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Anaphylaxis

Chapter 364 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 364

Key Clinical Points

  1. Anaphylaxis is a potentially life-threatening systemic allergic reaction involving one or more organ systems, typically occurring within seconds to minutes of exposure to triggers like drugs, food, or Hymenoptera stings.
  2. Approximately 80–90% of episodes are uniphasic; 10–20% are biphasic (symptoms recur ≥ 1 hour after initial resolution).
  3. First-line treatment is intramuscular (IM) epinephrine (0.3–0.5 mL of 1:1000), repeated at 5- to 20-minute intervals as needed.
  4. Serum tryptase peaks 60–90 min after onset and remains measurable for up to 5 hours; a level ≥ 20% above baseline + 2 ng/mL confirms significant mast cell activation.
  5. Non-IgE-mediated reactions can occur via MRGPRX2 (e.g., NMBDs, quinolones) or complement activation (e.g., paclitaxel/Cremophor, heparin/OSCS).
  6. Alpha-gal syndrome causes delayed anaphylaxis (3–6 h) after consuming mammalian meat (beef, lamb, pork) in patients with anti-alpha-gal IgE.
  7. Preexisting asthma and cardiovascular disease are major risk factors for rapid decompensation and increased mortality.
  8. Scombroid poisoning mimics anaphylaxis but is distinguished by a lack of tryptase elevation and negative skin tests; it results from histamine accumulation in fish.
  9. Beta-blockers may attenuate the response to epinephrine; alternative antihypertensives should be considered in high-risk patients.
  10. Hereditary alpha-tryptasemia (HAT) is a common, mostly benign condition with elevated baseline tryptase that can complicate the interpretation of anaphylactic events.

1. DEFINITION & OVERVIEW

• Definition: Anaphylaxis is a potentially life-threatening systemic allergic reaction involving one or more organ systems that typically occurs within seconds to minutes of exposure to the anaphylactic trigger (most commonly drug, food, or Hymenoptera sting). • Clinical Course: ◦ Uniphasic: 80–90% of cases. ◦ Biphasic: 10–20% of cases → symptoms return ≥ 1 hour after resolution of initial symptoms. • Critical Risks: Reactions are particularly dangerous when hypotension or hypoxia occurs, potentially leading to cardiovascular collapse or respiratory failure.

1.1 Clinical Presentation

• Upper Airway: Laryngeal edema may present as a 'lump' in the throat, hoarseness, or stridor. • Lower Airway: Bronchial obstruction is associated with chest tightness and/or audible wheezing. • Asthma Link: Patients with underlying asthma are predisposed to severe lower airway involvement and increased mortality.

2. EPIDEMIOLOGY

• Predisposing Factors: ◦ Asthma & Cardiovascular Disease: Lead to rapid decompensation. ◦ Atopy: Not a general risk factor for drug or Hymenoptera anaphylaxis; however, it is associated with radiocontrast sensitivity, exercise-induced anaphylaxis, idiopathic anaphylaxis, food allergy, and latex allergy. ◦ Mastocytosis: Significant risk for severe Hymenoptera-induced anaphylaxis (prominent hypotension). Baseline tryptase should be checked in these patients. ◦ Occupational Exposure: Higher incidence in beekeepers, trash haulers, and landscape workers.

• Carboplatin: ◦ ≥ 7 lifetime infusions → 27% hypersensitivity. ◦ ≥ 15 lifetime infusions → 46% hypersensitivity. ◦ Cystic Fibrosis: High incidence of allergic reactions to IV antibiotics (especially beta-lactams) during periodic 'clean-outs'.

