A case of chronic urticaria: medical workup to find the cause + initial treatment

 

Case Summary: 35-year-old previously healthy man with chronic urticaria present for 6 weeks; what is a plan for diagnostic workup to determine the cause.

Assessment Summary

35-year-old previously healthy man with 6 weeks of recurrent, transient itchy wheals (with or without angioedema) now meeting criteria for chronic urticaria. The goal is to:

• Confirm that this is true urticaria vs a mimicking condition.
• Classify: chronic spontaneous urticaria (CSU) vs inducible urticaria vs secondary urticaria (infection, autoimmune, medication, etc.) vs mimickers (e.g., urticarial vasculitis).
• Identify any treatable triggers or associated systemic disease.
• Establish baseline severity and impact.
• Begin evidence-based first-line treatment while the workup proceeds.

No extensive testing is planned initially; instead, a focused history/exam and limited labs with targeted add-ons only if indicated.

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Differential Diagnosis / Working Diagnosis

Working categories to distinguish:

1. Chronic Spontaneous Urticaria (CSU) (most likely)

   • Idiopathic/autoimmune; no consistent external trigger.
   • Typical wheals last <24 h, intensely pruritic, no bruising, no systemic symptoms.

2. Inducible (Physical) Urticarias

   • Dermographism (stroking the skin), delayed pressure, cold, heat, cholinergic (heat/exercise/sweat), solar, aquagenic, vibration.
   • Triggered by specific physical stimuli, often reproducible.

3. Secondary Urticaria

   • Medication-related: NSAIDs/aspirin, ACE inhibitors, opioids, antibiotics, contrast.
   • Infection-related: H. pylori, chronic ENT/dental, parasitic (with travel/eosinophilia), viral hepatitis/HIV (if risk factors).
   • Associated autoimmune disease: especially thyroid disease.

4. Mimickers / Systemic Disease

   • Urticarial vasculitis (painful/burning lesions, last >24–36 h, leave bruising or hyperpigmentation; elevated ESR/CRP; possible systemic symptoms).
   • Hereditary/acquired angioedema (recurrent angioedema without hives; poor response to antihistamines).
   • Autoinflammatory syndromes, connective tissue disease, mast cell disorders (if systemic symptoms, abnormal labs).

Provisional working diagnosis: Chronic urticaria, likely CSU, to be confirmed after history, exam, and limited labs, assuming typical features (wheals <24 h, no systemic red flags, no clear trigger).

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Workup Plan

1) Triage and Safety Screen (same day, before detailed workup)

Ask and examine for:

• Tongue/throat swelling, difficulty breathing, wheeze, chest tightness.
• Dizziness/syncope, hypotension.
• Severe abdominal pain.
• Fever, weight loss, night sweats, arthralgias.

If any are present or suspected anaphylaxis/airway involvement:
→ Immediate emergency evaluation and management (epinephrine, airway, IV fluids). This overrides the outpatient workup.

If stable, proceed with outpatient workup below.

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2) Focused History (Visit 1)

Obtain structured history to classify and guide targeted tests:

A. Urticaria characteristics

• Onset and time course: When did it start? Daily vs intermittent? Any days completely free?
• Duration of individual wheals:
  • “Do individual spots disappear within 24 hours without leaving marks?”
  • If >24–36 h, painful/burning, or leaving bruises/stains → suspect vasculitis.
• Appearance: size, shape, migratory pattern, nocturnal predominance.

B. Angioedema

• Swelling of lips, eyelids, tongue, hands, feet, genitals?
• With or without hives?
• Any throat tightness, voice change, difficulty swallowing?
• Response to antihistamines in past episodes?

