PRESENTER – DR. ASHRAY . V

ANAPHYLAXIS , ALLERGIC REACTIONS AND ANGIOEDEMA

DEFINITION In simple terms, "anaphylaxis is a serious allergic

reaction that is rapid in onset and may cause death.“

anaphylaxis is the term now used to refer to both IgE and non-IgE reactions (e.g., IgE-independent, IgG- and immune complex complement–mediated).

CLINICAL CRITERIA FOR ANAPHYLAXIS: 1) Acute onset of an illness (minutes to several hours) with involvement of

the skin and/or mucosal tissue (e.g., hives/urticaria, pruritus, flushing, swollen lips, tongue, or uvula) associated with at least one of the following:

i) Respiratory compromise (e.g., dyspnea, wheeze, stridor, etc.) or ii) Reduced blood pressure

or iii) Associated symptoms of organ dysfunction (e.g., hypotonia, syncope, incontinence, etc.)

2) Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): Involvement of the skin and/or mucosal tissue Respiratory compromise. Reduced blood pressure or associated symptoms Persistent GI symptoms (e.g., cramps, vomiting).

3) Anaphylaxis should be suspected when patients are exposed to a known allergen and develop hypotension

CAUSES OF ANAPHYLAXIS

1) DRUGS : Beta Lactam antibiotics , Acetylsalicylic acid , Trimethoprim-sulfamethoxazole , Vancomycin, NSAIDs , any other drugs.

2) FOODS AND ADDITIVES : Soybeans, peanuts , Wheat , Milk , eggs , Mango’s, Food containing Sulfites.

3) BITES : Hymenoptera stings (Bees , wasp’s) ,

4) RADIOGRAPHIC CONTRAST MATERIAL

5) LATEX ALLERGY : Surgical gloves .

6) VACCINES : D.P.T , MMR , Hepatitis – B .

The lifetime individual risk of anaphylaxis is presumed to be 1% to 3%, with a mortality rate of 1%.

In India, antibiotics, radiocontrast agents and anesthetic agents are considered major causes of anaphylaxis, and blood products, insulin and growth hormones are also mentioned (Ref – WORLD ALLERGY ORGANISATION website http://www.worldallergy.org/wao_societies/aboutwao.php).

PATHOPHYSIOLOGY AND MECHANISM Anaphylaxis is believed to arise from the activation of mast cells and

basophils generally involving crosslinking of IgE and aggregation of the high-affinity receptors for IgE.

Upon activation, mast cells and/or basophils quickly release preformed mediators from secretory granules like histamine, tryptase, carboxypeptidase A, and proteoglycans.

Downstream activation of phospholipase A2, followed by

cyclooxygenases and lipo-oxygenases, produces arachidonic acid metabolites, including prostaglandins, leukotrienes, and platelet-activating factor.

The inflammatory cytokine, tumor necrosis factor- is released as a preformed mediator, and also as a late-phase mediator with other cytokines and chemokines.

Many of these mediators are believed responsible for the pathophysiology of anaphylaxis.

MEDIATORS OF ANAPHYLAXIS Histamine : stimulates vasodilation and increases

vascular permeability, heart rate, cardiac contraction, and glandular secretion.

Prostaglandin D2 : is a bronchoconstrictor, pulmonary and coronary vasoconstrictor, and peripheral vasodilator.

Leukotrienes : produce bronchoconstriction, increase vascular permeability, and promote airway remodeling.

Platelet-activating factor : is also a potent bronchoconstrictor and increases vascular permeability.

Tumor necrosis factor: activates neutrophils, recruits other effector cells, and enhances chemokine synthesis.

CLINICAL FEATURES Early Symptoms - pruritus, cutaneous flushing, and urticaria ,

sense of fullness in the throat, anxiety, a sensation of chest tightness, shortness of breath, and light-headedness.

As the cascade progresses, decreased level of consciousness,

respiratory distress, and circulatory collapse may occur. In its severest form, loss of consciousness and cardiorespiratory arrest may occur. A complaint of a "lump in the throat" and hoarseness indicates life-threatening laryngeal edema in a patient with symptoms of anaphylaxis.

In the vast majority of patients, signs and symptoms begin suddenly, often within 60 minutes of exposure.

In general, the faster the onset of symptoms, the more severe the reaction, as evidenced by the fact that one half of anaphylactic fatalities occur within the first hour.

There is a risk of recurrence of symptoms and the exact incidence is not known but it has been reported in 3% to 20% of patients.

The Recurrence is caused by a second phase of mediator release, peaking 4 to 8 hours after the initial exposure and exhibiting itself clinically 3 to 4 hours after the initial clinical manifestations have cleared.

The late-phase allergic reaction is primarily mediated by the release of newly generated cysteinyl leukotrienes, the former slow-reacting substance of anaphylaxis.

DIAGNOSIS

The diagnosis is easily made if there is a clear history of exposure, such as a bee sting, shortly followed by the multisystem signs and symptoms .

