Understanding Anaphylaxis: Causes, Symptoms, and Treatment

• Anaphylaxis is a severe, life-threatening systemic hypersensitivity reaction.
• It involves multiple organ systems requiring immediate recognition and treatment.
• Anaphylaxis is caused by the release of mediators from mast cells and basophils.
• This release is triggered by immunologic (IgE-mediated) or non-immunologic mechanisms.
• Symptoms develop rapidly, progressing to respiratory distress, cardiovascular collapse, or death if not treated.
• Intramuscular epinephrine is essential for preventing severe morbidity and mortality.
• Anaphylaxis occurs within seconds to minutes of exposure to a trigger like a drug, food, or insect sting.
• The term "anaphylaxis" was first used in 1902 by Charles Richet and Paul Portier.
• They discovered that repeated administration of sea anemone toxin caused acute-onset death in dogs.
• Charles Richet received the Nobel Prize in 1913 for his insights into hypersensitivity and mast cell study.

Etiology

• Common triggers include foods (nuts, shellfish), medications (penicillin, NSAIDs), insect stings, and latex.
• IgE-mediated anaphylaxis occurs when allergens cross-link IgE antibodies on mast cells and basophils.
• This leads to degranulation and mediator release.
• Non-IgE mechanisms involve complement activation or direct mast cell activation by agents like opioids and radiocontrast media.
• Cofactors such as exercise, alcohol, or infections can amplify anaphylactic reactions.

Mediators

• Mediators are derived from mast cells, basophils, and eosinophils.
• Mast cells and basophils contain histamine, proteases (tryptase, chymase), proteoglycans, and tumor necrosis factor-α.
• These mediators are released upon cell activation (degranulation).
• Mast cells, basophils, and eosinophils also produce arachidonic acid-derived products like cysteinyl leukotrienes, prostaglandins, and platelet-activating factor (PAF).
• Histamine release leads to flushing, urticaria, pruritus, hypotension, and tachycardia.
• Cysteinyl leukotrienes and prostaglandin D2 cause bronchoconstriction and increased microvascular permeability.
• Prostaglandin D2 causes cutaneous flushing.
• Serum PAF levels correlate with anaphylaxis severity.
• Tryptase and chymase activate complement and coagulation pathways, resulting in anaphylotoxin production and activation of the kallikrein-kinin system.

Incidence

• Global incidence ranges from 0.49 to 328.7 cases per 100,000 annually.
• The US incidence is approximately 46 cases per 100,000 per year.
• Food-induced anaphylaxis is more common in children and adolescents.
• Drug- and venom-induced anaphylaxis is more predominant in adults.

Risk Factors

• Atopy, including allergic rhinitis, asthma, or eczema, increases susceptibility to IgE-mediated anaphylaxis.
• Older adults are at greater risk due to comorbidities and delayed epinephrine administration.
• Poorly controlled asthma exacerbates respiratory symptoms and increases the risk of fatal outcomes.
• Atopy is associated with radiocontrast sensitivity, exercise-induced anaphylaxis, idiopathic anaphylaxis, and allergy to foods or latex.
• Severe Hymenoptera-induced anaphylaxis can indicate underlying systemic mastocytosis.
• Occupations placing individuals near stinging insects (beekeepers, trash haulers) increase allergy risk.
• Allergen-induced cross-linking of IgE-bound receptors on mast cells and basophils starts signal transduction events leading to hypersensitivity.
• Allergen-specific IgE generation results from sensitization via the adaptive immune system.
• IgE-mediated drug allergies are most common with antibiotics and certain chemotherapy drugs.
• Repeated exposure to the allergy-causing antigen is an important risk factor.
• Patients with ≥7 lifetime infusions have a 27% hypersensitivity incidence, increasing to 46% with ≥15 infusions.
• Cystic fibrosis patients have a higher incidence of allergic reactions to IV antibiotics used for "clean-outs”.
• Drugs can function as haptens, forming immunogenic conjugates with host proteins.
• Recombinant biologics can induce IgE formation against proteins or glycosylated structures.
• Anaphylaxis outbreaks to cetuximab are linked to elevated IgE titers to alpha-1,3-galactose.
• Patients with multiple bites from Amblyomma americanum ticks are more likely to have anti-alpha-gal IgE.
• Sensitized individuals to alpha-gal can develop delayed-onset anaphylaxis to meat.
• Non-IgE-mediated mast cell activation by drugs can mimic IgE-mediated hypersensitivity.
• MRGPRX2, a G protein-coupled receptor, induces mast cell activation and mediator release secondary to neuromuscular blocking drugs (NMBDs).
• NMBDs are a common cause of perioperative anaphylaxis.
• Icatibant, a bradykinin-2 receptor antagonist, frequently causes local injection site reactions.
• Paclitaxel, solubilized with Cremophor, demonstrates non-IgE-mediated anaphylaxis.
• Abraxane, a version of paclitaxel bound to albumin nanoparticles, has a lower hypersensitivity rate.
• Reactions to radiocontrast and vancomycin are examples of non-IgE-mediated hypersensitivity.
• Opiates and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause similar adverse reactions.

