6.4 Allergic & Immunologic Disorders: Anaphylaxis, Urticaria, Angioedema & Immunodeficiency

Allergic & Immunologic Disorders: Anaphylaxis, Urticaria, Angioedema & Immunodeficiency

The ANCC blueprint lists immune among its thirteen body systems and names allergies explicitly under pharmacology management. Allergic emergencies are also the highest-acuity events that occur in an outpatient office, most often after an injection, a vaccine or an in-office medication.

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1. Anaphylaxis

Anaphylaxis is a clinical diagnosis. Do not wait for hypotension, and do not wait for a tryptase level. Diagnostic criteria are met when either of the following occurs:

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|                        ANAPHYLAXIS DIAGNOSTIC CRITERIA (EITHER PATTERN)                           |
|                                                                                                   |
|   CRITERION 1 -- Acute onset (minutes to hours) of SKIN and/or MUCOSAL involvement                |
|   (generalized hives, pruritus or flushing, swollen lips/tongue/uvula), PLUS AT LEAST ONE of:     |
|      a. RESPIRATORY compromise - dyspnea, wheeze, stridor, hypoxemia, reduced peak flow           |
|      b. REDUCED BLOOD PRESSURE or end-organ dysfunction - hypotonia, syncope, incontinence        |
|      c. SEVERE GASTROINTESTINAL symptoms - crampy abdominal pain, repetitive vomiting             |
|                                                                                                   |
|   CRITERION 2 -- Acute onset of HYPOTENSION, BRONCHOSPASM or LARYNGEAL involvement after          |
|   exposure to a KNOWN or HIGHLY PROBABLE allergen for that patient, EVEN WITHOUT SKIN FINDINGS.   |
|                                                                                                   |
|   KEY POINT: 10 to 20 percent of anaphylaxis has NO cutaneous findings. Absent hives never        |
|   excludes the diagnosis.                                                                         |
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Immediate management, in order:

1. Intramuscular epinephrine - 1 mg/mL concentration, 0.3 to 0.5 mg for adults, into the mid-outer thigh (vastus lateralis). Repeat every 5 to 15 minutes as needed. There is no absolute contraindication to epinephrine in anaphylaxis. The intramuscular thigh route achieves higher and faster peak concentrations than subcutaneous or deltoid administration.
2. Position supine with legs elevated (or in a position of comfort if there is respiratory distress or vomiting). Do not let the patient stand or sit up abruptly - the "empty ventricle" syndrome has caused sudden death.
3. Call emergency services, give high-flow oxygen, and establish intravenous access with an isotonic crystalloid bolus for hypotension.
4. Adjuncts only after epinephrine: an inhaled beta-2 agonist for bronchospasm, an H1 antihistamine for itch and hives, and a corticosteroid. None of these treats airway edema or shock, and none prevents biphasic reactions.
5. Beta-blocked patients may be refractory to epinephrine; glucagon 1 to 5 mg IV bypasses the beta receptor.

Discharge planning is examinable. Prescribe two epinephrine auto-injectors, demonstrate the technique, provide a written anaphylaxis emergency action plan, advise a medical identification bracelet, refer to allergy/immunology, and counsel on avoidance. Extended routine observation is no longer required for every uncomplicated, promptly treated episode; observation duration is individualized based on severity, response and access to care, with longer observation for severe reactions, repeat epinephrine dosing or unreliable access to emergency services. A serum tryptase drawn within 15 minutes to 3 hours can support the diagnosis retrospectively but must never delay treatment, and a normal level does not exclude anaphylaxis, particularly food-triggered episodes.

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2. Urticaria

Individual wheals in urticaria are transient, migratory and resolve within 24 hours without residual bruising. A wheal that lasts more than 24 hours, burns rather than itches, or leaves purpura or hyperpigmentation suggests urticarial vasculitis and requires a skin biopsy and an evaluation for connective tissue disease.

Treatment ladder for chronic spontaneous urticaria:

1. A second-generation H1 antihistamine at standard dose (cetirizine, levocetirizine, loratadine, fexofenadine, bilastine).
2. Uptitrate the same agent up to four times the standard dose - this is the step most often missed.
3. Add omalizumab (anti-IgE) for refractory disease; cyclosporine is an alternative in specialist care.
4. Avoid chronic systemic corticosteroids; short bursts only for severe exacerbations.

First-generation antihistamines are not preferred: they sedate, impair driving and cognition, and carry anticholinergic burden that is unacceptable in older adults.

