Immune System

Hereditary angioedema: diagnosis and management

Clinical Overview and When to Suspect Hereditary Angioedema

— Bradykinin (not histamine) drives the edema, explaining failure of antihistamines, epinephrine, and glucocorticoids

— Type I (~85%): low antigenic and functional C1-INH

— Type II (~15%): normal antigenic but low functional C1-INH (dysfunctional protein)

— HAE with normal C1-INH (formerly Type III): often factor XII, plasminogen, or angiopoietin-1 mutations; more common in women, estrogen-sensitive

— Recurrent angioedema without urticaria or pruritus, lasting 2–5 days

— Onset typically in childhood/adolescence, family history in ~75%

— Recurrent unexplained abdominal pain with vomiting (visceral edema mimicking surgical abdomen)

— Laryngeal edema episodes, often triggered by dental work, intubation, or trauma

— Failure to respond to epinephrine, antihistamines, and steroids

Board pearl: Any patient with recurrent angioedema unresponsive to antihistamines/steroids and no urticaria should prompt a C4 level—it is the best initial screening test and is low during and between attacks in HAE.

Hereditary angioedema (HAE) is an autosomal dominant disorder of the kallikrein-bradykinin pathway producing recurrent, self-limited, non-pruritic, non-urticarial subcutaneous and submucosal swelling

Pathophysiology: deficient or dysfunctional C1 esterase inhibitor (C1-INH) → unregulated activation of plasma kallikrein → excessive bradykinin generation → increased vascular permeability

Three classic forms:

When to suspect on Step 3:

Triggers: minor trauma, surgery/dental procedures, infections, stress, ACE inhibitors, and estrogen-containing OCPs/HRT

Epidemiology: prevalence ~1:50,000; substantial diagnostic delay (often 8–10 years)

Presentation Patterns and Key History

— Cutaneous (subcutaneous) swelling: non-pitting, non-pruritic, non-erythematous edema of extremities, face, genitals, buttocks; disfiguring but not dangerous

— Abdominal attacks: colicky pain, nausea, vomiting, diarrhea from bowel wall edema; can mimic appendicitis, SBO, or ovarian torsion and prompt unnecessary laparotomy

— Laryngeal attacks: hoarseness, dysphagia, "lump in throat," stridor; historically ~30% mortality before modern therapy if untreated

— Gradual onset over hours, peak 12–36h, resolves over 2–5 days

— Often preceded by a prodrome: tingling, fatigue, or erythema marginatum (serpiginous non-pruritic rash, pathognomonic when present)

— No urticaria, no pruritus — this is the defining negative

— Dental procedures, intubation, surgery (highest-risk for laryngeal attack)

— Estrogen exposure: menarche, OCPs, pregnancy, HRT

— ACE inhibitor initiation (potentiates bradykinin) — even in patients without HAE, but worse in HAE

— Emotional stress, infection (especially H. pylori in abdominal attacks)

— Minor trauma, prolonged sitting, tight clothing

— Autosomal dominant — ask about relatives with unexplained swelling, "allergic" deaths, or laryngeal swelling

— ~25% are de novo mutations, so absence of family history does not rule out HAE

Key distinction: Histaminergic angioedema = minutes to onset, urticaria/pruritus, responds to epinephrine. Bradykinin-mediated (HAE) = hours to onset, no urticaria, no response to standard anaphylaxis therapy.

Three stereotyped attack phenotypes — most patients experience all three over a lifetime:

Attack characteristics:

Trigger history to elicit:

Family history:

Age of onset: typically childhood, often worsens at puberty; rare new onset after age 40 (consider acquired C1-INH deficiency instead — lymphoproliferative or autoimmune)

Physical Exam Findings and Airway Assessment

— Non-pitting, firm, tense, non-erythematous swelling without surrounding warmth

— No hives, no wheals, no pruritus — if urticaria is present, reconsider HAE

— Possible erythema marginatum prodrome: flat, non-pruritic, serpiginous, blanching rash on trunk/extremities

— Face/lips/tongue/uvula: asymmetric or symmetric soft-tissue swelling; assess for tongue protrusion, drooling, muffled "hot potato" voice

— Larynx: hoarseness, stridor, dysphonia, dysphagia — these are airway red flags

— Extremities/genitals: tense, doughy swelling; functional impairment but rarely dangerous

— Abdomen: diffuse tenderness, guarding, hypoactive bowels; may have ascites on imaging; rebound is uncommon (helps distinguish from surgical abdomen)

— Hypotension, tachycardia, orthostasis from intravascular volume depletion

— Check for signs of shock; aggressive IV fluids may be needed alongside HAE-specific therapy

— Voice changes, stridor, accessory muscle use, oxygen saturation

— Low threshold for fiberoptic laryngoscopy to visualize supraglottic edema

— Anticipate difficult airway — early consultation with anesthesia/ENT

— Continuous pulse oximetry, capnography if available

— Repeat airway assessment every 15–30 minutes during evolving attack

CCS pearl: For any HAE patient presenting with voice change, drooling, or stridor, order: continuous pulse ox, ENT/anesthesia consult, prepare difficult airway cart, and administer on-demand HAE therapy immediately—do not wait for labs. Delayed intubation in a swollen airway can become surgical cricothyrotomy.