Prevention

• Avoid known allergens through careful label reading and avoidance strategies.
• Carry self-injectable epinephrine for individuals with a history of anaphylaxis or high-risk allergies.
• Immunotherapy for venom allergies can reduce recurrence risk in insect sting-induced anaphylaxis.
• Educate patients on recognizing early symptoms and seeking immediate medical attention.
• Patients with only large local reactions to Hymenoptera stings are unlikely to have anaphylaxis with subsequent stings.
• Venom immunotherapy should be started if skin or serologic IgE testing confirms the history.
• Immunotherapy involves subcutaneous administration of escalating allergen doses.
• Anaphylaxis can occur during immunotherapy, so extracts are administered under specialist care.
• Hymenoptera allergy patients receive venom immunotherapy extracts with a maintenance dose equivalent to 2–5 stings.
• The recommended treatment duration is 3-5 years.
• Severe respiratory or cardiovascular anaphylaxis patients are put on lifelong therapy.
• Preventative tolerance induction to foods occurs most frequently in infants and young children, and is a risk factor for anaphylaxis.
• Most allergies to egg, milk, soy, and/or wheat resolve spontaneously during childhood.
• About 80% of children with peanut allergy remain sensitive for life.
• Early introduction of peanut protein prevents peanut allergy development.
• Desensitization may be a short-term treatment option for drug allergy patients requiring the offending drug.
• Desensitization elicits a temporary state of tolerance through gradual escalating doses of drug.
• Drug desensitization works for IgE-mediated reactions and has been performed in non-IgE-mediated anaphylaxis cases.
• Multiple groups have shown desensitization can prevent non-IgE-mediated reactions.
• The decision to desensitize should be made with an allergy specialist.

Clinical Manifestations

• Cutaneous symptoms include urticaria and angioedema due to histamine release.
• Respiratory distress includes wheezing, stridor, or laryngeal edema causing airway obstruction.
• Cardiovascular collapse includes hypotension or shock due to vasodilation and capillary leakage.
• Gastrointestinal symptoms include nausea, vomiting, abdominal pain, or diarrhea in food-induced cases.
• Neurological symptoms include dizziness or syncope due to cerebral hypoperfusion.
• 80-90% of anaphylactic episodes are uniphasic; 10-20% are biphasic, with symptoms returning after resolution.
• Anaphylactic reactions with hypotension or hypoxia can lead to cardiovascular collapse or respiratory failure.
• Laryngeal edema may be experienced as a "lump" in the throat, hoarseness, or stridor.
• Bronchial obstruction is associated with chest tightness and wheezing.
• Patients with asthma are predisposed to severe lower airway involvement and increased mortality.
• Fatal cases show lung hyperinflation on examination.
• Angioedema can result in death by mechanical obstruction in the epiglottis and larynx.
• Cutaneous manifestations include urticarial eruptions, flushing, and a feeling of warmth.
• Urticarial eruptions are intensely pruritic and may be localized or disseminated.

Review of Systems

• Skin: Rash or swelling; pruritus.
• Respiratory: Shortness of breath; wheezing; throat tightness.
• Cardiovascular: Palpitations; dizziness; fainting.
• Gastrointestinal: Nausea; vomiting; diarrhea.
• Neurological: Confusion; loss of consciousness.

Physical Assessment Findings

• Generalized urticaria or angioedema involving lips or eyelids.
• Eyes: Periorbital swelling, erythema/itching.
• Oral: Angioedema or pruritus of tongue and lips.
• Skin: Urticaria, pruritus/flushing, angioedema.
• Wheezing on auscultation indicates bronchospasm.

Respiratory System

• Lower airway: Bronchospasm, wheezing, chest tightness, tachypnea, decreased PEF, cyanosis, respiratory collapse.
• Upper airway: Throat feels constricted, dry cough, trouble breathing, swallowing or speaking, changes in voice, stridor.

