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Allergy, Urticaria & Adult Immunodeficiency

Name: Allergy, Urticaria & Adult Immunodeficiency
Creator: Veli Bakalov, MD

When swelling itches vs when it does not — and which infections betray a missing defense

Infectious Disease·Immunocompromised Host & Allergy·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Urticaria = pruritic, blanching histamine wheals that each resolve within 24 hours; acute is under 6 weeks, chronic 6 weeks or longer (usually spontaneous or autoimmune).
Chronic urticaria: second-generation H1 antihistamine, uptitrate up to fourfold, then omalizumab, then cyclosporine; dupilumab and remibrutinib (2025) are newer options; H2 blocker or leukotriene antagonist add-ons appear in the older US practice parameter but are not routine in international guidelines; avoid chronic steroids.
Angioedema with hives and itch is histaminergic (epinephrine, antihistamines, steroids work); angioedema without hives or itch is usually bradykinin-mediated (ACE inhibitor or hereditary) and does not respond to them.
Hereditary angioedema: autosomal dominant C1-INH deficiency, recurrent face, larynx and gut swelling without urticaria; screen with C4 (low even between attacks), treat attacks with C1-INH concentrate, icatibant or ecallantide.
ACE inhibitor angioedema can appear years into therapy and is more common in Black patients; protect the airway, stop the ACE inhibitor permanently, and use an ARB if needed.
Allergic rhinitis: pale boggy turbinates; an intranasal corticosteroid is the most effective single therapy.
Anaphylaxis: IM epinephrine 0.3–0.5 mg (1 mg/mL) in the anterolateral thigh first; antihistamines and steroids are adjuncts; discharge with two auto-injectors and warn about biphasic reactions.
Most penicillin allergy labels are not IgE-mediated; cephalosporin cross-reactivity is about 1–2%, and desensitization gives only temporary tolerance (e.g., penicillin for syphilis in pregnancy).
CVID (low IgG plus IgA and/or IgM, poor vaccine response, sinopulmonary infections, Giardia, autoimmunity) is treated with IVIG; recurrent Neisseria means terminal complement deficiency (screen CH50, vaccinate); IgA deficiency causes anaphylaxis to blood products.

Urticaria

Wheals. Urticaria consists of pruritic, well-demarcated, blanching wheals, each resolving within 24 hours, driven by mast cell histamine release (type I). Individual lesions that last longer, burn or leave bruising suggest urticarial vasculitis and warrant biopsy.

Acute versus chronic. Acute urticaria (under 6 weeks) usually follows an infection, a food or a drug. Chronic urticaria (6 weeks or longer) is usually spontaneous (idiopathic) or autoimmune, with autoantibodies against IgE or its receptor, so broad allergy testing rarely helps. Physical triggers such as pressure, cold and scratching (dermatographism) cause inducible forms.

Second-generation H1 antihistaminecetirizine, loratadine or fexofenadine
Uptitrateup to fourfold the standard dose
Omalizumabanti-IgE monoclonal antibody for antihistamine-refractory chronic spontaneous urticaria (the older US practice parameter also allows an H2 blocker or leukotriene receptor antagonist add-on first; international guidelines no longer advise it)
Still refractorycyclosporine; newer options are dupilumab and the oral BTK inhibitor remibrutinib (both FDA approved 2025)

Stepwise therapy for chronic urticaria

Avoid chronic systemic steroids for urticaria; their harms outweigh the benefit.

Angioedema: histamine or bradykinin

The split. Angioedema is deeper swelling of the dermis and subcutaneous or submucosal tissue. Histaminergic (mast cell, allergic) angioedema comes WITH urticaria and itch, often as part of anaphylaxis, and responds to epinephrine, antihistamines and steroids. Bradykinin-mediated angioedema, from ACE inhibitors or hereditary C1-inhibitor deficiency, has NO urticaria and NO itch and does NOT respond to those drugs.

Three kinds of angioedema

Feature	Histaminergic	ACE inhibitor	Hereditary (HAE)
Mediator	Histamine	Bradykinin (ACE normally degrades it)	Bradykinin (unopposed kallikrein)
Urticaria, itch	Present	Absent	Absent
Sites	Face and lips, with hives, wheeze or hypotension	Lips, tongue, face, airway	Face, larynx, gut (abdominal pain mimicking a surgical abdomen)
C4	Normal	Normal	Persistently low
Acute treatment	Epinephrine, antihistamines, steroids	Airway first; stop the drug	C1-INH concentrate, icatibant or ecallantide; FFP as backup
Long term	Avoid the trigger	Never restart an ACE inhibitor; an ARB is generally tolerated	Prophylaxis with C1-INH, lanadelumab or attenuated androgens (danazol)

Hereditary angioedema. Autosomal dominant C1 esterase inhibitor deficiency, either low levels (type 1) or a dysfunctional protein (type 2), leaves kallikrein unchecked; C4 is consumed and bradykinin accumulates, increasing vascular permeability. Attacks recur from adolescence, often with a positive family history, and are triggered by trauma (including dental work), stress, estrogen and ACE inhibitors. Screen with C4, which is low both during and between attacks, and confirm with C1-INH level and function. Icatibant blocks the bradykinin B2 receptor; ecallantide inhibits kallikrein.