General appearance during an attack:

Site-specific exam:

Hemodynamic assessment — abdominal attacks can cause third-spacing:

Airway evaluation in suspected laryngeal attack (highest priority):

Vital signs and monitoring:

Diagnostic Workup — Initial Labs and Screening

— Persistently low during attacks AND between attacks in ~95% of HAE Type I/II patients

— Inexpensive, widely available

— Normal C4 between attacks makes HAE Type I/II unlikely (but does not exclude HAE with normal C1-INH)

— Low in Type I (~85% of cases)

— Normal in Type II and HAE with normal C1-INH

— Low in both Type I and Type II

— Required to diagnose Type II (where quantitative level is normal but protein doesn't work)

— C1q level: normal in HAE, LOW in acquired C1-INH deficiency (paraneoplastic, autoimmune)

— CBC, CMP, urinalysis — usually unremarkable

— If abdominal attack suspected: lipase, lactate, CT abdomen may show bowel wall edema, ascites without obstruction or ischemia

— C1-INH and C4 levels can be unreliable in infants <1 year (immature complement system)

— Repeat after age 1; genetic testing if uncertain

— AAE: onset >40, no family history, low C1q, associated with lymphoma, MGUS, autoimmune disease

— HAE: childhood/adolescent onset, family history common, normal C1q

Board pearl: Memorize the panel: C4 (screen) + C1-INH quantitative + C1-INH functional + C1q. Low C4 + low C1q = think acquired angioedema and screen for lymphoproliferative disorder. Low C4 + normal C1q = hereditary.

C4 level is the single best initial screening test:

C1 inhibitor antigenic (quantitative) level:

C1 inhibitor functional assay:

Confirm with repeat testing at least once, ideally separated by 1–3 months, to exclude lab error

Additional testing depending on context:

Pediatric considerations:

Differentiating acquired (AAE) from hereditary:

Diagnostic Workup — Confirmatory and Specialized Studies

— Confirms diagnosis when complement labs are equivocal

— Essential for HAE with normal C1-INH — test for mutations in F12 (factor XII), PLG (plasminogen), ANGPT1, KNG1, and others

— Useful in pediatric patients <1 year and for family screening

— Counsel on autosomal dominant inheritance and 50% transmission risk

— Single low value should be confirmed with repeat testing 1–3 months later

— Concurrent measurement of C4, C1-INH antigen, C1-INH function in same draw improves diagnostic accuracy

— SPEP/UPEP with immunofixation, serum free light chains → screen for MGUS/myeloma

— CT chest/abdomen/pelvis, peripheral smear, flow cytometry → screen for lymphoma/CLL

— ANA, anti-C1-INH autoantibody assay

— All first-degree relatives should undergo C4 and C1-INH testing, even if asymptomatic

— Early diagnosis allows preprocedural prophylaxis and avoidance of ACE inhibitors/estrogens

— Genetic counseling for reproductive-age patients

— Establish baseline attack frequency, severity, and prior triggers

— Validated tools: Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) — used to track response to long-term prophylaxis

— Many HAE patients have been labeled "allergic" or undergone exploratory laparotomy

— Reconcile prior records and re-test rather than assume

Step 3 management: Once HAE is biochemically confirmed, screen all first-degree relatives, refer to an allergist/immunologist with HAE expertise, and provide a written HAE action plan including on-demand therapy, emergency contacts, and a wallet card listing diagnosis and treatments.

Genetic testing:

Repeat complement panel:

Workup of acquired angioedema when C1q is low:

Family screening:

Documentation and disease registries:

Misdiagnosis pitfalls to address:

Risk Stratification and Management Framework

— On-demand (acute) treatment of attacks

— Short-term prophylaxis before known triggers (procedures, dental work)

— Long-term prophylaxis if attack burden warrants

— Severity: laryngeal > facial/oropharyngeal > abdominal > peripheral

— Frequency: >1 attack/month or any attack causing significant disability → consider long-term prophylaxis

— Location risk: any history of laryngeal attack confers lifetime risk and lowers threshold for prophylaxis

— Access to at least 2 doses of on-demand therapy at all times, kept at home and ideally on person