C. Triggers and patterns
Ask specifically about:

• Physical triggers:
  • Scratching/rubbing (dermographism)?
  • Tight clothing, belts, backpack straps (delayed pressure)?
  • Cold exposure (weather, cold drinks, ice packs)?
  • Heat, hot showers, saunas?
  • Exercise or sweating (cholinergic)?
  • Sun exposure, water contact, vibration tools (power tools, machinery)?
• Medications/supplements:
  • NSAIDs/aspirin use (ibuprofen, naproxen, etc.).
  • ACE inhibitor, ARB, beta-blocker.
  • Opioids, antibiotics started in last months, PPIs, supplements, herbal products.
• Foods/alcohol:
• Reproducible immediate reactions (within a few minutes of ingestion)

In addition:

Assessment Summary

35-year-old man with 6 weeks of recurrent pruritic wheals consistent with chronic urticaria (chronic threshold met). No prior major comorbidities noted. A structured workup has been started. Next steps aim to: (1) confirm typical chronic urticaria phenotype and exclude mimickers, (2) perform limited baseline labs plus any targeted tests suggested by history/exam, and (3) maintain symptom control during evaluation.

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Differential Diagnosis / Working Diagnosis

Working diagnosis

• Chronic urticaria, most likely:
  • Chronic spontaneous urticaria (CSU)
    ± possible inducible (physical) urticaria component depending on history and bedside tests.

Key differentials/mimickers to remain alert for

• Urticarial vasculitis.
• Bradykinin-mediated angioedema (hereditary or acquired C1-INH deficiency, ACE inhibitor–induced).
• Inducible urticarias (dermographism, cold, cholinergic, delayed pressure, others).
• Secondary urticaria associated with:
  • Infection (e.g., H. pylori, viral hepatitis, HIV, parasites).
  • Autoimmune/connective tissue disease (e.g., SLE).
  • Autoimmune thyroid disease.
• Mast cell disorders (systemic mastocytosis, clonal mast cell activation) if systemic flushing/anaphylaxis-like episodes.

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Workup Plan

1) Immediate Safety Screen (at this visit)

Ask, document, and examine for:

• Tongue or throat swelling, voice change, difficulty swallowing.
• Dyspnea, wheeze, chest tightness.
• Dizziness/syncope, palpitations, hypotension.
• Severe abdominal pain, vomiting, diarrhea.
• Fever, arthralgias, weight loss, night sweats.

If any concerning airway or systemic anaphylaxis signs are present:
→ Arrange urgent/emergency assessment and treat as anaphylaxis (epinephrine, airway support, etc.).
If absent → proceed with planned outpatient workup.

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2) Phenotype Confirmation and Classification

At this visit, explicitly confirm and document:

• Timing and morphology of skin lesions

  • Do individual wheals resolve completely within 24 hours?

  • Is there no residual bruising, purpura, or brown hyperpigmentation?

  • Predominantly pruritic vs painful/burning?

  • If >24–36 hours, painful/burning, or leaving staining/purpura → raise suspicion for urticarial vasculitis → see biopsies/labs below.

• Angioedema

  • Presence or absence.
  • Occurs with or without hives.
  • Response to antihistamines.
  • Any history of abdominal attacks or laryngeal edema.

• Severity and impact scores (for baseline and to guide future decisions)

  • Begin UAS7 (Urticaria Activity Score over 7 days; 0–42) – give patient a scoring sheet.
  • Urticaria Control Test (UCT) (0–16) – complete now.
  • Optional: Itch NRS (0–10), DLQI if impact on quality of life is unclear.

• Photo documentation

  • Ask patient to take photos of lesions during flares (date/time stamped) to assist in tracking morphology and duration.

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3) Screen for Inducible (Physical) Urticarias

Perform or confirm bedside provocation tests if safe and suggested by history:

• Dermographism: firm stroke across the upper back or forearm → wheal within 10 minutes.
• Cold urticaria: ice cube in plastic bag on forearm for 3–5 minutes, observe after rewarming 10–15 minutes.
  • Avoid if history of systemic reactions to cold (cold-water swimming, etc.).
• Delayed pressure urticaria: apply moderate weight/pressure (e.g., 10–15 lb on forearm or shoulder strap) for ~15 minutes; assess at 4–6 hours for delayed swelling.
• Cholinergic urticaria: history of small, pinpoint hives with heat/exercise/emotional stress; if unclear and safe, consider supervised light exercise/hot bath provocation.
• Other rare forms (solar, aquagenic, vibratory, heat) – evaluate only if strong history.

