Immunology Flashcards
Hypersensitivity reactions
The hypersensitivity reactions can be memorized with the mnemonic ACID: A – Allergic/Anaphylactic/Atopic (Type I); C – Cytotoxic (Type II); I – Immune complex deposition (Type III); D – Delayed (Type IV)
Hypersensitivity reactions occur when the normally protective immune system responds abnormally, potentially harming the body. Various autoimmune disorders as well as allergies fall under the umbrella of hypersensitivity reactions, the difference being that allergies are immune reactions to exogenous substances (antigens or allergens), whereas autoimmune diseases arise from an abnormal immune response to endogenous substances (autoantigens). A symptomatic reaction only occurs in sensitized individuals, i.e., they must have had at least one prior asymptomatic contact with the offending antigen. Hypersensitivity reactions are commonly classified into four types. Type I hypersensitivity reactions are immediate allergic reactions (e.g., food and pollen allergies, asthma, anaphylaxis). Type II hypersensitivity reactions are referred to as cytotoxic, as they involve antibodies that are specific to particular tissues within the body and cause destruction of cells in these tissues (e.g., autoimmune hemolytic anemia, Goodpasture syndrome). Type III hypersensitivity reactions are immune complex-mediated, with tissue damage caused by antigen-antibody complex deposition (e.g., many vasculitides and glomerulonephritides). Type IV hypersensitivity reactions (e.g., TB skin tests, contact dermatitis) are delayed and cell-mediated and are the only hypersensitivity reaction that involves sensitized T lymphocytes rather than antibodies. Unlike true hypersensitivity reactions, which occur after sensitization, nonallergic hypersensitivity reactions (e.g., pseudoallergies) cause mast cell activation and histamine release after initial exposure to a trigger substance (e.g., radiocontrast media).
Define hypersensitivity reaction, allergy, autoimmune disease.
Definitions
Hypersensitivity reaction: a condition in which the normally protective immune system has a harmful effect on the body
Allergy: an abnormal immunological response to an otherwise harmless environmental stimulus (e.g., food, pollen, animal dander)
Autoimmune disease: an abnormal immunological response directed against an antigen that is actually part of the body itself
Stages
Sensitization: initial asymptomatic contact with an antigen
Effect: harmful immune response following sensitization and subsequent antigen contact
Types: Hypersensitivity reactions are classified into four types.
Type 1: Immediate hypersensitivity reaction.
Preformed IgE antibodies coating mast cells and basophils are crosslinked by contact with free antigen
Cell degranulation and release of histamine and other inflammatory mediators.
Allergic or anaphylactic transfusion reactions, e.g., in patients with IgA deficiency
Anaphylaxis
Drug reactions (e.g., penicillin, muscle relaxants)
Food allergies (e.g., nuts, shellfish, eggs, soy, wheat)
Insect venom allergies (e.g., bee, wasp)
Reactions to inhaled or other environmental allergens (e.g., dust mites, animal dander, pollen, latex ) → asthma, allergic rhinitis, atopy
Type 2 cytotoxic
IgM or IgG antibodies bind to antigens on the cells of particular tissue types
Complement system activation and lysis or phagocytosis of cells
Antibody-dependent cell-mediated cytotoxicity (e.g., by natural killer cells)
Antibody interference with normal cell function.
Acute hemolytic transfusion reaction Autoimmune hemolytic anemia Bullous pemphigoid Pemphigus vulgaris Rheumatic fever Drug-induced neutropenia and agranulocytosis Goodpasture syndrome Graves disease Hemolytic disease of the fetus and newborn Immune thrombocytopenia (ITP) Hyperacute transplant rejection Myasthenia gravis Pernicious anemia
Type 3: immune complex
IgG antibodies bind to antigens in circulation
Immune complex formation and deposition in particular tissues
Deposits in tissue activate the complement system and attract neutrophils
Neutrophilic lysis or phagocytosis of cells.
Arthus reaction Drug-induced hypersensitivity vasculitis Hypersensitivity pneumonitis Polyarteritis nodosa (PAN) Poststreptococcal glomerulonephritis, IgA nephropathy, membranous glomerulopathy, lupus nephritis Serum sickness Serum sickness-like reaction (atypical without circulating immune-complex involvement) Systemic lupus erythematosus (SLE)
Type 4: Delayed (T-cell mediated)
Contact of antigen with presensitized T lymphocytes
Presensitized CD4+ T cells recognize antigens on antigen-presenting cells → release of inflammatory cytokines
Presensitized CD8+ T cells recognize antigens on somatic cells → cell-mediated cytotoxicity.