— Written emergency action plan; medical alert identification

— Avoidance of ACE inhibitors (use ARB if needed) and estrogen-containing contraceptives/HRT (progestin-only preferred)

— Treat all laryngeal attacks immediately, regardless of perceived severity

— Early treatment (within 1 hour of prodrome/onset) shortens duration and severity

— Frequent attacks (typically ≥1/month) OR

— Any history of laryngeal involvement OR

— Impaired quality of life despite optimized on-demand therapy OR

— Poor access to on-demand treatment

— Recognize prodrome (erythema marginatum, tingling) and self-administer early

— When to call EMS (any airway symptom)

— Avoid trigger medications and inform all providers (dentists, surgeons) of diagnosis

Board pearl: Every HAE patient — even mild — needs on-demand therapy available, an action plan, and avoidance of ACEi/estrogens. The decision point is whether to add long-term prophylaxis, driven by attack frequency, severity, and quality of life.

HAE management has three pillars — every patient needs a plan for each:

Risk stratification by attack characteristics:

Universal principles (apply to ALL HAE patients regardless of severity):

Indications for long-term prophylaxis (2020 WAO/EAACI guidance):

Patient education priorities:

Pharmacotherapy — On-Demand and Long-Term Prophylaxis

— Icatibant (bradykinin B2 receptor antagonist) — SC injection, self-administered

— Ecallantide (plasma kallikrein inhibitor) — SC; risk of anaphylaxis, must be given by HCP

— Plasma-derived C1-INH (Berinert, Cinryze) — IV, can be self-administered after training

— Recombinant C1-INH (Ruconest) — IV

— If none available: fresh frozen plasma (FFP) as last resort (contains C1-INH but also kininogen substrate — can worsen attacks rarely)

— Antihistamines, steroids, epinephrine DO NOT WORK in HAE; epinephrine may be given empirically if diagnosis uncertain but should not delay HAE-specific therapy

— IV plasma-derived C1-INH 1–6 hours before procedure (preferred)

— Alternatives: attenuated androgens (danazol) 5 days before and 2–3 days after

— Always have on-demand therapy available during and after procedure regardless of prophylaxis

— Subcutaneous C1-INH (Haegarda) — twice weekly SC

— Lanadelumab — monoclonal antibody against plasma kallikrein, SC every 2–4 weeks

— Berotralstat — oral plasma kallikrein inhibitor, once daily

— These have largely replaced older second-line agents

— Attenuated androgens (danazol, stanozolol) — hepatotoxicity, virilization, lipid changes; contraindicated in pregnancy/children

— Antifibrinolytics (tranexamic acid) — modest efficacy; thrombosis risk

Step 3 management: For an HAE patient presenting to the ED with facial/laryngeal swelling, administer on-demand therapy (icatibant or C1-INH concentrate) immediately, secure airway readiness, and do not delay for labs or for trials of epinephrine/antihistamines.

On-demand (acute) therapy — administer ASAP, ideally within 1 hour of symptom onset; treat ALL laryngeal attacks:

Short-term (preprocedural) prophylaxis — before dental work, surgery, intubation:

Long-term prophylaxis (LTP) — first-line agents (2020 guidelines):

Second-line LTP (older, more side effects):

Acute Management Algorithm and Procedural Considerations

— Step 1: Rapid airway assessment — voice, stridor, oxygen sat, oropharyngeal exam

— Step 2: Administer on-demand therapy immediately if HAE is known or strongly suspected (do not wait for confirmatory labs)

— Step 3: Position patient upright; prepare difficult airway equipment if any airway involvement

— Step 4: Consult ENT and anesthesia early for laryngeal/oropharyngeal attacks

— Step 5: Reassess every 15–30 minutes; repeat dosing per drug-specific guidelines if no improvement (e.g., icatibant can be redosed at 6h, up to 3 doses/24h)

— Awake fiberoptic intubation preferred for any signs of laryngeal involvement

— Surgical airway (cricothyrotomy/tracheostomy) must be readily available — laryngeal HAE can rapidly deteriorate

— Avoid repeated intubation attempts in a swollen airway

— On-demand HAE therapy is mainstay

— Aggressive IV fluid resuscitation for third-spacing

— Antiemetics, analgesia (opioids often required); avoid unnecessary surgery

— CT may show bowel wall thickening, ascites — these resolve with treatment

— Dental cleanings and minor work: short-term prophylaxis often given; on-demand on hand

— Intubation/major surgery: IV C1-INH 1–6 hours pre-op; have second dose available intraoperatively

— Pregnancy/labor: vaginal delivery preferred; C1-INH for forceps/vacuum/C-section

— Observe for ≥4 hours after on-demand therapy if peripheral attack resolving

— Admit for any laryngeal, persistent oropharyngeal, or severe abdominal attack

— ICU for actual or impending airway compromise

CCS pearl: For a known HAE patient scheduled for elective dental extraction, order IV plasma-derived C1-INH 1 hour pre-procedure, ensure on-demand therapy at bedside, and document a post-procedure observation plan. Never proceed with airway-related procedures in HAE without prophylaxis available.