Cardiovascular System

• Early: Tachycardia, diaphoresis, hypotension, delayed capillary refill, chest pain.
• Late: Bradycardia, shock, ST depression & T-wave inversion, cyanosis, cardiac arrest.

Gastrointestinal System

• Abdominal tenderness in food-induced anaphylaxis cases.
• Nausea, vomiting, diarrhea, abdominal cramps.

Neurological System

• Throbbing headache.
• Dizziness.
• Lightheaded.
• Confusion.
• Loss of consciousness.
• Aura of impending doom, anxiety.

General Findings

• Cyanosis or altered mental status in severe cases.

Assessment Tools and Grading

• NIAID/FAAN criteria: Diagnostic criteria based on symptom onset and organ system involvement.
• Severity Grading System: Classifies reactions from mild to severe based on symptom intensity.
• Diagnostic Studies & Possible Findings
• Diagnosis is based primarily on detailed history and clinical symptoms.
• History includes exposures and events prior to symptom onset.
• Symptoms’ onset occurs within minutes to hours after exposure to an allergen.
• Symptoms usually occur in two or more body systems.
• Lab tests are not usually helpful.

Diagnostic Studies & Possible Findings

• Allergen skin testing or serologic testing for serum IgE will detect sensitivity to an allergen.
• Allergy testing is helpful to determine the allergen and avoid it in the future if a patient experiences anaphylaxis to an unknown allergen.
• Serum Tryptase: Elevated levels confirm mast cell degranulation during anaphylaxis.
• Histamine Levels: Elevated within minutes of reaction onset but normalize quickly.
• ECG: Rules out arrhythmias contributing to hypotension or syncope.
• Chest X-ray: May show pulmonary edema in severe cases with respiratory failure.
• Blood Gas Analysis: Identifies hypoxemia or metabolic acidosis.

Clinical Criteria for Diagnosis

• Anaphylaxis is probable when any 1 of 3 criteria are met:
• Acute onset of illness with involvement of skin or mucosal tissue, along with at least one of the following: respiratory symptoms OR hypotension/LOC

Treatment Prioritization

• Administer intramuscular epinephrine immediately as first-line treatment.
• Ensure airway patency and provide supplemental oxygen if needed.
• Establish IV access for fluid resuscitation in hypotensive patients.
• Administer adjunctive therapies like H1-antihistamines for cutaneous symptoms.
• Monitor vitals continuously for biphasic reactions.
• Position patient supine with legs elevated unless contraindicated by respiratory distress.
• Rapidly assess circulation, airway, breathing.

Pharmacological Management

• Administer epinephrine IM 0.3-0.5 mg every 5-15 minutes as needed.
• Adults: 0.3-0.5 mg IM x 1 dose, repeated 5-15 minutes later if needed.
• Infants/children: 0.01 mg/kg IM x 1 dose, repeated 5-15 minutes later if needed.
• Inject epinephrine into the muscle of anterolateral thigh (vastus lateralis).
• 2nd Line: Diphenhydramine—25–50 mg IV/IM for cutaneous symptoms.
• 3rd Line: Corticosteroids—Hydrocortisone 200 mg IV for refractory symptoms.

Consultation/Referral

• Allergist/Immunologist for long-term management and allergen testing.
• Emergency Medicine specialist for acute management of refractory cases.
• Pulmonologist if respiratory complications persist post-reaction.

Initial Diagnosis Patient Guidance

• Educate on recognizing early signs of anaphylaxis and using epinephrine auto-injectors promptly.
• Advise avoiding known allergens and carrying medical alert identification.

Follow Up and Surveillance

• Schedule follow-up within one week post-reaction to review allergen testing results and adjust prevention strategies as needed.

Expected Course

• Most patients recover fully with prompt treatment but require ongoing vigilance due to risk of recurrence.

Possible Complications

• Biphasic reactions occurring hours after initial resolution.
• Symptoms reoccur within 1-72 hours after initial symptoms have resolved.

Geriatric Consideration:

• Cardiovascular collapse leading to multi-organ failure if untreated promptly.
• Increased risk for anaphylaxis due to increased age and additional medications (e.g. beta blockers).
• Increased risk for adverse effects from epinephrine due to concomitant conditions (respiratory, cardiovascular, etc.).
• Older adults account for most cases of fatal anaphylaxis due to medication/drug allergy.