Acute and chronic transplant rejection Contact dermatitis (e.g., nickel, poison ivy, cosmetics, rubber gloves) Drug reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) Graft-versus-host disease Mantoux tuberculin skin test for latent tuberculosis Candida skin test Multiple sclerosis Guillain-Barré syndrome* Hashimoto's thyroiditis* Rheumatoid arthritis* Type 1 diabetes mellitus* * Autoantibodies present
Type 1 hypersensitivity DR DEAC PIMP
D: Type I hypersensitivity reactions are referred to as immediate and include anaphylactic and atopic immune responses.
For the specific causes of type I hypersensitivity, see the overview of hypersensitivity reactions above.
R:
D: carcinoid, phaeochromocytoma, systemic mastocytosis, hereditary angioedema.
E:More common in europe, america, austrailia, very uncommon in africa and some parts of asia.
A:
C: Course
Immediate reaction: allergic reaction within minutes of contact with the antigen
Late-phase reaction: occurs hours after immediate reaction for a duration of 24–72 hours
Main symptoms: pruritus, edema, rash, rhinitis, bronchospasm, and abdominal cramping
Specific manifestations
Allergic conjunctivitis
Allergic rhinitis
Allergic asthma
Atopy: genetic predisposition to producing IgE antibodies against certain harmless environmental allergens (e.g., pollen, mites, molds, certain foods)
Associated conditions: asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, food allergies
Urticaria (hives): well-circumscribed, raised, pruritic, and erythematous plaques with a round, oval, or serpiginous shape; up to several centimeters in diameter (wheals); caused by mast cell activation in the superficial dermis
Angioedema: due to mast cell activation in the dermis and/or subcutaneous tissue
Anaphylaxis
P: Pathophysiology
IgE is formed as a result of prior sensitization (i.e., previous contact with the antigen) and coats mast cells and basophils.
Subsequent encounter with antigen results in an IgE-mediated reaction by preformed IgE antibodies: Free antigen binds to two adjacent IgE antibodies (crosslinking) → degranulation of cells
Release of histamine and other mediators (e.g., prostaglandin, platelet-activating factor, leukotrienes, heparin, tryptase) → lead to:
Increased smooth muscle contraction + peripheral vasodilation + increased vascular permeability → bronchospasm, abdominal cramping, and rhinitis → hypovolemia, hypoxia
Extravasation of capillary blood → erythema
Fluid shift into the interstitial space → edema, pulmonary edema
Pruritus
Eosinophil and neutrophil chemotaxis induced by basophil and mast cell mediators → eosinophilia.
Cross-reactivity :
Cross-reactivity
Individuals with allergies may also react to substances that contain particles that are similar to the main antigen.
Examples (primary allergen – cross-reactant allergen) [9][10]
Pollen – various foods (e.g., apple, hazelnut, carrot, kiwi, apricots, peaches)
Mites – crustaceans
Latex – exotic fruits (e.g., banana, avocado, kiwi)
Bird dander – egg yolk
Cat dander – pork
I: In vivo skin testing
General principle: Small amounts of allergens (e.g., pollen) are introduced into the skin to test for a local allergic reaction.
Higher sensitivity may be achieved with more invasive testing. However, the more invasive the test, the higher the risk of anaphylactic shock.
Test results are usually available after 20 minutes.
Evaluation: skin reddening and size of wheals
Skin prick test
Tiny amounts of various allergens are applied to the skin ; a lancet is then used to prick the surface of the skin so that allergen extracts may enter.
Positive result: wheal equal to or larger than histamine control (or greater than 3 mm) [11]
Scratch test: comparable to prick test; a scratch (about 1 cm) is made and the allergen subsequently applied
Intradermal test: intradermal injection of small amounts of the allergen on the back or arm
In vitro testing
Tryptase in serum (a relatively specific marker of mast cell activation): if elevated → increased risk of severe reactions
Allergen-specific IgE
Indicated in patients with known allergic triggers and clinical symptoms
Preferable to in vivo skin testing in patients in whom the risk of anaphylaxis is high with skin testing
Total IgE
Often elevated in patients with allergic conditions
Because normal levels of IgE do not exclude allergy, in vitro testing should not be used as a definitive test for allergy diagnosis.
Management: Treatment of type I hypersensitivity reactions depends on the etiology of the reaction (see the overview of hypersensitivity reactions above).