Unfortunately, diagnosis is not always easy or clear, because: Symptom onset may be delayed, symptoms mimic other presentations (e.g., syncope, gastroenteritis, and anxiety), or anaphylaxis may be a component of other diseases (e.g., asthma).

And in most cases , like as in food allergy, the inciting substance may not be known.

DIFFERENTIAL DIAGNOSIS FOR ANAPHYLAXIS : Vasovagal reactions myocardial ischemia, arrhythmias, status asthmaticus, Seizure, Epiglottitis, Hereditary angioedema, Foreign body airway obstruction, Carcinoid Vocal cord dysfunction, Non–IgE-mediated drug reactions.

The most common anaphylaxis imitator is a vasovagal reaction, which is characterized by hypotension, pallor,

bradycardia, diaphoresis, and weakness, and sometimes by syncope.

MANAGEMENT AND TREATMENT

FIRST LINE THERAPY Emergency management starts with the ABC’s (airway, breathing, circulation) of resuscitation. Vital signs, IV access, oxygen administration, cardiac monitoring, and pulse oximetry measurements should be done immediately.

AIRWAY MANAGEMENT : Check for signs and symptoms of angioedema e.g., uvula edema , audible stridor, respiratory distress, hypoxia. Intubation should be done early when angioedema is causing respiratory distress to prevent complete airway obstruction.

DECONTAMINATION : exposure to the causative agent needs to be terminated . Sting remnants need to be removed in cases

of insect stings to prevent further envenomation .

EPINEPHRINE IN ANAPHYLAXIS Epinephrine is the drug of choice and the first drug that should be

administered in acute anaphylaxis

The dose is epinephrine, 0.3 to 0.5 milligram (0.3 to 0.5 mL of the 1:1000 dilution) IM repeated every 5 to 10 minutes according to response or relapse.

Most patients do not need more than a single dose.

IM dosing provides higher, more consistent, and more rapid peak blood epinephrine levels than SC administration, and should now be the treatment of choice for adults and children. Injections into the thigh are more effective at achieving peak blood levels than are injections into the deltoid area.

Caution is warranted in patients taking -blockers, because epinephrine use may result in severe hypertension secondary to unopposed -

adrenergic stimulation.

If the patient is refractory to treatment despite repeated IM epinephrine, or with signs of cardiovascular compromise or collapse, then an IV infusion of epinephrine is given. Initially, epinephrine, 100 micrograms (0.1 milligram) direct IV( 1:100,000 dilution).

OR 0.1 milligram (0.1 mL of the 1:1000 dilution), in 10

mL of normal saline (NS) solution and infusing it over 5 to 10 minutes (a rate of 1 to 2 mL/min).3

If the patient is refractory to the initial bolus, then epinephrine infusion -1 milligram (1.0 mL of the 1:1000 dilution), in 500 mL of 5% dextrose or NS and administering at a rate of 1 to 4 micrograms/min (0.5 to 2 mL/min), titrating to effect.

Side effects - tachycardia, arrhythmia, tremor .The initial adult dose is very dilute & is given over 5 to 10

minutes, and can be stopped immediately if arrhythmias or chest pain occur.

CRYSTALLOIDS : If hypotension is present, it is generally the result of

distributive shock and responds to fluid resuscitation.

Patients should receive an NS bolus of 1 to 2 L in adults (10 to 20 mL/kg in children) concurrently with the epinephrine infusion.

There is no evidence that albumin or hypertonic saline should replace NS at this time .

SECOND LINE THERAPY :

1) Corticosteroids

2) Antihistamines 3)Agents for Allergic Bronchospasm (Asthma medications).

4)Glucagon.

TREATMENT OF BRONCHOSPASM ADULT DOSE PEDIATRIC

DOSE

URTICARIA :

Urticaria, or hives, is a cutaneous reaction marked by the development of pruritic, erythremic wheals of varying size that generally are described as "fleeting.“

ANGIOEDEMA :

Angioedema is believed to be a similar to urticaria but is a deeper reaction characterized by edema formation in the dermis, mostly involving the face and neck, and distal extremities.

Prophylaxis of acute attacks is by attenuated androgens, such as stanozolol, 2 milligrams/d, or danazol, 200 milligrams/d.

Acute attacks can be shortened by C1 esterase inhibitor replacement by a concentrate or conestat alfa (trade name Ruconest).

Successful treatment with fresh frozen plasma has also been reported and may be tried if C1 esterase inhibitor is not available.

Treatment of patients is complex and best done in coordination with the appropriate specialist

FOOD ALLERGIES Caused by IgE-mediated reactions to food proteins and,

rarely, by additives.

IgE-coated mast cells lining the GI tract react to allergens in ingested foods and produce clinical findings associated with the release of anaphylaxis mediators.

Dairy products, eggs, nuts, and shellfish , are some of the most commonly implicated foods.

Symptoms of food allergy : include swelling and itching of the lips, mouth, and pharynx; nausea; abdominal cramps; vomiting; and diarrhea.