ACE inhibitor angioedema. Because ACE also breaks down bradykinin, ACE inhibitors can cause angioedema even years into therapy, more often in Black patients. Prioritize the airway, since allergy drugs fail, then stop the ACE inhibitor permanently; switching to a different ACE inhibitor is never appropriate.

Laryngeal swelling in any angioedema can kill: secure the airway early, with fiberoptic intubation or a surgical airway if needed.

Allergic rhinitis and food allergy

Allergic rhinitis. IgE-mediated sneezing, clear rhinorrhea, nasal congestion and itchy, watery eyes, with pale, boggy turbinates; allergic shiners and a transverse nasal crease are common. The single most effective treatment is an intranasal corticosteroid. Add a second-generation oral or intranasal antihistamine and allergen avoidance, and reserve allergen immunotherapy for refractory disease. Topical decongestants used for more than a few days cause rebound congestion (rhinitis medicamentosa).

Food allergy. IgE-mediated reactions to peanut, tree nuts, shellfish, milk and egg are managed by strict avoidance and a ready epinephrine auto-injector. Early dietary peanut introduction (the LEAP trial) reduces peanut allergy in high-risk infants.

Anaphylaxis and drug allergy

Anaphylaxis. Immediate intramuscular epinephrine, 0.3–0.5 mg of 1:1000 (1 mg/mL) into the anterolateral thigh, is first-line and life-saving, repeated every 5–15 minutes if needed. Antihistamines and steroids are adjuncts only; add IV fluids and supine positioning, and use glucagon for patients on β-blockers who do not respond to epinephrine. An elevated serum tryptase supports mast cell activation.

After the event. Observe for biphasic reactions, which can recur hours later. Prescribe two epinephrine auto-injectors, refer to allergy, and identify and avoid triggers.

Penicillin allergy. True penicillin allergy is an IgE-mediated type I reaction (urticaria, anaphylaxis). Most reported penicillin allergy is not IgE-mediated and can be de-labeled: penicillin skin testing has a high negative predictive value, and low-risk histories can proceed to a supervised oral amoxicillin challenge. A rash alone is usually not a contraindication, and cephalosporin cross-reactivity is only about 1–2%, mainly with early-generation agents, far below the historically taught 10%.

Desensitization. When a truly allergic patient needs a specific drug (penicillin for syphilis in pregnancy, aspirin in coronary disease or aspirin-exacerbated respiratory disease, some chemotherapies), rapidly escalating tiny-to-full doses are given under monitoring to induce temporary tolerance. Tolerance is lost once the drug is stopped, so the drug must be continued without interruption or the desensitization repeated.

Desensitization is for IgE-type reactions; never rechallenge after SJS/TEN or DRESS.

Adult immunodeficiency

Pattern recognition. Recurrent, severe or unusual infections in an adult deserve a look for a missing defense, and the organism points to which one.

Humoral and complement defects in adults

Defect	Labs	Infections	Associations	Management
CVID	Low IgG plus low IgA and/or IgM; poor vaccine response	Encapsulated sinopulmonary bacteria, chronic Giardia	Bronchiectasis, autoimmune cytopenias, lymphoma	IVIG
Selective IgA deficiency	Isolated low IgA	Usually none; mild sinopulmonary and GI	Anaphylaxis to blood products (anti-IgA), celiac disease	IgA-deficient or washed blood products
Terminal complement (C5–C9, membrane attack complex)	Low CH50; normal immunoglobulins	Recurrent Neisseria (meningococcemia, disseminated gonococcemia)	Eculizumab (C5 blockade) mimics it	Meningococcal vaccination
Early classical (C1, C2, C4)	Low CH50	Pyogenic infections	Lupus-like autoimmunity	Vaccinate, treat autoimmunity

CVID. Common variable immunodeficiency is the most common symptomatic primary immunodeficiency in adults and presents at ages 20–40. B cells are present but fail to become antibody-secreting plasma cells, unlike X-linked agammaglobulinemia, which lacks B cells and presents in infant boys. Immunoglobulin replacement reduces infections.

Complement screening. CH50 tests the whole classical pathway; a low or absent value flags a component defect and prompts measurement of individual components.

Selective IgA deficiency. This is the most common primary immunodeficiency overall and is usually asymptomatic. When screening these patients for celiac disease, IgA-based serology is falsely negative, so IgG-based tests are used.