Urticaria : avoid offending agent (if known), H1-receptor blocker (e.g., cetirizine), glucocorticoids
Drug reactions
Mild reactions (mild urticaria/angioedema) may be treated by removing the offending drug and monitoring ± antihistamines.
Moderate reactions (more pronounced urticaria/angioedema) should be treated with withdrawal of the offending drug and antihistamines ± glucocorticoids.
Severe reactions require emergency resuscitation (see anaphylaxis).
Emergency (self‑) medication: Patients with known allergic reactions to food or insect venom, for example, may be provided with antihistamines, corticosteroids, and epinephrine auto-injectors for self-treatment (in patients at risk of anaphylaxis).
Allergen immunotherapy (desensitization)
Indication
Documented IgE-mediated allergy (e.g., allergic rhinitis, allergic asthma, allergy to wasp or bee venom) [12]
Significant symptoms and inadequate relief from symptomatic therapy and exposure prophylaxis
Significant symptoms despite symptomatic therapy and avoidance of the allergen
Method
Only available for some allergens but can be quite effective
Application of specific antigen in subclinical dose (subcutaneous, mucosal)
Slow escalation of dose
Goal: increased production of IgG antibodies instead of excessive IgE production (isotype switching)
Duration of treatment: at least 3 years
Prognosis
Success in up to ⅔ of patients
Younger patients see comparatively more benefits.
Higher success rates in patients with sensitivity to only one allergen (monovalent) as opposed to patients with sensitivity to many allergens (polyvalent).
Prevention
Breastfeeding: There is conflicting data regarding the beneficial effect of breastfeeding in preventing asthma and atopic dermatitis.
Contact prevention and avoidance of offending agents is the best treatment for allergies!
P:
Anaphylaxis- Dr Deac Pimp
D: Refers to a potentially life-threatening acute reaction, classically a type I hypersensitivity, involving the sudden release of mediators from mast cells and basophils.
May lead to circulatory failure (distributive shock).
Anaphylactic-like symptoms may also be caused by a pseudoallergic reaction (see pseudoallergy).
R:
D:
E:
A:
C: Symptoms: acute onset (within minutes to hours of exposure to a likely antigen)
Skin or mucous membranes: flushing, urticaria, pruritus, erythema, swelling of the eyelids, angioedema
Respiratory: nasal congestion, cough, sneezing, hoarseness, chest tightness, dyspnea (due to bronchospasm or laryngeal edema)
Cardiovascular: hypotension, tachycardia, chest pain (myocardial ischemia due to hypoxia and hypotension)
GI: abdominal pain, nausea, and vomiting (especially in food allergies).
P:
I:
M: reatment of anaphylaxis
Withdrawal of offending agent if possible (e.g., in drug reactions)
Airway: examination of airway and intubation if obstruction seems imminent
Epinephrine IM
Antihistamines
H1 antihistamine (e.g., diphenhydramine) IV for urticaria
H2 antihistamine (e.g., ranitidine) IV
Methylprednisolone
Positioning: The patient should be placed in a recumbent/supine position with elevation of the lower extremities.
O2 by facemask
If the patient is hypotensive: volume replacement – normal saline 1–2 L IV rapid bolus
Bronchospasm and no benefit of epinephrine: nebulized albuterol (salbutamol)
Continuous monitoring of blood pressure, heart rate, heart function, and pulse oximetry; urine output should also be monitored in hypotensive patients receiving resuscitation.
See also “Emergency (self‑)medication” in type I hypersensitivity reaction above.
Antihistamines and glucocorticoids should be administered in anaphylaxis only after the initial dose of epinephrine IM!
P:
Type 2 Hypersensitivity reaction pathophysiology
Overview
Type II hypersensitivity reactions are referred to as cytotoxic and play a role in several autoimmune diseases.
Clinical features, diagnostics, and treatment depend on the underlying etiology (see also overview of hypersensitivity reactions above).
Distribution of disease: often limited to a particular tissue type
Diagnosis may involve autoantibody testing (see antibody diagnosis of autoimmune diseases) and the Coombs test.
Pathophysiology
IgM and IgG bind to antigens on cells in the body mistakenly detected as foreign and cause:
Complement activation and Fc-mediated immune cell activation
Cellular lysis or phagocytosis
Opsonization → phagocytosis and/or complement activation
Complement-mediated lysis
Antibody-dependent cell-mediated cytotoxicity (NK cells or macrophages)
Inhibition or activation of the downstream signaling pathways.
Type II is cy-2-toxic.
