Allergy Testing

• Immediate hypersensitivity skin test (IHST): Stop antihistamines for 5 days before testing. Use the prick technique (introduce antigen intracutaneously via pricking or puncturing). Positive predictive value is good for inhalants, moderate for foods (high rate of false-positive results); negative predictive value is excellent for foods and inhalants.
  
• Serum tests: Serum eosinophilia is often present (low diagnostic value); serum IgE is often elevated with atopic dermatitis (low diagnostic value); serum allergen-specific IgE assays (eg, RAST) measure circulating Ag-specific IgE and have similar predictive value to skin testing.

Anaphylaxis

• Definition: A serious allergic reaction that is rapid in onset and may cause death
  
• Differential Diagnosis:
  
  
  
  • Vasovagal syncope, panic attack, hyperventilation, systemic mastocytosis, scombroid fish poisoning. Rare causes include carcinoid syndrome, pheochromocytoma, and idiosyncratic causes.
    
  • Anaphylactoid reactions, which have complement activation, but are not IgE mediated.
    
  • Example: Radiocontrast media, drugs (NSAIDS, opiate), blood products, exercise induced, and idiopathic. Clinical presentation and treatment are the same as for anaphylaxis.
  
  
• Major Trigger: Food (most commonly peanut, tree nuts, shellfish, fish, eggs, milk), insect venom, latex, drugs, immunotherapy
  
• Pathophysiology: Production of IgE in a susceptible individual (sensitization)→ IgE-sensitized mast cells and basophils→ exposure of allergen and then allergen binding leads to mast cell degranulation.
  
• Clinical Symptoms and PE
  
  
  
  • Variable symptoms: Angioedema, shortness of breath, wheezing, flushing, urticaria, pruritus, hypotension, chest pain, syncope, abdominal pain, vomiting, diarrhea, aura of impending doom.
    
  • Time pattern: Uniphasic, biphasic (recur up to 8 h later in 3%–20%), or protracted syndrome.
  
  
• Diagnostic Studies
  
  
  
  • Markers of mast cell degranulation, including plasma histamine (only elevated for 1 h after the onset of symptoms), urinary histamine and metabolites (elevated for longer), or serum tryptase level (peaks is 90 minutes and stays elevated for as long as 5 h) may be useful when the diagnosis is uncertain. Undetectable levels do not rule out anaphylaxis (tryptase is positive <50%).
    
  • In vitro allergen-specific IgE assays or IHST may be used later to confirm. IHST may not be reliably positive in sensitized individuals for up to 4 to 6 weeks after an episode of anaphylaxis. In sensitized individuals, the test should be repeated if results are negative.
  
  
• Treatment
  
  
  
  • Monitor patients with mild reactions limited to flushing, urticaria, angioedema, and mild bronchospasm in the ED for a minimum of 6 to 8 hours. Consider longer observation of patients with mild symptoms who have received epinephrine because epinephrine may have minimized the symptoms.
    
  • Provide prolonged observation of patients with moderate to severe reactions, asthma with wheezing, ingested antigen with the possibility of continued absorption, or a history of biphasic response.
    
  • See table below.

• Anaphylaxis Prevention: Identify trigger; avoidance; wear identification; carry epinephrine auto-injector; and provide patient and family school education.

Urticaria and Angioedema

• Definition: Urticaria is extravasation of plasma into dermis (wheal ± erythema); angioedema is plasma extravasation into subcutaneous tissue.
  
• Epidemiology: The prevalence of urticaria/angioedema in the United States is 15% to 20%.
  
• Differential Diagnosis: Erythema multiforme minor, bullous pemphigoid, dermatitis herpetiformis and mastocytosis
  
• Classification
  
  
  
  • Acute: ≤6 to 8 weeks; viral infections, insect stings, foods, drugs (ACEI angioedema)
    
  • Chronic: > 8 weeks; physical urticaria (cold, cholinergic, pressure, vibratory, dermographism, exercise); urticarial vasculitis (biopsy for dx); autoimmune urticaria (anti-IgE receptor antibody, anti-thyroglobulin antibody, antimicrosomal antibody); chronic idiopathic urticaria (most likely cause autoimmune)
    
  • Hereditary angioedema (HAE): AD heredity as well as spontaneous mutations (50%); painless, nonpruritic, nonpitting swelling following trauma or stress.
    
    
    
    • HAE I: ↓C1 esterase inhibitor (C1-INH) level; ↓C2, C4 level
      
    • HAE II: C1-INH level is normal or high, but function is ↓; ↓C2, C4 level
      
    • HAE III (estrogen dependent): Normal C1-INH level and function; normal C2, C4
    
    
  • Acquired angioedema (AAE): Acquired C1-INH deficiency
    
    
    
    • AAE type I: Very rare lymphoproliferative disorder; monoclonal gammopathy
      
    • AAE type II: Very rare; anti-IgG to C1-INH
      
    • Low C1q level in addition to depletion of C4 and C2
  
  
• Diagnosis
  
  
  
  • Workup is based on the history and clinical presentation.
    
