphylactic shock, second is throat swelling and asphyxation |
| How is anaphylaxis dx? | . |
| How is anaphylaxis tx? | Treament for immediate hypersensitivity diseases (3 As):
– Avoidance of the allergen, and give
– Antihistamines (occasionally steroids) and
– Allergen-specific immunotherapy
Several antagonistic drugs are used to block the action
of allergic mediators or to prevent activation of cells and
degranulation processes.
➢ These include antihistamines, glucocorticoids, and
epinephrine (adrenaline).
Epinephrine counteracts, rather than blocks as
antihistamines do, the effects of histamine and it is
most effective in treating anaphylaxis
Patients at high risk for anaphylaxis, such as beekeepers, should get an epinephrine auto-injection kit |