ED algorithm for suspected HAE attack:

Airway management:

Abdominal attacks:

Periprocedural prophylaxis pearls:

Disposition:

Special Populations — Elderly and Hepatic/Renal Impairment

— Diagnosis often delayed; new symptoms after age 40 should raise concern for acquired C1-INH deficiency rather than HAE — check C1q and screen for malignancy

— Comorbid hypertension is common — strictly avoid ACE inhibitors; ARBs are acceptable

— Coronary disease management: aspirin and statins are safe; consider bleeding risk with antifibrinolytics

— Polypharmacy review for bradykinin-potentiating drugs (DPP-4 inhibitors like sitagliptin can rarely potentiate angioedema, especially in combination with ACEi)

— Avoid attenuated androgens (danazol) — hepatotoxicity, hepatic adenomas with long-term use

— Plasma-derived and recombinant C1-INH are safe; no dose adjustment

— Lanadelumab and berotralstat: limited data in severe hepatic disease — use cautiously

— Monitor LFTs at baseline and periodically on any long-term prophylaxis

— No dose adjustment needed for C1-INH products, icatibant, or lanadelumab

— Berotralstat: limited data in severe CKD; monitor

— Tranexamic acid: renally cleared — dose-reduce in CKD and avoid in advanced kidney disease (thrombosis risk)

— Ecallantide: monitor; minimal renal excretion

— Berotralstat is a CYP2D6/CYP3A4 inhibitor — check for interactions with metoprolol, codeine, tamoxifen, statins

— Review concomitant anticoagulants if antifibrinolytics considered

— Late-onset angioedema with low C1q warrants age-appropriate malignancy screening and hematologic workup (CBC, SPEP, peripheral smear, imaging) for lymphoproliferative disease

Key distinction: New-onset angioedema in a patient >40 with no family history and low C1q = acquired C1-INH deficiency, often paraneoplastic. Workup for lymphoma, MGUS, and autoimmune disease is mandatory before chronic HAE-style therapy.

Elderly HAE patients:

Hepatic impairment:

Renal impairment:

Drug interactions in older patients:

Cancer screening:

Special Populations — Pregnancy, Pediatrics, and Reproductive Health

— Attack frequency is unpredictable — may improve, worsen, or stay the same; often worsens in third trimester

— Plasma-derived C1-INH is the drug of choice for on-demand, short-term, and long-term prophylaxis in pregnancy and lactation (extensive safety data)

— Avoid: attenuated androgens (virilization of female fetus, teratogenic), icatibant and lanadelumab (limited pregnancy data; case-by-case), berotralstat (limited data)

— Tranexamic acid: generally considered safe but not preferred

— Estrogens are contraindicated postpartum — use progestin-only contraception

— Vaginal delivery preferred — lower trauma than C-section

— Prophylactic C1-INH for operative vaginal delivery (forceps/vacuum), C-section, or epidural placement in patients with frequent attacks

— Have on-demand therapy at bedside during labor

— Avoid prolonged intubation; regional anesthesia preferred over general

— Onset often in childhood; attacks may worsen at puberty

— Plasma-derived C1-INH approved across pediatric age ranges

— Icatibant approved ≥2 years; lanadelumab ≥2 years; berotralstat ≥12 years (check current labels)

— Avoid attenuated androgens in children — growth plate closure, virilization

— Test all children of affected parents; reliable testing after age 1

— Counsel on avoiding estrogen-containing OCPs; progestin-only or non-hormonal contraception preferred

— Address school accommodations, sports participation, mental health

— Autosomal dominant: 50% transmission per pregnancy

— Preimplantation genetic diagnosis is available but rarely pursued

Board pearl: In pregnancy, plasma-derived C1-INH is the safest and preferred agent for both on-demand and prophylaxis. Danazol is teratogenic and contraindicated; estrogens worsen disease.