3. ETIOLOGY & PATHOPHYSIOLOGY

• Mast Cell Mediators: ◦ Preformed Granules: Histamine, proteases (tryptase, chymase), proteoglycans (heparin, chondroitin sulfate), and TNF-α. ◦ Histamine Effects: Flushing, urticaria, pruritus; high concentrations → hypotension and tachycardia. ◦ Leukotrienes & Prostaglandins: ◦ Cysteinyl leukotrienes and Prostaglandin D → bronchoconstriction and increased microvascular permeability. ◦ Prostaglandin D → cutaneous flushing, recruits eosinophils/basophils. ◦ Tryptase & Chymase: Activate complement and coagulation pathways → production of anaphylatoxins (C3a, C5a) and activation of the kallikrein-kinin system. ◦ Platelet-Activating Factor (PAF): Serum levels correlate with severity; inversely proportional to constitutive PAF acetylhydrolase.

3.1 Non-IgE Mechanisms

• MRGPRX2 Activation: G protein–coupled receptor on skin mast cells → activation by NMBDs, quinolones, and icatibant. ◦ Complement Activation: ◦ Paclitaxel: Solubilized by Cremophor → complement-dependent histamine release. → Abraxane (albumin-bound) has a lower rate of hypersensitivity. ◦ Heparin: Contamination with oversulfated chondroitin sulfate (OSCS) → activates contact activation system → bradykinin and anaphylatoxins (C3a, C5a). ◦ Scombroid Poisoning: ◦ Cause: Histine-rich fish (mahi-mahi, mackerel, tuna) + bacteria → histamine. ◦ Characteristics: Symptoms include flushing, pruritus, nausea; Tryptase not elevated; negative skin test. ◦ Other Non-IgE: Radiocontrast, opiates, vancomycin, and NSAIDs.

4. CLINICAL FEATURES

• Cutaneous Manifestations: >90% of cases; urticarial eruptions (intensely pruritic), flushing, and diffuse erythema. ◦ Duration: Urticarial plaques seldom persist > 48 h. ◦ Histopathology: Wide separation of collagen fibers/glandular elements; vascular congestion and eosinophilic infiltration.

4.1 Respiratory & Cardiovascular

• Respiratory: ◦ Laryngeal edema → 'lump' in throat, hoarseness, or stridor. ◦ Bronchial obstruction → chest tightness and audible wheezing. ◦ Fatal cases with bronchial obstruction show marked hyperinflation on gross/microscopic exam. ◦ Cardiovascular: ◦ Hypotension or hypoxia → cardiovascular collapse or respiratory failure. ◦ Vascular collapse without prior hypoxia may involve visceral congestion and loss of intravascular volume.

4.2 Gastrointestinal Manifestations

• Symptoms: Nausea, vomiting, crampy abdominal pain, fecal incontinence. ◦ Mechanism: Angioedema of the bowel wall → intravascular volume depletion → cardiovascular collapse.

5. DIFFERENTIAL DIAGNOSIS

• Key Distinctions (Table 364-1): ◦ Mastocytosis: Elevated baseline tryptase, spindle-shaped mast cells (MCs) on bone marrow. ◦ Pheochromocytoma: [No specific marker provided in source] ◦ Carcinoid syndrome: [No specific marker provided in source] ◦ Hereditary angioedema: [No specific marker provided in source] ◦ Acquired angioedema: Decreased C1q. ◦ Systemic capillary leak syndrome: [No specific marker provided in source] ◦ Scombroid poisoning: Tryptase not elevated; negative skin test and oral challenge to fish. ◦ Drug-specific (opiates, NMBDs, vancomycin): Direct mast cell degranulation via MRGPRX2. ◦ Radiocontrast: Unknown mechanism.

5.1 Diagnostic Strategy

• Identification: Attempt to identify specific cause to minimize recurrence risk. ◦ Confirmation: Use skin or serum-specific IgE testing for suspected drugs/foods. ◦ Broad Workup: If trigger unknown, evaluate underlying atopic diatheses.

