2.2 Hypersensitivity Reactions, Allergy & Anaphylaxis
Key Takeaways
- Anaphylaxis is diagnosed by acute skin/mucosal involvement paired with respiratory compromise or hypotension/end-organ dysfunction, confirmed diagnostically by serum tryptase levels peaking 1–2 hours post-event.
- First-line immediate treatment for anaphylaxis is intramuscular epinephrine 0.3–0.5 mg (1:1,000 dilution) into the mid-outer thigh (vastus lateralis), repeatable every 5–15 minutes; adjunctive antihistamines and steroids must never delay epinephrine.
- Biphasic anaphylactic reactions occur in up to 20% of cases within 1 to 72 hours (median 8–12 hours) after initial symptom resolution, necessitating a mandatory observation period of 4–8 hours post-stabilization.
- Type II hypersensitivity involves antibody-mediated (IgG/IgM) cytotoxic destruction via complement activation or ADCC (e.g., Goodpasture syndrome, autoimmune hemolytic anemia), whereas Type III involves immune complex deposition causing vasculitis and complement consumption (e.g., Serum sickness, SLE nephritis).
- Type IV hypersensitivity is cell-mediated by CD4+ and CD8+ T lymphocytes with delayed onset (48–72 hours), evaluated clinically via patch testing for allergic contact dermatitis or PPD/IGRA for tuberculosis.
Hypersensitivity Reactions, Allergy & Anaphylaxis
Gell & Coombs Classification of Hypersensitivity
Hypersensitivity reactions are exaggerated or inappropriate immune responses causing tissue destruction or organ dysfunction. Gell and Coombs categorized these reactions into four immunological types based on effector mechanism, immune components involved, and time to onset.
Comparison of Hypersensitivity Types
| Type | Name | Primary Immune Mechanism | Key Mediators | Clinical Examples | Typical Onset |
|---|---|---|---|---|---|
| Type I | Immediate (Allergic) | IgE cross-linking on mast cells/basophils | Histamine, leukotrienes (LTC4, LTD4, LTE4), tryptase | Anaphylaxis, allergic asthma, food allergy, allergic rhinitis | Immediate (Minutes to <1 hour) |
| Type II | Antibody-Mediated (Cytotoxic) | IgG or IgM binding to cell surface/tissue antigens | Complement activation (C3a, C5a), MAC, ADCC, phagocytosis | Goodpasture syndrome, Autoimmune hemolytic anemia, ITP, Rheumatic fever | Hours to days |
| Type III | Immune Complex-Mediated | Circulating IgG/IgM-antigen complexes depositing in vessel walls | Complement consumption (C3/C4), neutrophil recruitment | Serum sickness, Systemic Lupus Erythematosus nephritis, Post-streptococcal glomerulonephritis | 1 to 3 weeks |
| Type IV | Cell-Mediated (Delayed) | Sensitized T cells (CD4+ Th1/Th17, CD8+ CTLs) releasing cytokines | IFN-gamma, TNF-alpha, interleukins, macrophage activation | Contact dermatitis (poison ivy, nickel), Stevens-Johnson syndrome, Graft-vs-host disease, PPD test | 48 to 72 hours |
Type I Hypersensitivity & Anaphylaxis
Pathophysiology
Sensitization occurs upon initial allergen exposure when antigen-presenting cells drive CD4+ T helper 2 (Th2) differentiation. Th2 cells secrete IL-4 and IL-13, stimulating B-cell class switching to IgE. Specific IgE binds high-affinity FcεRI receptors on tissue mast cells and circulating basophils. Upon re-exposure, multivalent allergen cross-links membrane-bound IgE, inducing immediate degranulation. Preformed mediators (histamine, tryptase, carboxypeptidase A) cause rapid vasodilation, increased vascular permeability, smooth muscle contraction, and mucus hypersecretion. Membrane phospholipid metabolism subsequently releases synthesized mediators: leukotrienes (LTC4, LTD4, LTE4) (potent bronchoconstrictors) and prostaglandin D2.
Clinical Diagnostic Criteria for Anaphylaxis
Anaphylaxis is a life-threatening systemic reaction. Diagnosis is clinical and requires meeting any ONE of the following three scenarios:
- Acute onset (minutes to hours) involving skin/mucosal tissue (urticaria, angioedema, flushing, pruritus) PLUS AT LEAST ONE OF:
- Respiratory compromise (dyspnea, wheezing, stridor, hypoxemia, peak expiratory flow reduction)
- Reduced blood pressure or associated end-organ dysfunction (syncope, incontinence, hypotonia)
- Two or more of the following occurring rapidly after exposure to a likely allergen:
- Skin-mucosal involvement
- Respiratory compromise
- Reduced blood pressure or end-organ dysfunction
- Persistent gastrointestinal symptoms (crampy abdominal pain, vomiting)
- Hypotension after exposure to a known allergen for that patient (systolic BP <90 mmHg or >30% drop from baseline).
Serum tryptase levels peak 1 to 2 hours post-event and confirm mast cell activation if the diagnosis is ambiguous.
Acute Management Protocol for Anaphylaxis
First-line treatment must never be delayed for diagnostic testing. Intramuscular epinephrine is the cornerstone of emergency therapy.
