What is the possible diagnosis and next steps for a 29-year-old male (M) with a history of asthma and a family history of asthma, presenting with recurrent rashes characterized by wheals starting from the cheeks and temple, radiating to the trunk and arms, accompanied by sudden sharp pain, fever, and no known allergens, unresponsive to antihistamines?

Possible Diagnosis: Acute Urticaria with Systemic Symptoms

This patient most likely has acute urticaria (hives) with systemic symptoms, possibly triggered by an infection or representing an early presentation of urticarial vasculitis or autoinflammatory syndrome, and requires immediate workup including complete blood count, inflammatory markers (ESR/CRP), and consideration of infectious etiologies.

Clinical Reasoning

The presentation of transient wheals with sharp pain, spontaneous resolution within one hour, and recurrence with fever is highly characteristic of urticaria, but several atypical features warrant careful evaluation:

Key Diagnostic Features

Urticaria characteristics present:

• Wheals (raised, erythematous lesions) starting from face and spreading to trunk and arms
• Transient nature with complete resolution within 1 hour (classic urticarial behavior)
• Recurrent episodes
• Failure to respond to antihistamines (suggests more severe or atypical process)

Atypical features requiring investigation:

• Accompanying sharp pain (urticaria typically causes pruritus, not pain; pain suggests urticarial vasculitis or deeper process)
• Associated fever (suggests systemic inflammatory process or infection)
• No identifiable trigger despite thorough history
• Patient's atopic background (asthma) increases likelihood of allergic/immunologic etiology 1

Immediate Next Steps

1. Laboratory Workup (Priority)

Essential initial tests:

• Complete blood count with differential (evaluate for eosinophilia, leukocytosis suggesting infection or inflammatory process)
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to assess systemic inflammation
• Comprehensive metabolic panel to rule out hepatic or renal triggers
• Urinalysis to evaluate for systemic involvement

If initial workup abnormal or symptoms persist:

• Complement levels (C3, C4, CH50) if urticarial vasculitis suspected
• Antinuclear antibodies (ANA) if autoimmune process considered
• Infectious workup: throat culture, viral serologies, hepatitis panel
• Skin biopsy of active lesion if lesions last >24 hours or are painful (to differentiate urticarial vasculitis)

2. Clinical Monitoring

Document carefully:

• Duration of individual wheals (if >24 hours, strongly suggests urticarial vasculitis)
• Presence of residual bruising or hyperpigmentation after wheals resolve (indicates vasculitis)
• Pattern of fever in relation to rash episodes
• Any new systemic symptoms: joint pain, abdominal pain, respiratory symptoms

3. Therapeutic Trial

Immediate management:

• High-dose second-generation antihistamine (e.g., cetirizine 20mg daily or up to 4 times standard dose) 1
• Consider adding H2-blocker (ranitidine or famotidine) for refractory cases
• Short course of oral corticosteroids (prednisone 40-60mg daily for 5-7 days) if severe or progressive 2
• Avoid aspirin and NSAIDs which can worsen urticaria

Monitor asthma status closely:

• Given patient's asthma history, assess for any respiratory symptoms, wheezing, or chest tightness 1
• Have patient monitor peak expiratory flow if available
• Ensure patient has rescue inhaler accessible

Differential Diagnoses to Consider

Primary Considerations:

1. Acute spontaneous urticaria with systemic symptoms

• Most common in this presentation
• May be triggered by occult viral infection causing both fever and urticaria
• Typically self-limited over days to weeks

2. Urticarial vasculitis

• Painful rather than pruritic wheals (matches this patient)
• Individual lesions last >24 hours
• May leave residual bruising or hyperpigmentation
• Associated with systemic symptoms including fever
• Requires skin biopsy for definitive diagnosis

3. Autoinflammatory syndrome (e.g., Schnitzler syndrome, adult-onset Still's disease)

• Recurrent urticaria with fever
• May have elevated inflammatory markers
• Typically requires rheumatology consultation

4. Drug reaction (despite no reported allergens)

• Question about any recent medications, supplements, or herbal preparations
• Consider delayed reaction to previously tolerated medications

Less Likely but Important to Exclude:

5. Serum sickness-like reaction

• Would typically have history of recent medication or biologic exposure
• Associated with fever, urticaria, arthralgias

6. Viral exanthem with urticarial features

• Common viral infections can present with both fever and urticaria
• Consider EBV, hepatitis, parvovirus

Critical Pitfalls to Avoid

Do not dismiss as simple allergic reaction:

• The combination of pain (not just itching), fever, and antihistamine resistance suggests more complex pathophysiology
• Simple allergic urticaria rarely presents with fever

Do not overlook systemic involvement:

• Assess for angioedema (especially airway involvement given asthma history) 1
• Monitor for development of anaphylaxis features: hypotension, respiratory distress, gastrointestinal symptoms
• Have epinephrine available if any concern for progression

Do not delay specialist referral if:

• Symptoms persist beyond 6 weeks (chronic urticaria)
• Individual wheals last >24 hours
• Systemic symptoms worsen or new symptoms develop
• Inadequate response to high-dose antihistamines and corticosteroids
• Evidence of vasculitis on examination or biopsy

Follow-up Plan

Within 48-72 hours:

• Review laboratory results
• Reassess clinical response to treatment
• Document any new lesions or systemic symptoms

Refer to allergist/immunologist if:

• Symptoms persist beyond 2 weeks despite treatment
• Recurrent episodes continue
• Need for allergy testing to identify triggers 1

Refer to rheumatology if:

• Evidence of urticarial vasculitis
• Persistent systemic symptoms suggesting autoinflammatory syndrome
• Elevated inflammatory markers without clear infectious cause