Type 3 hypersensitivity reaction pathophysiology
Type III hypersensitivity reactions are referred to as immune complex reactions and include many glomerulonephritides and vasculitides.
Clinical features, diagnostics, and treatment depend on the underlying etiology (see also the overview of hypersensitivity reactions above)
Distribution of disease: systemic
Pathophysiology
Antigen (e.g., the molecules of a drug in circulation) binds to IgG to form an immune complex = antigen-antibody complex
Immune complexes are deposited in tissue, especially blood vessels → initiation of complement cascade → release of lysosomal enzymes from neutrophils → cell death → inflammation → vasculitis.
Serum sickness
Definition
Serum sickness is classically a type III hypersensitivity reaction appearing as a complication of antitoxin or antivenom administration.
Serum sickness-like reaction is much more common than actual serum sickness. Serum sickness-like reactions are:
Caused by medications or infections
Pathogenesis unclear: likely not the result of a type III hypersensitivity reaction
Difficult to distinguish from classic serum sickness, as they both present similarly (see “Clinical features” below).
Etiology
Antivenom or antitoxin containing animal proteins or serum (→ “serum” sickness)
Medications, most frequently antibiotics (e.g., penicillin, amoxicillin, cefaclor, trimethoprim-sulfamethoxazole)
Infections: Hepatitis B virus
Clinical features
Fever
Rash (urticarial or purpuric)
Arthralgias, myalgia
Headache, blurred vision
Abdominal pain, diarrhea, nausea/vomiting
Lymphadenopathy
Course
Symptoms appear 1–2 weeks following initial exposure.
They resolve within a few weeks of discontinuation.
Treatment: stop the offending agent
Prognosis: excellent once the offending drug is stopped or once the causative infection has resolved clinically
Arthus reaction
Definition: local subacute type III hypersensitivity reaction
Pathogenesis: antigen injected intradermally (e.g., immunization) → antibody formation → antigen-antibody complexes form in skin → local inflammation and possibly necrosis
Trigger: vaccination against tetanus, diphtheria
Clinical findings
Localized swelling, erythema, hemorrhage
Sometimes superficial skin necrosis within a few hours of booster vaccination
Reaction peaks 12–36 hours later.
Treatment:
Reaction is self-limited.
Symptomatic relief of swelling (e.g., cold compresses, limb elevation, NSAIDs)
Prevention [27][28]
After Arthus reaction to tetanus toxoid-containing vaccine: always observe a 10-year interval between tetanus toxoid-containing vaccines.
After Arthus reaction to diphtheria toxoid-containing vaccine: use of tetanus toxoid rather than Tdap vaccine
Type III means three things stuck together: antigen + antibody + complement
serum sickness
Serum sickness
Definition
Serum sickness is classically a type III hypersensitivity reaction appearing as a complication of antitoxin or antivenom administration.
Serum sickness-like reaction is much more common than actual serum sickness. Serum sickness-like reactions are:
Caused by medications or infections
Pathogenesis unclear: likely not the result of a type III hypersensitivity reaction
Difficult to distinguish from classic serum sickness, as they both present similarly (see “Clinical features” below).
Etiology
Antivenom or antitoxin containing animal proteins or serum (→ “serum” sickness)
Medications, most frequently antibiotics (e.g., penicillin, amoxicillin, cefaclor, trimethoprim-sulfamethoxazole)
Infections: Hepatitis B virus
Clinical features
Fever
Rash (urticarial or purpuric)
Arthralgias, myalgia
Headache, blurred vision
Abdominal pain, diarrhea, nausea/vomiting
Lymphadenopathy
Course
Symptoms appear 1–2 weeks following initial exposure.
They resolve within a few weeks of discontinuation.
Treatment: stop the offending agent
Prognosis: excellent once the offending drug is stopped or once the causative infection has resolved clinically
Arthus reaction
Arthus reaction
Definition: local subacute type III hypersensitivity reaction
Pathogenesis: antigen injected intradermally (e.g., immunization) → antibody formation → antigen-antibody complexes form in skin → local inflammation and possibly necrosis
Trigger: vaccination against tetanus, diphtheria
Clinical findings
Localized swelling, erythema, hemorrhage
Sometimes superficial skin necrosis within a few hours of booster vaccination
Reaction peaks 12–36 hours later.
Treatment:
Reaction is self-limited.
Symptomatic relief of swelling (e.g., cold compresses, limb elevation, NSAIDs)
Prevention [27][28]
After Arthus reaction to tetanus toxoid-containing vaccine: always observe a 10-year interval between tetanus toxoid-containing vaccines.