6. INVESTIGATIONS & DIAGNOSIS

  1. Clinical Assessment: Identify symptoms (urticaria, hypotension) occurring within seconds to minutes of exposure. ◦ Exception: Alpha-gal syndrome → delayed onset (3–6 h).
  2. Biomarker Collection: Measure serum tryptase in acute setting. ◦ Timing: Peak 60–90 min; measurable for up to 5 hours post-onset.
  3. Interpretation of Tryptase: ◦ Rule: "20% + 2" rule. ◦ Calculation: Current value ≥ (Patient Baseline + 20%) + 2 ng/mL → Diagnosis of significant mast cell activation.
  4. Baseline Establishment: Follow up with a second measurement when stable to establish baseline serum tryptase (BST) for future comparison.

7. MANAGEMENT & TREATMENT

  1. First-Line Therapy: ◦ Action: Intramuscular (IM) epinephrine. ◦ Dose: 0.3–0.5 mL of 1:1000. ◦ Frequency: Repeat every 5–20 minutes as needed for severe reaction. ◦ Timing: Failure to use within first 20 min → risk factor for poor outcome. ◦ Mechanism: α- and β-adrenergic effects → vasoconstriction, bronchial relaxation, reduced permeability.
  2. Supportive Care: ◦ Hypotension: IV fluids and vasopressor agents. ◦ Respiratory Distress: Oxygen via nasal catheter or nebulized albuterol. ◦ Critical Airway: Endotracheal intubation or tracheostomy if progressive hypoxia develops.
  3. Adjunctive Therapies (Post-Stabilization): ◦ Antihistamines, glucocorticoids, and bronchodilators for urticaria/angioedema and bronchospasm.
  4. Beta-Blocker Management: ◦ Note: Beta-blockers may attenuate the response to epinephrine; use alternative antihypertensives in patients at high risk of needing emergency epinephrine.

8. PROGNOSIS & COMPLICATIONS

• Biphasic Reaction: 10–20% of cases → symptoms return ≥ 1 hour after resolution. ◦ Risk: Particularly dangerous when hypotension or hypoxia is present. ◦ Outcome: Potential for cardiovascular collapse or respiratory failure. ◦ Mortality Factors: ◦ Presence of underlying asthma (severe lower airway involvement). ◦ Clinical bronchial obstruction (marked hyperinflation on imaging/gross exam). ◦ Vascular collapse without preceding hypoxia → visceral congestion and volume loss.

9. SPECIAL CONSIDERATIONS

• Alpha-Gal Syndrome: Delayed anaphylaxis (3–6 h) to mammalian meat; associated with anti-alpha-gal IgE. ◦ Drug-Specific Risks: ◦ Carboplatin: High incidence of hypersensitivity in multiple infusions. ◦ Cystic Fibrosis: High risk for beta-lactam reactions during airway clear-outs. ◦ Non-IgE Drug Reactions: Radiocontrast, opiates, vancomycin, and NSAIDs. ◦ Occupational Risk: Higher incidence of Hymenoptera allergy in beekeepers, trash haulers, and landscape workers.

10. KEY PEARLS & CLINICAL TRAPS

• Tryptase Rule: Use the "20% + 2" rule to distinguish significant mast cell activation from high baseline tryptase (e.g., in HAT). ◦ HAT: ~6% of Western population; benign but can be a risk factor for severe anaphylaxis. ◦ Scombroid Distinction: Tryptase is NOT elevated in scombroid poisoning because the source of histamine is exogenous. ◦ Epinephrine Timing: Delay > 20 minutes in administering epinephrine is linked to poorer outcomes. ◦ Beta-Blocker Interaction: Be aware that beta-blockers can blunt the effect of epinephrine; plan for alternative antihypertensives if needed.

Reference Tables

TABLE 364-1 Differential Diagnoses for IgE-Mediated Anaphylaxis CONDITION Mastocytosis Pheochromocytoma Carcinoid…

Harrison's 22e, p.2813

CONDITION DISTINGUISHED BY
Mastocytosis Elevated baseline tryptase, spindle-
shaped mast cells (MCs) on bone marrow
Carcinoid syndrome Elevated urine 5-hydroxyindoleacetic
acid
Acquired angioedema Decreased C1q
Scombroid poisoning Tryptase not elevated; negative skin test
and oral challenge to fish