Pregnancy:

Labor and delivery:

Pediatrics:

Adolescents:

Reproductive counseling:

Complications and Adverse Outcomes

— Laryngeal edema is the leading cause of HAE-related death

— Pre-modern-therapy mortality from laryngeal attacks: ~30%

— Sudden death can occur within hours; never observe a laryngeal attack without treatment

— Abdominal attacks frequently misdiagnosed as appendicitis, cholecystitis, SBO, or ovarian torsion

— Negative laparotomy is a common historical event in undiagnosed patients

— Iatrogenic intubation in a misdiagnosed attack can precipitate worsening laryngeal edema

— Anxiety, depression, social withdrawal due to unpredictable attacks and disfigurement

— High rates of work/school absenteeism

— Document AE-QoL and screen for depression/anxiety annually

— Attenuated androgens: hepatic adenomas/HCC, hyperlipidemia, virilization, mood changes, menstrual irregularities, growth suppression

— Antifibrinolytics: thrombosis, myalgia, GI upset

— Plasma-derived products: theoretical infectious risk (modern viral inactivation makes this very low)

— Ecallantide: anaphylaxis (~3%) — must be administered by trained personnel

— Lanadelumab/berotralstat: injection site reactions, GI upset; berotralstat — QT effects, drug interactions

— Average diagnostic delay 8–10 years

— Patients incorrectly treated with steroids/epinephrine repeatedly with no benefit

— Increased attack frequency during labor and postpartum

— Risk of postpartum hemorrhage with antifibrinolytics

Step 3 management: When a patient with recurrent abdominal pain has had a negative ex-lap or repeated negative workups, add HAE to the differential, draw a C4 level, and avoid further invasive workup until complement testing returns.

Airway compromise and death:

Unnecessary surgical interventions:

Quality of life and psychiatric burden:

Treatment-related complications:

Diagnostic delay complications:

Pregnancy complications:

When to Escalate Care — ICU, Consult, and Admission

— Stridor, hoarseness with progression, oxygen desaturation, or any actual airway compromise

— Need for intubation or ongoing airway monitoring

— Hemodynamic instability from severe abdominal attack with third-spacing

— Failure to respond to on-demand therapy within expected window (icatibant: improvement within 1 hour)

— Resolving but persistent oropharyngeal swelling

— Severe abdominal attack requiring IV fluids, analgesia, antiemetics

— Inability to tolerate PO

— Social/access barriers preventing safe outpatient observation

— Allergy/immunology with HAE expertise: every confirmed or suspected case for long-term plan

— ENT and anesthesia: any oropharyngeal/laryngeal attack; difficult airway anticipation

— OB: pregnant patients for delivery planning

— Hematology/oncology: suspected acquired C1-INH deficiency

— Genetic counseling: family planning, family screening

— Peripheral or mild facial attacks responding to on-demand therapy

— No airway involvement

— Reliable access to second dose of on-demand therapy

— Established follow-up

— Ensure on-demand therapy is in the patient's possession at discharge — not just prescribed

— Communicate diagnosis to PCP, dentist, and pharmacy

— Verify insurance authorization for high-cost specialty medications before discharge

— Schedule HAE specialist follow-up within 2–4 weeks

CCS pearl: For an HAE patient discharged from the ED after a treated peripheral attack, order: on-demand therapy refill to pharmacy, allergy/immunology referral within 2 weeks, PCP follow-up within 1 week, MedicAlert bracelet education, and discontinue any ACEi.

Immediate ICU admission criteria:

Inpatient (non-ICU) admission criteria:

Specialist consultations:

Outpatient management criteria:

Transitions of care:

Key Differentials — Other Causes of Angioedema

— Onset minutes after trigger; resolves within 24–48h

— Urticaria, pruritus, flushing common

— Responds to antihistamines, epinephrine, glucocorticoids

— Triggers: foods, drugs (NSAIDs, antibiotics), insect stings, latex

— Recurrent angioedema without identifiable trigger or family history

— Normal complement studies

— Often responds to high-dose H1 antihistamines; some respond to omalizumab

— Bradykinin-mediated (same pathway as HAE) but no complement abnormality

— Often involves face/tongue/lips; can occur years after starting ACEi

— Higher incidence in Black patients

— Management: stop ACEi permanently, switch to ARB (small cross-reactivity ~1–10%)

— Recently FDA-approved: icatibant for ACEi angioedema in some contexts; supportive care otherwise

— Onset >40, no family history

— Low C4, low C1-INH, LOW C1q, often anti-C1-INH autoantibodies

— Associated with lymphoma, MGUS, CLL, autoimmune disease

— Treat underlying disease + HAE-style therapy

— Normal C4, C1-INH antigen and function

— Genetic testing reveals F12, PLG, ANGPT1, KNG1 mutations

— Female predominance; estrogen-sensitive

— Chronic urticaria with angioedema — has urticaria, responds to antihistamines

— Mast cell activation syndrome — flushing, GI, often with elevated tryptase

Key distinction: C1q is the discriminator — normal in HAE, low in acquired C1-INH deficiency. Low C1q late-onset angioedema → workup for lymphoproliferative disease.