Interpretation:

• Positive tests help classify (CSU with inducible component vs pure inducible urticaria) and guide counseling on avoidance but do not change the baseline CSU laboratory workup.

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4) Medication, Exposure, and Trigger Audit (Actionable Today)

Review all current and recent (last 3–6 months) medications/supplements, and make concrete changes:

• Stop or avoid when possible for at least 2–3 weeks:
  • All non-essential NSAIDs/aspirin (including OTC ibuprofen, naproxen). Prefer acetaminophen for pain/fever.
  • Opioids if not essential (they can trigger histamine release).
• ACE inhibitors
  • If present and there is any angioedema, discontinue and switch to an alternative antihypertensive.
• Review for:
  • Newly started antibiotics, PPIs, psychotropics, supplements/herbals, and consider pausing suspected agents if safe and temporally related to onset.
• Mechanical triggers
  • If delayed pressure suspected: minimize tight belts, straps, heavy backpacks; use padding at pressure points.
• Alcohol
  • Advise moderation or temporary avoidance as it can exacerbate hives in some individuals.
• Infection history-based screen
  • Dental pain, sinus congestion, chronic cough, dyspepsia/ulcer symptoms, GI symptoms, urinary symptoms, skin infections; pursue testing only if localized symptoms suggest a focus.

Dietary considerations

• Do not order routine broad food allergy testing in CSU.
• If the patient reports clear, immediate and reproducible hives after specific foods:
  • Consider a targeted, time-limited elimination of that food and/or referral for formal allergy assessment.
• Otherwise, avoid broad restrictive or pseudoallergen/low-histamine diets as part of routine workup; they can be considered later, short-term, only if the patient strongly perceives food-related flares.

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5) Laboratory Studies

A. Limited Baseline Labs (for all chronic urticaria, done once if not already)

Order:

1. CBC with differential

   • Rationale: look for anemia, eosinophilia (parasites, atopy), leukocytosis (infection/inflammation).

2. ESR or CRP (choose one)

   • Rationale: screen for systemic inflammation or vasculitic/autoimmune process.

3. TSH

   • Rationale: autoimmune thyroid disease association with CSU.

4. Optional but helpful if available:

   • Thyroid peroxidase (TPO) antibodies – prognostic/association with autoimmune urticaria.
   • Total IgE – may help with later biologic decisions in some centers but not mandatory.

5. Basic metabolic panel (BMP) and liver function tests (LFTs)

   • Rationale: baseline if systemic therapy (e.g., cyclosporine) may be considered later.

6. Urinalysis

   • Recommended if systemic symptoms, suspicion of vasculitis, or autoimmune disease; otherwise optional but reasonable baseline.

B. Targeted Add-On Tests – Only if prompted by history/exam

1. Suspected urticarial vasculitis (wheals >24–36 h, painful/burning, residual pigmentation/purpura, systemic symptoms):

   • CMP (if not already ordered), ESR/CRP (if not done).
   • C3, C4 complement levels.
   • ANA (± ENA panel guided by clinical suspicion).
   • Urinalysis (hematuria/proteinuria for renal involvement).
   • Skin biopsy (see Procedures below).

2. Angioedema without hives, poor antihistamine response, abdominal/laryngeal attacks → evaluate for bradykinin-mediated angioedema:

   • C4 level.
   • C1 inhibitor (C1-INH) level and function.
   • C1q if late onset or concern for acquired C1-INH deficiency.

3. Systemic infection/parasite suspicion:

   • H. pylori stool antigen or urea breath test if persistent dyspepsia or ulcer history/high local prevalence.
   • Hepatitis B surface antigen, Hepatitis C antibody, HIV if risk factors.
   • Stool O&P if eosinophilia, travel to endemic areas, or chronic GI symptoms.

4. Mast cell disorder suspicion (flushing, syncope, hypotension, anaphylaxis episodes, pigmented macules):

   • Baseline serum tryptase.
   • If elevated → refer to Allergy/Immunology or Hematology for further workup (e.g., KIT mutation testing, bone marrow in select cases).