Step-by-Step Management Algorithm
Patient Presenting with Suspected Anaphylaxis
├─ Step 1: IMMEDIATE INTERVENTION
│ ├─ Administer Epinephrine 1:1,000 (1 mg/mL) IM into Anterolateral Thigh
│ │ ├─ Adult Dose: 0.3 to 0.5 mg IM
│ │ └─ Pediatric Dose: 0.01 mg/kg IM (Max 0.3 mg)
│ ├─ Call for emergency assistance / Airway management team
│ ├─ Place patient in recumbent position with legs elevated (unless airway compromised)
│ └─ Administer supplemental high-flow oxygen via non-rebreather mask
│
├─ Step 2: CIRCULATORY & AIRWAY RESUSCITATION
│ ├─ Establish dual large-bore IV access (14-16 gauge)
│ ├─ Rapid IV normal saline bolus (1–2 Liters for adults; 20 mL/kg for children)
│ └─ Prepare for early endotracheal intubation if stridor, airway edema, or voice change occurs
│
├─ Step 3: SECOND-LINE ADJUNCTIVE THERAPIES (Do NOT delay Epinephrine!)
│ ├─ H1 Antihistamine: IV Diphenhydramine (25–50 mg) for urticaria and pruritus
│ ├─ H2 Antihistamine: IV Famotidine (20 mg) for vascular stabilization
│ ├─ Inhaled Beta-2 Agonist: Albuterol nebulizer for refractory bronchospasm
│ └─ Systemic Corticosteroids: IV Methylprednisolone (1–2 mg/kg) to prevent protracted symptoms
│
└─ Step 4: POST-STABILIZATION MONITORING
├─ Mandatory observation for 4 to 8 hours due to risk of Biphasic Reaction (occurs in up to 20%)
└─ Discharge prescription: Two Epinephrine Auto-Injectors + Written Allergy Action Plan
Epinephrine Pharmacology
Epinephrine acts as an agonist across multiple adrenergic receptor subtypes:
- Alpha-1 receptor agonist: Causes peripheral vasoconstriction, reversing hypotension, mucosal edema, and urticaria.
- Beta-1 receptor agonist: Increases cardiac inotropy and chronotropy.
- Beta-2 receptor agonist: Induces bronchodilation and inhibits further mediator release from mast cells and basophils.
Type II, III, and IV Hypersensitivity Disorders
Type II (Cytotoxic Antibody-Mediated)
Circulating IgG or IgM autoantibodies bind fixed tissue antigens. Mechanisms include:
- Complement-mediated lysis and opsonization: Autoimmune hemolytic anemia, transfusion reactions.
- Antibody-dependent cellular cytotoxicity (ADCC): Natural killer cells bind Fc regions of antibodies to destroy target cells.
- Antibody-mediated cell dysfunction: Antibodies stimulate or block cell surface receptors without tissue destruction. Examples include Graves disease (activating TSH-receptor antibodies) and Myasthenia gravis (blocking/internalizing ACh-receptor antibodies).
Type III (Immune Complex-Mediated)
Antigen-antibody complexes form in the bloodstream and deposit in microvascular beds (renal glomeruli, synovia, skin capillaries). Deposited complexes activate complement, generating C3a and C5a (anaphylatoxins) that recruit neutrophils. Neutrophils release lysosomal enzymes, causing leukocytoclastic vasculitis and tissue necrosis.
- Serum Sickness: Occurs 7 to 14 days after exposure to foreign protein (e.g., chimeric monoclonal antibodies, antivenom). Symptoms include fever, urticaria, polyarthralgias, lymphadenopathy, proteinuria, and low complement levels (C3/C4).
Type IV (Cell-Mediated / Delayed-Type)
Unlike Types I–III, Type IV reactions do not involve antibodies. Sensitized CD4+ Th1 cells release IFN-gamma, activating macrophages, or CD8+ cytotoxic T cells directly kill target cells presenting haptenized peptides.
- Allergic Contact Dermatitis: Triggered by haptens such as urushiol (poison ivy/oak), nickel, or topical antibiotics. Presents 48–72 hours post-exposure with erythematous, pruritic vesicles. Diagnosis is evaluated using patch testing.
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Life-threatening Type IV drug reaction presenting 2–8 weeks after drug initiation (e.g., allopurinol, antiepileptics), featuring fever, facial edema, diffuse morbilliform exanthem, eosinophilia (>1,500/mm³), and internal organ involvement (hepatitis, nephritis).
A 34-year-old male is brought to the emergency department by ambulance after being stung by a yellow jacket while gardening 20 minutes ago. He reports severe dyspnea, throat tightness, and lightheadedness. On physical examination, temperature is 36.8°C (98.2°F), heart rate is 132/min, blood pressure is 78/42 mmHg, respiratory rate is 28/min, and oxygen saturation is 88% on room air. Inspection reveals diffuse urticarial plaques across his chest and trunk, inspiratory stridor, and audible expiratory wheezing. Which of the following is the most immediate next step in management?
A 24-year-old female presents to the urgent care clinic 10 days after completing a course of oral cefaclor for a urinary tract infection. She complains of fever, severe joint pain in her knees and wrists, and a widespread itchy skin rash. Physical examination reveals a temperature of 38.5°C (101.3°F), mild swelling and tenderness of both wrists, diffuse urticarial lesions with central clearing, and palpable cervical lymphadenopathy. Urinalysis demonstrates mild proteinuria and microscopic hematuria. Serum complement levels reveal decreased C3 and C4 concentrations. Which immunologic mechanism is responsible for this clinical syndrome?
A 42-year-old male with a history of hypertension presents to his primary care physician with a 3-day history of a severely pruritic, erythematous rash on his left wrist and forearm. He reports buying a new stainless-steel wristwatch 5 days ago. Physical examination reveals well-demarcated erythematous plaques studded with tiny vesicles corresponding exactly to the shape of the watch casing and clasp. Which diagnostic test is most appropriate to confirm the etiology of this skin condition?