Histaminergic (mast cell-mediated) angioedema — most common type:

Idiopathic angioedema:

ACE inhibitor–induced angioedema:

Acquired C1-INH deficiency (AAE):

HAE with normal C1-INH:

Hereditary angioedema mimics:

Key Differentials — Non-Angioedema Mimics

— Multi-system (respiratory, skin, GI, cardiovascular), urticaria, hypotension

— Rapid onset minutes after trigger

— Responds to IM epinephrine — always give epinephrine if anaphylaxis cannot be excluded

— Tryptase elevated within 1–4 hours of attack

— Warm, red, tender, often with fever and leukocytosis

— Asymmetric, with skin changes; usually a portal of entry

— Lab evidence of infection; HAE is afebrile with no inflammatory markers

— Pruritic, erythematous, sometimes vesicular

— Distribution matches exposure

— Facial swelling, neck vein distention, dyspnea

— Imaging shows mediastinal mass or central venous obstruction

— Non-pitting facial puffiness, but chronic and progressive, with systemic features

— Distinguished by mechanism, history, and exam

— Acute intermittent porphyria: neurovisceral attacks, autonomic instability, neuropsychiatric features, dark urine

— Familial Mediterranean fever: fever, serositis, ethnic predisposition, responds to colchicine

— Functional abdominal pain/IBS: chronic, normal imaging, no third-spacing

— Endometriosis: cyclic, gynecologic exam findings

— Eosinophilic gastroenteritis: peripheral eosinophilia, biopsy findings

— Bowel ischemia, SBO, appendicitis: imaging, surgical exam findings

Board pearl: Erythema marginatum (serpiginous non-pruritic rash) preceding an attack is essentially pathognomonic for HAE when present — distinguishes from anaphylaxis (urticarial) and other mimics.

Conditions that mimic HAE attacks beyond classic angioedema:

Anaphylaxis:

Cellulitis/erysipelas:

Contact dermatitis:

Superior vena cava syndrome:

Hypothyroidism (myxedema):

Subcutaneous emphysema, hematoma, lymphedema:

Differential for recurrent abdominal pain mimicking HAE abdominal attacks:

Key feature distinguishing HAE: recurrent stereotyped attacks + family history + abnormal complement

Long-Term Plan, Secondary Prevention, and Medication Reconciliation

— Reassess attack frequency, severity, location every 3–6 months

— Initiate LTP if ≥1 attack/month, prior laryngeal attack, impaired QoL, or limited access to on-demand therapy

— First-line LTP options: subcutaneous C1-INH, lanadelumab, berotralstat

— Continue on-demand therapy availability even on LTP — breakthrough attacks occur

— Discontinue ACE inhibitors permanently; ARBs are acceptable

— Replace estrogen-containing contraceptives with progestin-only or non-hormonal methods

— Avoid estrogen HRT

— Review for DPP-4 inhibitors, neprilysin inhibitors (sacubitril) which can potentiate bradykinin

— Update vaccinations (no specific HAE contraindications beyond standard)

— Confirm patient carries 2 doses of on-demand therapy at all times

— Annual self-injection technique review

— Written HAE action plan updated yearly

— Medical alert bracelet/wallet card listing diagnosis, treatments, emergency contacts

— Notify dentists, surgeons, anesthesiologists of diagnosis well in advance

— Pre-procedure prophylaxis with IV C1-INH 1–6 hours before

— On-demand therapy at bedside

— Discuss genetic counseling

— Test all first-degree relatives

— Contraceptive counseling: progestin-only preferred

— HAE medications are extraordinarily expensive ($300,000–$600,000/year for LTP)

— Insurance prior authorization, copay assistance programs, manufacturer support critical

— Specialty pharmacy coordination

Step 3 management: At every HAE visit, reconcile meds (no ACEi, no estrogens), confirm on-demand therapy at home, document attack diary, screen for depression/anxiety, update action plan, and verify insurance coverage for next refill.

Long-term prophylaxis (LTP) decisions at follow-up:

Medication reconciliation at every visit:

Patient self-management:

Procedural planning:

Family planning:

Health systems considerations:

Follow-Up, Monitoring, and Counseling

— Allergy/immunology specialist: every 3–6 months initially, then 6–12 months once stable

— PCP: at least annually; coordinate medication reconciliation

— More frequent during pregnancy, peri-procedure, or after treatment change

— Attack diary: frequency, severity, location, triggers, treatment response

— Validated tools: AAS (Angioedema Activity Score), AE-QoL at each specialist visit

— On long-term prophylaxis:

— Subcutaneous/IV C1-INH: no routine labs required

— Lanadelumab: no routine labs required

— Berotralstat: baseline ECG (QT), LFTs; periodic monitoring; drug interaction review

— Danazol (if used): LFTs, lipid panel, hepatic ultrasound annually (adenoma screening), CBC