5. Autoimmune/connective tissue concern (arthralgias, Raynaud’s, photosensitivity, cytopenias, weight loss, etc.):

   • ANA and disease-specific serologies (e.g., dsDNA, ENA, complements) as clinically indicated.

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6) Imaging

• No routine imaging is indicated in typical CSU without systemic red flags.
• Order imaging only if directed by abnormal labs or systemic symptoms (e.g., ultrasound/CT if concern for malignancy or deep infection; echocardiogram in systemic vasculitis, guided by specialists).

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7) Procedures

• Skin punch biopsy (H&E + direct immunofluorescence)

  • Indications:
    • Lesions lasting >24–36 hours.
    • Painful/burning rather than just pruritic.
    • Residual bruising, purpura, or hyperpigmentation.
    • Systemic symptoms (fever, arthralgias, weight loss) suggesting vasculitis or connective tissue disease.
  • Technique:
    • Biopsy a fresh, fully developed lesion (preferably <24 h old) for routine histology.
    • Separate specimen for direct immunofluorescence from involved or perilesional skin.

• Formal provocation testing or threshold testing for inducible urticarias

  • Typically performed in specialty centers (Derm/Allergy) if:
    • Diagnostic uncertainty persists.
    • Occupational or lifestyle implications (e.g., cold exposure, physical activity) need formal documentation.

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Treatment Plan

Symptom control should proceed in parallel with the workup.

1) Medications

First-line: Second-generation H1 antihistamine (daily, scheduled)

• Start or continue one second-generation antihistamine:
  • Options: cetirizine 10 mg, levocetirizine 5 mg, fexofenadine 180 mg, loratadine 10 mg, desloratadine 5 mg once daily.
• Instruct patient to take daily, not only as needed.

Dose escalation (per guidelines) if not adequately controlled after ~1–2 weeks:

• Up-titrate the same agent up to 4× the standard daily dose, as tolerated. For example:
  • Cetirizine: 10 mg → 20 mg → 30–40 mg/day (often split BID).
  • Fexofenadine: 180 mg → 360 mg → 540–720 mg/day (often split).
• Monitor for sedation (though second-generation agents are relatively non-sedating) and other side effects.

Adjunctive options for partial responders or specific scenarios:

• Leukotriene receptor antagonist
  • Montelukast 10 mg once daily at night, particularly if:
    • Suspicion of NSAID-exacerbated cutaneous disease.
    • Coexisting cold or cholinergic features.
• Sedating H1 antihistamine at night (short term only, if sleep is markedly impaired):
  • E.g., hydroxyzine 10–25 mg or diphenhydramine 25–50 mg at bedtime.
  • Warn about next-day sedation and impaired driving; avoid in those who need high alertness.

Systemic corticosteroids

• Not for routine use.
• Reserve a short burst only for severe, acute flares significantly impairing function:
  • Example: Prednisone 0.5 mg/kg/day (≈30–40 mg) for 3–5 days then stop (no long tapers for short courses).
  • Avoid repeated or long-term use due to metabolic, bone, and cardiovascular risks.

Escalation if uncontrolled after adequate trial (2–4 weeks) of high-dose second-generation antihistamines

If UAS7 remains high (e.g., >16) or UCT <12 despite adherence:

• Omalizumab (Xolair)

  • Dose: 300 mg subcutaneously every 4 weeks.
  • Usually initiated and monitored by Allergy/Immunology or Dermatology.
  • Some refractory cases may require adjusted dosing schedules per specialist.

• Cyclosporine

  • Considered in refractory disease (often after or in parallel with omalizumab, per local practice and access).
  • Typical dose: 3–5 mg/kg/day in divided doses.
  • Requires careful monitoring:
    • Blood pressure, renal function (BUN/Cr), electrolytes.
    • Drug–drug interactions (e.g., with statins, azole antifungals, CCBs).

• Other biologics or immunomodulators (e.g., dupilumab, newer anti-IgE/anti-Siglec-8 agents) may be used in specialty settings based on evolving evidence and availability.