Cutaneous manifestations: such as angioedema and urticaria, as well as anaphylaxis, can occur.

Treatment for mild reactions is supportive, with the administration of antihistamines to lessen symptoms.

INSECT STING ALLERGIC REACTIONS. Insect stings can produce significant, and sometimes fatal, reactions,

particularly in sensitized patients. True stinging insects belong to the order Hymenoptera, which includes

three families: 1) Apidae (honeybees),2) Formicidae (fire ants),3) Vespidae (wasps, yellow jackets, and hornets)

Diagnosis depends on clinical history, H/o past reactions, and an examination to locate the site of the sting.

Mild local reactions can be managed with application of ice and oral antihistamines.

More generalized reactions or local reactions of the head and neck may benefit from a short course of corticosteroids.

Patients with severe reactions should be advised to carry self-administered epinephrine and antihistamines.

ALLERGIC DRUG REACTIONS :

Penicillin is the drug most common drug causing allergic reactions and accounts for approximately 90% of all allergic drug reactions.

When a drug or metabolite becomes protein-bound, either in serum or on cell surfaces, the drug–protein complex can become an allergen and stimulate immune system responses. Thus, the ability of a drug or its metabolites to sensitize the immune system depends on the ability to bind to tissue proteins.

A generalized reaction similar to immune-complex or serum sickness reactions is very common, especially with common agents like trimethoprim-sulfamethoxazole and certain cephalosporins (cefaclor being the most frequent).

Serum sickness usually begins in the first or second week after the administration of the drug and can take many weeks to subside after drug withdrawal.

Generalized malaise, arthralgias, arthritis, pruritus, urticarial eruptions, fever, adenopathy, and hepatosplenomegaly are common signs

and symptoms of serum sickness.

Drug fever : may occur without other associated clinical findings and may also occur without an immunologic basis.

Circulating immune complexes are responsible for the lupus-like reactions caused by some drugs.

Cytotoxic reactions: such as penicillin-induced hemolytic anemia, can occur. Skin eruptions include erythema, pruritus, urticaria, angioedema, erythema multiforme, and photosensitivity.

Severe reactions, such as those seen in Stevens-Johnson syndrome and toxic epidermal necrolysis, may also occur. Pulmonary complications, including bronchospasm and airway obstruction, can occur.

Immunotherapy Medical procedure that uses controlled exposure to known

allergens to reduce the severity of allergic disease Disease accepted to be treated by immunotherapy:

◦ Allergic rhinitis, allergic asthma, allergic conjunctivitis, insect sting hypersensitivity

Disease not accepted to be treated by immunotherapy:◦ Food allergy, urticaria, atopic dermatitis .

MECHANISM: B CELL RESPONSE Gradual increase of allergen-specific IgG antibodies --

especially IgG4 subclasses (blocking antibody)◦ Intercept and neutralize allergen before it bound to cell-

surface IgE. ◦ Form IgG-antigen-IgE complex and bind to the IgG

receptor resulting co-aggregation with the IgE receptor and inhibition of IgE receptor triggering.

Decreased allergen-specific IgE antibodies

Increase IgA and IgM antigen-specific B lymphocytes ◦ May limit antigen penetration into the body from mucosa

Mechanism: T cell response moving immune

system from CD4+Th2 cell to Th1 cell pathway

Alter cytokine production◦ IL-4, IL-5 as Th2

cytokines◦ IFN-gamma as Th1

cytokines

Patient selection Proven allergy ina patient with skin test positive. With allergic symptoms that are significant to the patient Attempts to avoid allergens fail or impractical Treatment with medicine is not fully successful or when

medication is not well tolerated. Young patients without chronic irreversible changes in the

upper airways Patient needs to be motivated and compliant with

treatment

Subcutaneous Immunotherapy Subcutaneous immunotherapy is most commonly used. Subcutaneous immunotherapy normally involves a weekly

subcutaneous injection of an extract of the allergen, in solution, in increasing doses until a standard maintenance dose is reached.

This dose is then injected subcutaneously on a regular basis (at intervals of approximately 20 days) for not less than 3 years for perennial allergens.

Short term immunotherapy does not affect the cytokine profile and do not have long-term efficacy after discontinuation

It is started at an earlier age, so that adverse changes to the immune system can be prevented before they become

irreversible

Sublingual immunotherapy Widely used and investigated in Europe since late 1980’s

The extract of the allergen is kept under the tongue for a couple of minutes and then patient is asked to swallow it

Dose of allergen is greater than subcutaneous immunotherapy (about 3-300 times higher).

Efficacy of Immunotherapy Wilson et al.:

◦ systemic review of literature in Cochrane library

◦ 22 clinical studies, a total of 979 patients

◦ They noted a highly significant reduction in symptoms as well as definite decrease in medicine intake for symptoms

◦ whether sublingual therapy equals the efficacy of subcutaneous immunotherapy is not clear