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3. Angioedema: The Distinction That Changes Management

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|              HISTAMINERGIC (MAST-CELL) vs BRADYKININ-MEDIATED ANGIOEDEMA                          |
|                                                                                                   |
|   FEATURE            HISTAMINERGIC (allergic)          BRADYKININ-MEDIATED                        |
|   ================   ===========================       ==========================                 |
|   Urticaria/itch     PRESENT - hives, pruritus         ABSENT - no hives, no itch                 |
|   Onset              Minutes                           Hours (often overnight)                    |
|   Duration           Hours to ~24 hours                24 to 72+ hours                            |
|   Typical causes     Foods, drugs, stings, latex       ACE INHIBITORS; hereditary or acquired     |
|                                                        C1 esterase inhibitor deficiency           |
|   Epinephrine        EFFECTIVE                         INEFFECTIVE (may be trialed empirically    |
|                                                        when the mechanism is unclear)             |
|   Antihistamines /   EFFECTIVE                         INEFFECTIVE                                |
|   corticosteroids                                                                                 |
|   Specific therapy   Epinephrine, H1/H2 blockade       Icatibant, ecallantide, C1-INH concentrate,|
|                                                        or fresh frozen plasma if unavailable      |
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ACE inhibitor-induced angioedema deserves its own paragraph because it is so heavily tested. It occurs in roughly 0.1 to 0.7 percent of users, is several times more common in Black patients, and - critically - can begin at any time, from the first dose to years into uneventful therapy. Because it is bradykinin-mediated, there is no urticaria and no pruritus. Management is airway assessment first, then permanent discontinuation of the entire ACE inhibitor class. Rechallenge is contraindicated. Substituting an ARB carries a small cross-reactivity risk (roughly 2 to 10 percent in observational data); many clinicians switch to a different class altogether, and if an ARB is used it should follow full resolution with informed counseling. Sacubitril/valsartan must not be started until at least 36 hours after the last ACE inhibitor dose.

Hereditary angioedema: recurrent, non-pruritic swelling of the face, extremities, genitals, bowel wall (presenting as recurrent unexplained severe abdominal pain) and larynx, frequently starting in adolescence with a positive family history. Screening test: a low C4 between attacks; then C1 inhibitor level and function. It does not respond to epinephrine, antihistamines or corticosteroids.

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4. Drug Allergy and Penicillin Delabeling

Distinguish a true IgE-mediated (type I) reaction - urticaria, angioedema, bronchospasm, hypotension within minutes to an hour - from a benign predictable adverse effect such as nausea, from a delayed benign maculopapular rash, and from severe cutaneous adverse reactions. The severe reactions - Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS (drug reaction with eosinophilia and systemic symptoms) and acute generalized exanthematous pustulosis - are absolute contraindications to rechallenge and to any skin testing or oral challenge.

Roughly 10 percent of the US population carries a penicillin allergy label, and about 90 percent of them are not truly allergic, because childhood viral exanthems were mislabeled and because IgE sensitivity wanes over time - about 80 percent of true penicillin allergy resolves after 10 years. Carrying an incorrect label is not harmless: it drives use of vancomycin, fluoroquinolones and clindamycin, with more Clostridioides difficile infection, more resistant organisms, higher costs and worse surgical outcomes. Delabeling through a structured history, penicillin skin testing, or a direct oral amoxicillin challenge in low-risk patients is now standard practice and is an appropriate primary care referral.

Cross-reactivity between penicillins and cephalosporins is far lower than historically taught - on the order of 1 to 2 percent - and is driven by shared R1 side chains rather than by the beta-lactam ring itself.

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5. Suspecting Adult Primary Immunodeficiency

Most adult "recurrent infection" is explained by anatomy, smoking, allergic disease, diabetes, medications or a secondary immunodeficiency such as HIV, malignancy, or biologic and corticosteroid therapy. Still, primary immunodeficiency is frequently diagnosed for the first time in adulthood.

Consider evaluation when a patient has:

• Two or more episodes of pneumonia in a year, or recurrent bacterial sinusitis or otitis requiring repeated antibiotics
• Bronchiectasis without another explanation
• Recurrent deep-seated infections or abscesses, or infection with an unusual or opportunistic organism
• Chronic diarrhea with weight loss, or unexplained splenomegaly and lymphadenopathy alongside infections
• A family history of immunodeficiency

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency in adults, with a bimodal onset and a peak in the second to fourth decades. Laboratory findings are low IgG together with low IgA and/or low IgM, plus impaired responses to vaccine antigens (measured as pneumococcal and tetanus titers before and after immunization). Treatment is immunoglobulin replacement and aggressive infection management. Selective IgA deficiency is the most common primary immunodeficiency overall, usually asymptomatic, but associated with celiac disease, autoimmune conditions, and rare anaphylactic transfusion reactions to IgA-containing blood products.

Initial primary care screen: CBC with differential, quantitative immunoglobulins (IgG, IgA, IgM), HIV testing, and vaccine-response titers, with referral to allergy/immunology for anything abnormal. Live vaccines are contraindicated in significant antibody or combined immunodeficiency and in patients receiving immunoglobulin replacement, which also blunts serologic testing.