  • Consider removal of exacerbating agents (drugs) and use elimination from diet approach.
    
  • Consider CBC, UA, CXR, ESR, LFT, TSH or T4, ANA, and antithyroid antibodies (with strong FHx).
    
  • Consider autologous skin testing (using patient’s serum) to dx autoimmune urticaria.
    
  • C4 level and qualitative and quantitative C1-INH to evaluate HAE.
    
  • C1q in addition to C4 and C2 level to evaluate AAE.
  
  
• Treatment
  
  
  
  • Treatment depends on the etiology of urticaria/angioedema.
    
  • Antihistamine (H1 blocker) works best for acute types (preferably nonsedating form).
    
  • Ranitidine, montelukast, cyproheptadine, and doxepin can be considered as adjunct therapy.
    
  • Reserve steroids and other immunosuppressants for severe or refractory urticaria.
    
  • Treatment for HAE includes supportive care ± FFP during acute attacks; prophylactic danozol with epsilon aminocaproic acid is an option. Recombinant human C1-INH is FDA approved in the United States for prophylaxis.

• Definition: Adverse drug reaction results from the production of antibodies or cytotoxic T-cells directed against the drug or its metabolized products.
  
• Pathophysiology: Immunologic mechanism → type I, II, III or IV hypersensitivity or other unknown mechanism (SJS, TEN, drug fever, acute interstitial nephritis, and pulmonary infiltrates with eosinophilia).
  
• Diagnosis
  
  
  
  • Clinical symptoms and PE: Most commonly see alterations in skin and mucous membranes (maculopapular rash, urticaria, angioedema, fixed drug eruptions, contact dermatitis, erythema multiforme [SJS], TEN, serum sickness syndrome, SLE-like drug reactions, drug fever, anaphylaxis).
    
  • Diagnostic studies
    
    
    
    • IHST (antibiotics, low-molecular-weight drugs such as toxoids, antisera, and vaccines with egg protein).
      
    • Patch test is used to evaluate for type IV contact hypersensitivity to a topical agent.
      
    • Drug-specific IgE antibody for limited drugs; less sensitive than IHST.
      
      
      
      • Drug challenge using a graduated dose protocol (under strict medical supervision of a specialist) to administer drugs with a low probability of allergic reaction; this is contraindicated if the patient has a history of serum sickness, SJS, TEN, or anaphylaxis.
  
  
• Treatment:
  
  
  
  • Discontinue or substitute with non–cross-reacting drugs.
    
  • Antihistamines and corticosteroids are the mainstays of symptomatic treatment.
    
  • Follow established practice guidelines for treatment of patients with anaphylaxis, urticaria, angioedema, and contact dermatitis.
    
  • Desensitization in IgE-mediated drug allergic reactions only.
    
  • Repeat desensitization process if the drug is discontinued for 24 hours or more.

• Definition: Allergic response to insect venom
  
• Etiology:
  
  
  
  • Stinging insects in the Hymenoptera order include Apidae family (honeybees and bumblebees), Vespidae family (yellow jackets, hornets, and wasps), and Formicidae (fire and harvester ants).
    
  • Biting insects: Mosquitoes cause large local reactions; anaphylaxis is very rare. Deerflies and kissing bugs may cause bite-induced anaphylaxis.
  
  
• Pathophysiology:
  
  
  
  • IgE-mediated reactions underlie the majority of insect stings allergy.
    
  • Non-IgE immune reactions have been reported (eg, serum sickness, neuritis).
    
  • Toxic reactions in massive attacks may lead to death.
  
  
• Diagnosis:
  
  
  
  • Clinical symptoms and PE:
    
    
    
    • Skin: Pain, swelling, flushing, urticaria and angioedema (lips, tongue, throat).
      
    • Respiratory and CVS: Stridor, wheezing, fainting, dizziness, palpitations.
      
    • GI: Nausea, vomiting, diarrhea, and abdominal cramps.
      
    • Other: Fever, fatigue, skin rashes, joint pains, mental or sensory complaints.
      
    • Most fatal reactions occur within 4 hours of the stinging incident.
    
    
  • Diagnostic studies:
    
    
    
    • IHST using purified venom (bee, yellow jacket, hornet, and wasp) or whole-body extract (fire ants) are the mainstays diagnostic workup.
      
    • Delay IHST 4 to 6 weeks after a systemic reaction to insect sting to avoid false-negative results.
      
    • All stinging insects should be tested to avoid missing the diagnosis with fatal sequelae.
      
    • Cross-reactivity of skin testing has been observed within the Hymenoptera family.
      
    • Allergen- specific IgE assay is 80% sensitive compared with IHST but detects an additional 10% of allergic patients with negative skin test results.
  
  
• Treatment:
  
  
  
  • Local reaction: Antihistamine, analgesics, and cold compression; for severe reactions, add a 2- to 3-day course of moderate doses of prednisone.
    
  • Systemic reaction and anaphylaxis: Follow guidelines for anaphylaxis treatment.
    