After Arthus reaction to diphtheria toxoid-containing vaccine: use of tetanus toxoid rather than Tdap vaccine
Type III means three things stuck together: antigen + antibody + complement
Type 4 hypersensitivity reaction pathophysiology
Overview
Type IV hypersensitivity reactions are referred to as delayed and cell-mediated.
For the specific causes of type IV hypersensitivity, see the overview of hypersensitivity reactions above.
Clinical features, diagnostics, and treatment depend on the underlying etiology.
4 Ts associated with the type IV hypersensitivity: T cells, Transplant rejection, TB skin tests, Touching (contact dermatitis).
Pathophysiology
T cell-mediated reaction
Sensitization: antigen penetrates the skin → uptake by Langerhans cell → migration to lymph nodes and formation of sensitized T lymphocytes
Eruption: repeated contact with antigen → secretion of lymphokines and cytokines (e.g., IFNγ, TNF α) by presensitized T lymphocytes → macrophage activation and inflammatory reaction in the tissue.
Examples:
Examples
Allergic contact dermatitis
Epidemiology
One of the most common dermatological diagnoses
Prevalence of ∼ 1–6%
Etiology
Poison ivy, poison oak, poison sumac (urushiol-induced contact dermatitis)
Nickel, cobalt, chromium
Perfumes, soaps, cosmetics
Latex or rubber gloves
Topical medications: hydrocortisone, topical antibiotics (e.g., neomycin), benzocaine
Course
First contact with allergen → sensitization
Repeated contact with allergen → development of a rash after 12–48 hours
Rash
Intensely pruritic, erythematous, papular
Vesicles and serous oozing in severe cases
Can spread to other parts of the body through antigen transfer by the hands or in the circulation
Diagnosis
Diagnosis is based on clinical findings.
Patch test: testing for specific allergens in allergic contact dermatitis
Allergen is fixed on a patch and then attached to the arm or back.
Reaction is recorded at two times: at 48 hours and 4–5 days following initial application
Positive result: erythema, papules, and vesicles under the area of contact
“Angry back” reaction
A few strong positive reactions may cause other patch tests to be falsely positive in patients with “angry backs.”
Mechanism unknown
Separate, sequential testing of allergens is necessary in these patients.[32]
Treatment
Avoidance of the allergen is the best treatment and preventative measure.
Acute phase
Mild to moderate cases: topical corticosteroids, oatmeal baths, soothing lotions (e.g., calamine), wet dressings (especially for oozing, crusting lesions), topical antihistamines
Severe cases: systemic corticosteroids, systemic antihistamines
Contact dermatitis due to poison oak, poison ivy, or poison sumac is the most likely cause in a patient presenting with itching, burning, red skin lesions arranged in a linear pattern appearing 24 hours after a camping trip.
Allergic contact dermatitisAllergic contact dermatitisUrushiol-induced contact dermatitisUrushiol-induced contact dermatitisEczema
Type IV drug reactions
Local drug reaction following topical application of drug; see allergic contact dermatitis above
Maculopapular or morbilliform (measles-like) drug eruption
Stevens-Johnson syndrome and toxic epidermal necrolysis
DRESS syndrome (drug rash with eosinophilia and systemic symptoms syndrome; also known as drug-induced hypersensitivity syndrome): delayed hypersensitivity reaction to a drug (within 1–8 weeks following administration)
Etiology
Allopurinol
Antiepileptic drugs (e.g., lamotrigine, phenytoin, carbamazepine)
Antibiotics (e.g., sulfonamide)
Clinical features
Fever
Pruritic morbilliform rash
Facial edema
Hepatomegaly
Diffuse lymphadenopathy
Possible multiorgan failure
Laboratory tests
Eosinophilia
Thrombocytopenia
Atypical lymphocytosis
Treatment
Drug withdrawal
Symptomatic: Corticosteroids are often used, but their effect is disputed.
Prognosis: fatal in ∼ 10% of cases
Nonallergic hypersensitivity
Pseudoallergy
Definition: an IgE-independent reaction that is clinically indistinguishable from type I hypersensitivity
Etiology: radiocontrast media, narcotics, vancomycin, NSAIDs
Pathophysiology
Substances cause direct (or complement-mediated in case of anaphylactoid reaction) mast cell activation and subsequent release of histamine not mediated by immunoglobulin.
In contrast to true anaphylactic reactions, no sensitization to allergens is required → First contact can already lead to anaphylactic shock.
Clinical presentation
Symptoms are dose dependent.