— Tranexamic acid: assess for thrombotic symptoms

— Recognize prodrome (tingling, erythema marginatum) and treat early

— Self-injection training for on-demand therapy — verify competence at each visit

— Trigger avoidance: review ACEi/estrogen list at every encounter

— Stress management, sleep hygiene, infection prevention

— Importance of communicating diagnosis to all healthcare providers including dentist

— Screen for depression and anxiety (PHQ-9, GAD-7) annually

— Connect with patient advocacy groups (HAEA in the US) for peer support

— Consider therapy referral for chronic disease coping

— Maintain routine immunizations; infections are common triggers

— Annual influenza, age-appropriate pneumococcal, COVID-19 boosters

— Carry on-demand therapy in carry-on with prescription documentation

— Know location of nearest HAE-knowledgeable facility at destination

Board pearl: Early self-treatment during the prodrome shortens attack duration and prevents progression to laryngeal involvement — patient education is among the highest-yield interventions in HAE care.

Follow-up cadence:

Monitoring parameters:

Patient counseling priorities:

Psychological support:

Vaccination and infections:

Travel counseling:

Ethical, Legal, and Patient Safety Considerations

— HAE medications can cost $300,000–$600,000/year; discuss cost transparently

— Document shared decision-making about LTP versus on-demand-only approach

— Engage social work for insurance navigation and copay assistance

— Autosomal dominant inheritance — duty to inform first-degree relatives

— Provider should counsel patient about familial risk but cannot directly contact relatives without consent (HIPAA)

— Offer genetic counseling before testing minors; discuss implications for insurability (GINA protections apply to health insurance but not life/disability insurance in the US)

— Test children of affected parents after age 1

— Adolescents should provide assent for testing and treatment decisions

— ED to home: ensure patient leaves with on-demand therapy in hand, not just prescription

— PCP to ED: ensure HAE diagnosis is documented prominently in chart (problem list, allergy list with "DO NOT GIVE ACE INHIBITORS")

— Hospital admission: HAE patients are at risk for delayed treatment because staff may default to anaphylaxis algorithms — provide patient with "HAE protocol card"

— Never administer ACE inhibitors to HAE patients — flag in EHR

— Pre-operative checklists must include HAE diagnosis and prophylaxis plan

— Difficult airway alert for any HAE patient requiring intubation

— Not a reportable condition, but eligible for disability accommodations under ADA

— School/workplace accommodations for attack absences

— Many HAE drugs approved via small trials — emphasize ongoing pharmacovigilance

— Encourage registry participation

Step 3 management: At hospital discharge after an HAE attack, place an EHR allergy alert for ACE inhibitors, document HAE on the problem list, provide a written wallet card, confirm on-demand therapy is in patient's possession, and fax records to PCP and dentist — transitions of care are the most common point of preventable HAE harm.

Informed consent for high-cost therapy:

Genetic testing and family screening:

Pediatric consent and assent:

Transitions of care — high-risk failure points:

Patient safety alerts:

Mandatory reporting and disability:

Research ethics:

High-Yield Associations and Rapid-Fire Facts

Board pearl: If a question describes recurrent angioedema unresponsive to epinephrine and antihistamines with low C4, the answer is HAE. If C1q is also low and onset >40, switch to acquired C1-INH deficiency with malignancy workup.

C4 is always low in HAE Type I and II — best initial screen

C1q normal in HAE, low in acquired C1-INH deficiency

Type I (85%): low C1-INH antigen AND function

Type II (15%): normal C1-INH antigen, low function

HAE with normal C1-INH: F12 mutation most common; female predominance; estrogen-sensitive

Autosomal dominant; ~25% de novo mutations

Erythema marginatum = serpiginous, non-pruritic prodromal rash; near-pathognomonic

No urticaria, no pruritus in HAE — distinguishes from histaminergic causes

Attacks last 2–5 days, peak at 12–36 hours

Antihistamines, epinephrine, steroids do NOT work in HAE

Bradykinin is the mediator; therapies target kallikrein or bradykinin B2 receptor

Icatibant = bradykinin B2 receptor antagonist

Ecallantide = plasma kallikrein inhibitor; anaphylaxis risk

Lanadelumab = anti-plasma-kallikrein monoclonal antibody

Berotralstat = oral plasma kallikrein inhibitor

C1-INH concentrate (plasma-derived) is preferred in pregnancy and pediatrics

Danazol: avoid in pregnancy (teratogenic), children (growth), liver disease

Triggers: ACE inhibitors, estrogens, trauma, dental work, stress, infection

Laryngeal attacks: ~30% historical mortality if untreated

Average diagnostic delay: 8–10 years

Abdominal attacks → bowel wall edema, ascites on CT; mimic surgical abdomen

Acquired C1-INH deficiency → screen for lymphoma, MGUS, CLL

ACEi-induced angioedema: more common in Black patients; can occur years after initiation