  • Long-term management: Avoid stinging insects, use epinephrine auto-injector, wear Medic-Alert bracelets.
    
  • Venom immunotherapy (VIT) administered by a specialist is a standard of care for proven insect allergy patients.

• Definition: Adverse food reactions for which an immunologic mechanism has been identified; other adverse food reactions include idiopathic, toxic, and pharmacologic reactions.
  
• Epidemiology: High public perception (20%–25%); confirmed allergy (oral challenge) in 6% to 8% of children (30% have severe atopic dermatitis, and 10% of those with asthma have food allergies).
  
• Etiology: In children, cow’s milk, egg, soy, wheat, peanut, and tree nuts; in adults peanut, tree nuts, shellfish, fish, fruits, and vegetables.
  
• Natural history: Nearly one-third of children and adults lose clinical reactivity after 1 to 2 years of allergen avoidance. Foods associated with fatal anaphylaxis (eg, peanuts, tree nuts, seafood) require lifelong elimination from the diet.
  
• Clinical Presentation:
  
  
  
  • Anaphylaxis syndromes
    
    
    
    • Food-induced anaphylaxis (milk, egg, peanut, tree nuts, seafood): Respiratory (wheezing, stridor), cutaneous (urticarial, angioedema), GI (acute emesis, abdominal pain, diarrhea)
      
    • Food-dependent (wheat, celery most common), exercise induced
    
    
  • Oral allergy syndrome: IgE-mediated (perioral pruritus or rash) results from cross-reactivity of fresh fruits and vegetables with aeroallergens (eg, birch, ragweed, grass).
    
  • Latex food syndrome: About 30% to 50% of those with latex allergy are sensitive to foods because of cross-reactive IgE (banana, avocado, kiwi, chestnut).
    
  • Pediatric GI syndrome (enterocolitis, enteropathy, proctitis): Patients present with colic, bloody stool, FTT, vomit, diarrhea; non–IgE mediated, typically milk or soy induced.
    
  • Celiac disease: Immune-mediated (IgE and IgA) enteropathy triggered by gluten peptides; patients present with FTT, weight loss, diarrhea, and abdominal pain.
    
  • Eosinophilic gastrointestinal disorder: Patients present with postprandial nausea, vomiting, diarrhea, FTT, GER, dysphagia or food impaction; diagnosed by GI biopsy with more than 20 eosinophils/HPF.
    
  • Non-IgE syndromes of the skin and lung
    
    
    
    • Dermatitis herpetiformis: Vesicular, pruritic rash associated with celiac disease
      
    • Heiner’s syndrome: Infantile pulmonary hemosiderosis caused by non IgE-mediated response to cow’s milk
  
  
• Diagnostic Studies:
  
  
  
  • Food diaries from patient often reveal unexpected associations and help interpret lab data.
    
  • Skin prick tests are safe except in patients with history of anaphylaxis.
    
    
    
    • Positive skin test results or food-specific IgE: ∼90% sensitivity, ∼50% false positive
      
    • Negative skin tests or specific IgE: Essentially excludes food allergy (<95% specificity)
    
    
  • Other tests may be indicated: CBC (eosinophilia in chronic allergies), hydrogen breath test (lactose intolerance), and endoscopic biopsies (eosinophilic syndrome of GI tract).
    
  • Double blind, placebo-controlled food challenge is the gold standard for diagnosing food allergy; however, it is rarely performed because of cost and the risk of anaphylaxis.
  
  
• Treatment:
  
  
  
  • Complete avoidance of specific food triggers, ensure patients’ nutritional needs are met.
    
  • Thorough education of the patient, family, and care providers and anaphylaxis kits (including epinephrine injections) are the most powerful life-saving measures for patients with severe food allergy.
    
  • Children with milk protein allergy can be managed with formula substitutes using soy-based formula (eg, Isomil), casein protein hydrolysate formula (eg, Nutramigen), or elemental amino-acid based formula (eg, Neocate).
    
  • There is no role for immunotherapy in the treatment of patients with food allergy.

• Definition: IgE-mediated immediate reaction that occurs when a person is exposed to natural rubber latex.
  
• Epidemiology: Affects about 7% to 10% of health care professionals and 28% to 67% of patients with spina bifida or urogenital diseases.
  
• Clinical presentations:
  
  
  
  • IgE-mediated hypersensitivity in the form of contact urticaria, angioedema, bronchospasm, or anaphylaxis (true latex allergy); contact dermatitis (type IV hypersensitivity); or irritant contact dermatitis (not an immunologic reaction). Direct mucosa, inhalant, and parenteral exposure ↑ association with anaphylaxis.
    
  • Cross-reactivity with foods, including chestnut, kiwi, avocado, banana, tomato, and potato, has been detected in 30% to 50% of latex allergic individuals.
  
  
• Treatment:
  
  
  
  • Prevention through avoidance
    
  • Type I reactions are treated with H1 blockers, epinephrine, steroids, and H2 blockers.
    
  • Type IV reactions are treated with topical steroids.