Urticaria, pruritus, edema, hypotension, or even symptoms of anaphylactic shock
Diagnosis and treatment
Minor reactions: Treat with avoidance of offending drug; give antihistamines for pruritus or urticaria.
Pseudoallergy with anaphylactic characteristics (see anaphylaxis)
Infection-induced urticaria
Etiology:
Viral (e.g., rotavirus and rhinovirus) or bacterial infections (esp. Mycoplasma pneumoniae and group A streptococcal pharyngitis).
Parasitic infections (e.g., Anisakis simplex infection from eating raw fish and Plasmodium falciparum)
Pathophysiology: mast cell activation and subsequent release of histamine, most likely IgE-independent
Clinical presentation: see urticaria
Diagnosis and treatment:
Clinical diagnosis: based on physical examination and patient history
Usually self-limited; antihistamines may be given for pruritus or urticaria
Clinical handbook, management of anaphylactic shock
Secure the airway, give 100% oxygen.
Remove the cause, raising the feet may help restore circulation.
Give adrenaline IM 0.5mg (i.e 0.5mL of 1:1000)
Tepeat every 5 min, if needed as guided by BP, pulse and respiratory function until better.
Secure IV access.
Chlorphenamine (antihistamine) 10mg IV and hydrocortisone (steroid) 200mg IV.
IVI , titrate against blood pressure.
Adrenaline is given IM not IV unless the patient is severely ill, or has no pulse. The IV dose is different: 100mcg/min-titrating with the response. If on a beta blocker consider salbutamol IV in place of adrenaline.
Route of adrenaline administration
Intramuscular
Epipen-300 micrograms, then 300 micrograms after 5-15 minutes.
Difference between food poisoning vs food borne infection
Foodborne illness is an infection or intoxication that results from eating food contaminated with viable (live) microorganisms or their toxins. Foodborne illness also includes allergic reactions and other conditions where foods act as a carrier of the allergen. Food poisoning is a form of foodborne illness and is caused by the ingestion of preformed toxins.
Food poisoning, or foodborne illness, occurs following the ingestion of food or water contaminated with bacteria, bacterial toxins, viruses, parasites, or chemical substances
Food allergies, Dr Deac Pimp
Food allergies are hypersensitivity reactions to allergens contained in food. They are the most common cause of anaphylaxis-related emergency admissions. Young children are commonly affected, usually beginning in the first two years of life. IgE-mediated reactions are the most common type and have an onset within minutes after ingestion. Clinical features include urticaria, angioedema, wheezing, rhinitis, and abdominal pain. Food intolerance on the other hand does not result in an immune reaction and usually only causes abdominal discomfort. A thorough patient history followed by a skin prick test or radioallergosorbent test (RAST) usually confirm the suspected allergen. Management includes desensitization, avoidance of triggers, treatment of symptoms, and, in the event of anaphylaxis, administration of epinephrine.
D:
R:
D: Infantile colic
Etiology
Unknown
Gastrointestinal (e.g., overfeeding or underfeeding, aerophagia, cow’s milk intolerance), biologic (e.g., increased serotonin levels, tobacco exposure, dysfunctional motor regulation related to immaturity), and psychosocial (e.g., exposure to stress) factors are suspected
Clinical features
Healthy and thriving infant
Paroxysmal episodes of loud and high pitched crying
Hypertonia (e.g., clenched fists) during episodes
Infant is not easily consoled
Diagnosis: crying that lasts ≥ 3 hours per day, ≥ 3 days per week, for ≥ 3 weeks in an otherwise healthy infant <3 months
Treatment
Reassurance
Trial of various feeding and soothing techniques
Intolerance reactions
Lactose and fructose intolerance
Celiac disease
E: Most common cause of anaphylaxis-related emergency admissions
5% of adults, 8% of children
Sex: ♂ > ♀ in children; ♀ > ♂ in adults
Age of onset: first and second year of life.
A: Hypersensitivity reaction against select ingredients in food
The most common food allergens are cow’s milk, eggs, nuts, peanuts , seafood (e.g., shellfish, fish), soy, wheat, fruits (e.g., kiwi).
C: Skin (most common): pruritus, urticaria, exanthem, angioedema, atopic dermatitis
Respiratory: rhinitis (often with sneezing), nasal congestion, dyspnea, wheezing, laryngeal edema
Gastrointestinal tract: oral allergy syndrome (oral pruritus, tingling numbness, and swelling of the lips, tongue, palate, and throat) , nausea, vomiting, abdominal pain, diarrhea
Cardiovascular: hypotension, tachycardia, dysrhythmias
CNS: headache
Non-IgE or mixed reactions are typically limited to the skin and the gastrointestinal tract.