2) Lifestyle Modifications

• Avoid non-essential NSAIDs; choose acetaminophen when needed.
• Reduce alcohol intake, particularly during active flares.
• Minimize identified mechanical or physical triggers (heat, cold, tight clothing, pressure, hot showers) as guided by history and provocation testing.
• Gentle skin care:
  • Use fragrance-free, non-soap cleansers.
  • Regular emollients to support the skin barrier (may reduce irritant itching).
• Stress and sleep:
  • Discuss that stress can exacerbate symptoms; encourage regular sleep, basic stress management techniques (exercise as tolerated, relaxation, mindfulness).

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Patient Education

Key counseling points:

• Nature of disease

  • Chronic urticaria is common and often not due to a specific allergy.
  • In many patients, no single trigger is found (CSU); however, the condition often improves or remits over time.
  • Broad allergy testing and restrictive diets are usually not helpful and may be harmful.

• Goal of treatment

  • Aim for complete or near-complete symptom control with regular medication.
  • Workup is focused and targeted to avoid unnecessary testing.

• How to use medications

  • Take the daily antihistamine every day, not only when hives are present.
  • Report any excessive drowsiness or side effects for dose adjustment or switching.
  • Explain step-up approach (higher antihistamine doses, then consideration of biologics if needed).

• Tracking disease

  • Explain and provide UAS7 and UCT forms (or apps) and ask patient to bring them to the next visit.
  • Encourage photographs of typical lesions and any suspected triggers.

• Trigger management

  • Avoid NSAIDs and unnecessary medications that may aggravate hives.
  • Avoid “chasing” multiple unproven triggers; focus on patterns that are consistent and reproducible.

• Prognosis

  • Many patients see improvement within months to a few years.
  • Ongoing follow-up allows stepwise intensification and later tapering of treatment.

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Follow-up Schedule

Short-term (2–4 weeks)

• Review:
  • Symptom scores: UAS7, UCT, possibly DLQI.
  • Response to daily (and possibly up-titrated) antihistamines ± montelukast.
  • Adherence, side effects.
  • Results of baseline and any targeted labs.
• Actions:
  • Confirm classification: CSU vs inducible vs secondary vs mimicker.
  • If inadequate control and good adherence → consider further antihistamine up-titration (if not maximized) and/or initiate omalizumab referral.
  • Reassess need for any additional targeted tests if new symptoms or abnormal labs.

Intermediate (6–12 weeks)

• For persistent CSU:
  • Re-evaluate control (UAS7, UCT).
  • If still poorly controlled despite maximized antihistamines:
    • Ensure trigger avoidance trial (NSAIDs, offending meds) has been completed.
    • Refer to Dermatology/Allergy for:
      • Omalizumab initiation or alternative advanced therapies.
      • Further evaluation of any abnormal labs or atypical features.

Long-term

• Follow-up every 3–6 months once stable, to:
  • Monitor control (UCT, DLQI).
  • Discuss gradual down-titration of antihistamine dose when well controlled for several months.
  • Avoid repeating labs unless new systemic symptoms emerge or therapy changes (e.g., cyclosporine).

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Red Flags / When to Return Sooner

Instruct the patient to seek immediate medical attention (ER/urgent care) if any of the following occur:

• Tongue, throat, or lip swelling with:
  • Difficulty breathing, swallowing, or speaking.
  • Noisy breathing or sensation of throat closing.
• Chest tightness, wheezing, or shortness of breath.
• Dizziness, fainting, or feeling of impending loss of consciousness.
• Generalized flushing or hives with hypotension, confusion, or severe abdominal pain.
• Fever, weight loss, joint pains, or persistent lesions leaving bruises or dark marks.

And to contact the clinic promptly (urgent, same-week review) if:

• Lesions start lasting >24–36 hours, become painful, or leave purpura/hyperpigmentation.
• New systemic symptoms (fevers, night sweats, arthralgias, new GI or urinary symptoms) develop.
• Swelling episodes occur without hives, especially if not relieved by antihistamines.
• Hives remain severe and uncontrolled despite taking the prescribed maximum-dose antihistamine regularly.

This unified plan balances focused, evidence-based evaluation with proactive symptom control and clear thresholds for escalation and referral.