Tryptase: elevated in anaphylaxis, normal in HAE

Vaginal delivery preferred over C-section in pregnancy

Progestin-only contraception preferred over combined OCPs

Pre-procedural prophylaxis: IV C1-INH 1–6 hours before dental/surgical procedures

On-demand therapy must be available at all times — at least 2 doses

Cinryze, Berinert = plasma-derived C1-INH; Ruconest = recombinant

Board Question Stem Patterns

— 22-year-old with recurrent face/lip swelling and abdominal pain since adolescence, no urticaria, father had similar episodes, no response to Benadryl

— Answer: check C4 level (initial), then C1-INH antigen and function

— Known HAE patient with hoarseness, stridor after dental work; epinephrine given without improvement

— Answer: icatibant or C1-INH concentrate IV; secure airway with anesthesia/ENT

— 65-year-old with new-onset angioedema, no family history, low C4, low C1-INH, low C1q

— Answer: acquired C1-INH deficiency; workup for lymphoma/MGUS (SPEP, imaging, peripheral smear)

— Hypertensive Black patient on lisinopril x 2 years presents with tongue swelling

— Answer: stop ACEi permanently; switch to ARB or non-RAAS agent

— HAE patient scheduled for tooth extraction

— Answer: IV plasma-derived C1-INH 1–6 hours pre-procedure, on-demand therapy at bedside

— Pregnant HAE patient with worsening attacks in third trimester

— Answer: plasma-derived C1-INH for on-demand and prophylaxis; avoid danazol (teratogenic), avoid estrogen postpartum

— Young woman with recurrent abdominal pain, vomiting, ascites on CT, normal endoscopy, prior negative ex-lap, family history of "allergic deaths"

— Answer: check C4; suspect HAE

— HAE patient with 2 attacks/month and prior laryngeal episode

— Answer: initiate subcutaneous C1-INH, lanadelumab, or berotralstat

— HAE patient with new hypertension diagnosis — which to avoid?

— Answer: ACE inhibitor (use ARB, CCB, or thiazide)

— 7-year-old with recurrent swelling, father with confirmed HAE

— Answer: complement testing; if confirmed, plasma-derived C1-INH preferred; avoid androgens

Key distinction: Look for the negative findings in HAE stems — no urticaria, no pruritus, no response to epinephrine. These eliminate anaphylaxis and point to bradykinin-mediated angioedema.

Stem 1 — Classic HAE presentation:

Stem 2 — Acute laryngeal attack:

Stem 3 — Acquired vs. hereditary:

Stem 4 — ACEi angioedema:

Stem 5 — Preprocedural prophylaxis:

Stem 6 — Pregnancy:

Stem 7 — Abdominal attack mimicker:

Stem 8 — Long-term prophylaxis indication:

Stem 9 — Medication to avoid:

Stem 10 — Pediatric onset:

One-Line Recap

Hereditary angioedema is a bradykinin-mediated, autosomal dominant disorder of C1 esterase inhibitor deficiency or dysfunction causing recurrent non-urticarial, non-pruritic angioedema that does not respond to epinephrine/antihistamines/steroids and is diagnosed by low C4 with confirmation by C1-INH antigen/function (and C1q to distinguish hereditary from acquired), and managed with bradykinin pathway–targeted on-demand therapy, short-term peri-procedural prophylaxis, and long-term prophylaxis based on attack burden — with strict avoidance of ACE inhibitors and estrogen-containing therapies.

High-yield recap bullets:

Board pearl: When the stem says "recurrent angioedema without hives, no response to epinephrine, family history positive" — the answer pathway is C4 → C1-INH testing → bradykinin-targeted therapy → avoid ACEi/estrogens → screen family. This single algorithm covers >90% of HAE board questions.

Diagnose: Low C4 (screen) + low C1-INH antigen (Type I) or low function with normal antigen (Type II); normal C1q distinguishes hereditary from acquired; genetic testing for HAE with normal C1-INH

Treat acutely: Icatibant, ecallantide, plasma-derived or recombinant C1-INH — administered immediately for any laryngeal/airway attack; epinephrine/antihistamines/steroids do NOT work

Prevent: Long-term prophylaxis with SC C1-INH, lanadelumab, or berotralstat for ≥1 attack/month, prior laryngeal involvement, or impaired QoL; short-term prophylaxis with IV C1-INH 1–6h before procedures

Avoid: ACE inhibitors (permanent contraindication), estrogen-containing contraceptives and HRT, attenuated androgens in pregnancy/children/liver disease; ensure on-demand therapy always available, action plan in place, family screened, and EHR allergy alerts active