Respiratory manifestations can be fatal!
P: Commonly IgE-mediated: Type I hypersensitivity reaction (immediate onset; within minutes to 2 hours of ingestion)
Mixed IgE/non-IgE-mediated and non-IgE-mediated reactions are also possible (delayed onset; hours to days after ingestion).
I: Patient history: determine type of food, time and amount of ingestion, and the type of reaction
Suspected IgE-mediated reaction
IgE skin prick test or RAST (radioallergosorbent test)
If above tests are inconclusive or suspected food is not a common allergen
Elimination diet
Oral food challenge: the effect of potential allergens on the mucous membranes is tested (the patient is given different foods that contain potential allergens to chew but not swallow in increasing doses over a fixed period of time). May be implemented after a positive elimination diet.
M:
Treatment
Avoid allergens and, in case of emergency, treat anaphylactic reactions (see treatment of anaphylaxis)
Oral immunotherapy is a novel approach, that is still being studied and not widely available.
P:The majority of children with milk and egg allergies will outgrow them by 5 years of age.
A lot of children with food allergies will develop asthma and allergic rhinitis.
Adult-onset food allergies usually remain for life.
Adrenaline MICA
in book
Grave’s disease
Type 2 hypersensitivity:
What normally happens is that the pituitary gland releases a hormone called TSH, which activates on the thyroid to cause the release of thyroxin. Then, the levels of thyroxin in the blood causes negative feedback, reducing the amount of TSH being produced. Occassionally, an immune response is generated against those receptors which causes long term stimulation of receptors with release of thyroxine, leading to excess levels of thyroxin in blood with no negative feedback. This results in disease or thyrotoxicosis, or graves disease.
Myasthenia Gravis
In the normal neuromuscular junction, nerve is activated, releases a neurotransmitter called acetylcholine which stimulates receptors on the post synaptic junction of the muscle cell, causing contraction of the muscle.
What may happen occasionally is that you may get an immune response directed against the post synaptic junction receptors. This blocks the nerve transmission, resulting in paralysis.
This is an example of myasthenia gravis, you get this ptosis, where the eyelid droops down, caused by this particular effect.
The antibodies may block or destroy nicotinic acetylcholine receptors at the junction between the nerve and the muscle.
Process of mast cell activation, degranulation, mediators release and clinical effects
Effector mediators produced by mast cells:
Early phase:
Histamine: increase vascular permeability, cause smooth muscle contraction.
leukotrienes: Increase vascular permeability, cause smooth muscle contraction, stimulates mucus secretion.
prostaglandins: Chemoattractants for T cells, eosinophils and basophils.
Late phase: Cytokines –> IL4, IL3: promote Th2, promotes IgE.
TnF-a: promotes tissue inflammation.
Mast cell activation: mast cell activation can cause different effects on different tissues:
-Mast-cell activation and granule release;
Gi tract: increased fluid secretion, increased peristalsis, expulsion of gastrointestinal tract contents (diarrhea, vomiting).
-Airways: decreased diameter, increased mucus secretion. Congestion and blockage of airways (wheezing, coughing, phlegm). Swelling and mucus secretion in nasal passages.
-Blood vessels: increased blood flow, increased permeability, increased fluid in tissues causing increased flow of lymph to lymph nodes, increased cells and protein in tissues, increased effector response in tissues.
Treatment of allergy in the clinic
Blockage of effector pathways:
inhibit effects of mediators on specific receptors
anti-histamine (block the histamine H1 receptor)
inhibit mast cell degranulation
mast cell stabilizer (e.g. chromoglycate)
inhibit synthesis of specific mediators
lipoxygenase inhibitors (e.g montelukast)
Steroids – Act directly on DNA to increase transcription of anti-inflammatory mediators (e.g. IL-10) and decrease transcription of pro-inflammatory mediators (e.g prednisolone)
Bronchodilators – Reverse acute effect of allergy on airways (e.g B2 agonist salbutamol)
Immunotherapy – Reverses the sensitisation to allergen by means of tolerising exposure
What is allergy?
Allergy is an inappropriate response to otherwise benign antigen
2 important phases:
Sensitisation – allergen presented by DC to Th2 CD4 T cells and B cells
Reaction – IgE on mast cells cross-linked by cognate antigen leading to inflammation
Simple model is that it is a Th2 disease
Case 1
- 25 year old man, noticed significant worsening of grass pollen hayfever type syndrome.
- took the intermittent antihistamine tablet
- no history of wheezing or asthma.
Advice:
-take a regular antihistamaine prophylactically. Antihistamines work best when start treatment just before the onset of symptoms. Once it is released, will link up with receptor, produce symptoms.
-steroid nasal sprays.
Management: make FC.
• Oral antihistamine (non-sedating, long acting)
e.g Loratadine, cetirizine
• Aqueous steroid nasal spray
Beclometasone (Beconase)
Fluticasone furoate (Avamys)commonly prescribed.
• Azelastine+ fluticasone (Dymista) nasal spraycombination of antihistamine and fluticasone, sometimes helps patient.
• Cromoglycate eye dropsfor eye symptoms.
• Olopatadine (Opatanol) eye drops
• Pollen avoidance measures (room; nasal filters, gel)
• Other non-validated ‘treatments’, close windows, different clothes from outside and inside as may have pollen on old clothes local honey, worms
More recently we have decided on pollen immunotherapy.
Only in very selected patients where optimal treatment has been tried and has failed to completely control the symptoms.
This treatment is usually offered by subcutaneous injections, over 3 years.
Immunotherapy: when optimal medical treatment fails to control symptoms (interferes with work, sleep etc)
• Subcutaneous injections (3 years)more for adults
Pollinex grass mix, Pollinex Trees etc
Alutard
• Oral/Sublingual route (3 years)particularly helpful in children, but often there is non-compliance, patients use it when they have symptoms, and then during winter months when they feel better, they often forget to take it.
Stallergenes
Oralvac
Grazax
Case 2:
30 year old film maker, who develops frequent episodes of a runny nose and bouts of sneezing,
Recently acquired a kitten.
Positive SPT to cat, negative to aeroallergens
What would you advise?
-immunotherapy after antihistamines and steroids. Immunotherapy has its own dangers, with grass and green pollens that have been tested numerously, the response is good with immunotherapy for severe symptoms which are uncontrolled with antihistamines and nasal sprays.
Some have had a wheeze attack after shots. Some get a bad allergic reaction with the next dose. Cold/flu.
Cat allergen, don’t offer it too easily, we prefer if patient can take max preventative measures.
-can you limit the cat to a certain part of house?
Management:
Take oral antihistamines, and steroids (not absorbed, or very tiny amounts absorbed, esp with spray and nasal treatments).
• Avoid exposure
• Wash the cat?
• Cat allergen 70% higher inside a home with pet cats - Why?
(Cats roam – difficult to confine them. Cat allergen Fel d1 has a tendency to persist
on carpets, furnishing etc)
• GM cats? -cost of producing a cat which does not produce the Ig1, turns out to be expensive, probably cost of small car. GM.
Case 3:
A 40 year old electrician noticed that whenever he was called to a house with cats, he developed streaming eyes, nasal dripping and bouts of sneezing. Tests confirmed positive result to cat and negative results to HDM and other aero-allergens. He took a tablet of loratadine (a long acting, non-sedating antihistamine) before home visits, and used nasal sprays, with only partial control of his symptoms.
He was concerned that his symptoms were affecting his ability to earn his living. What advice can you offer him?
Advice:
-offer him immunotherapy?
-first make sure he is taking antihistamine in correct dosages.
-doubling dose, esp if he is a big man.
-esp non-sedative.
-double the dose, fairly big man.
If he has tried all of tat, and taken nasal spray, and it is really affecting his quality of life, then we would be more inclined to offer him immunotherapy.
-But make sure he is aware of the side effects, and we will monitor him really closely.
Immunotherapy:
-allergen (Fel-d1), over a three year period.
Start with low dose, gradually increasing dosage weekly.
What is immunotherapy?
Immunotherapy:
-allergen (Fel-d1), over a three year period.
Start with low dose, gradually increasing dosage weekly.
Injection immunotherapy using standardised Cat allergen (Fel-d1), aftr informed consent.
Start with low dose.
Incremental weekly increase in dose until maintenance dose is reached.
Maintenance dose: monthly for 3 years.
Keep under observation for allergic symptoms for at least 50 minutes after the injection.
KUP and monitor PEFT before and after the injection.
Every Monday when they come for shots, check if they have any underlying conditions, fever, flu. Even a cold, can make side effects worse.
Immunotherapy can have very serious side effects.
Particularly, cat immunotherapy, and we are very cautious and prescribe it only when appropriate.
