What is the approach to diagnosing and managing a patient with a systemic rash?

Systemic Rash Differential Diagnosis

When evaluating a patient with systemic rash, immediately assess for life-threatening conditions by determining if the rash is non-blanching (petechial/purpuric), then evaluate for fever and systemic symptoms, as these features distinguish emergent conditions requiring urgent intervention from benign dermatoses. 1

Immediate Risk Stratification

Step 1: Assess for Non-Blanching Rash

• Perform the blanching test on all rashes - press firmly on the lesion and observe if it disappears 1
• Non-blanching petechial or purpuric rash carries significant mortality risk and demands urgent evaluation for meningococcal sepsis 1
• Calculate NEWS2 score immediately: score ≥7 indicates high risk of severe illness or death 1
• Administer antibiotics within 1 hour for high-risk patients - do not delay for diagnostic procedures 1

Step 2: Categorize Rash Morphology

Classify the rash into one of four categories based on visual and tactile characteristics 2:

• Petechial/purpuric: Non-blanching, flat lesions suggesting vasculitis, thrombocytopenia, or meningococcemia 3
• Erythematous: Diffuse redness suggesting drug reaction, viral exanthem, or toxic shock 3
• Maculopapular: Flat and raised lesions suggesting drug reaction, viral infection, or rickettsial disease 3
• Vesiculobullous: Fluid-filled lesions suggesting Stevens-Johnson syndrome, toxic epidermal necrolysis, or autoimmune bullous disease 3, 4

Step 3: Evaluate for Fever and Systemic Involvement

Febrile patients with rash require urgent evaluation for:

• Rocky Mountain Spotted Fever (RMSF): Maculopapular rash starting on wrists/ankles spreading centrally, appearing 2-4 days after fever onset; palms and soles involvement indicates advanced disease 3
• Meningococcemia: Rapidly progressive petechial rash that may start as blanching maculopapular then become purpuric 3
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Fever, lymphadenopathy, facial edema, eosinophilia >10%, and organ involvement (hepatitis most common) appearing 2-8 weeks after drug initiation 5, 6
• Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: Targetoid lesions with mucosal involvement, skin pain, and epidermal detachment 3, 4

Detailed Diagnostic Approach by Morphology

Petechial/Purpuric Rash with Fever

This presentation is a medical emergency until proven otherwise 1

• Look for high-risk features: cyanosis of skin/lips/tongue, NEWS2 ≥7, systemic sepsis signs 1
• Differential includes: meningococcemia, RMSF, endocarditis, thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura 3
• Common pitfall: Sending patients home at first presentation before rash appears or when rash is still blanching 1
• RMSF can present with petechiae on palms/soles by day 5-6, but this is late-stage disease 3

Maculopapular Rash with Fever

Assess distribution pattern and timing relative to fever onset:

• RMSF pattern: Starts on extremities (wrists, ankles, forearms) then spreads centrally, typically appearing 2-4 days after fever 3
• Viral exanthem pattern: Often starts on trunk/face then spreads peripherally 3
• Drug reaction pattern: Typically symmetric, may spare palms/soles initially 3

Critical historical features to elicit:

• Tick exposure in past 2 weeks (RMSF incubation 3-12 days) 3
• New medications in past 2-8 weeks (DRESS) or 1-3 weeks (other drug reactions) 5, 6
• Travel history, outdoor activities, sick contacts 3

Vesiculobullous Rash

Assess body surface area (BSA) involvement and mucosal surfaces:

• Grade 1: <10% BSA, asymptomatic - observe with local wound care 3
• Grade 2: 10-30% BSA or >30% BSA with mild symptoms - hold offending agent, consider oral prednisone 0.5-1 mg/kg 3
• Grade 3: >30% BSA with moderate-severe symptoms limiting self-care - hold offending agent, consult dermatology, initiate prednisone 1 mg/kg 3
• Grade 4: Severe consequences requiring hospitalization - immediate hold of offending agent, admit to burn unit, IV methylprednisolone 1-2 mg/kg 3

Examine all mucosal surfaces (eyes, nares, oropharynx, genitals, perianal area) as involvement suggests Stevens-Johnson syndrome or toxic epidermal necrolysis 3, 4

Erythematous Rash

Assess for targetoid lesions suggesting erythema multiforme spectrum:

• Typical targets: Three distinct zones (central dusky area, pale edematous ring, erythematous outer ring) suggest erythema multiforme 4
• Atypical targets: Two zones or poorly defined borders suggest drug reaction or viral exanthem 4
• Mucosal involvement with targetoid lesions indicates Stevens-Johnson syndrome 4

Drug-Induced Rash Evaluation

Most common causative agents are antibiotics (37-40%), followed by anticonvulsants (27-35%), NSAIDs, and sulfonamides 6

DRESS Syndrome Recognition

• Onset 2-8 weeks after drug initiation (longer than typical drug reactions) 5
• Classic triad: Fever, rash, lymphadenopathy 5
• Organ involvement: Hepatitis (most common), pneumonitis, nephritis, myocarditis 5
• Eosinophilia >10% and atypical lymphocytosis 5, 6
• Facial edema is characteristic 5

Acute Generalized Exanthematous Pustulosis (AGEP)

• Fever with numerous small, superficial, sterile pustules on edematous erythema 7
• Discontinue hydroxyzine or other causative agent at first appearance 7
• Avoid cetirizine or levocetirizine in patients with prior AGEP from hydroxyzine due to cross-sensitivity 7

Workup and Management Algorithm

Initial Assessment (All Patients)

• Vital signs including temperature and NEWS2 score calculation 1
• Complete skin examination including all body surfaces and mucosal membranes 3
• Assess for lymphadenopathy and facial/extremity swelling 3
• Review of systems: skin pain, fevers, malaise, myalgias, arthralgias, abdominal pain, ocular symptoms, oropharyngeal symptoms, genitourinary symptoms 3

Laboratory Evaluation (Based on Clinical Suspicion)

• Complete blood count with differential (assess for eosinophilia, thrombocytopenia, leukocytosis) 3, 1
• Comprehensive metabolic panel (assess for hepatitis, renal involvement) 3, 1
• Blood cultures if febrile 1
• Urinalysis 1
• Consider skin biopsy with direct immunofluorescence for unclear cases 3

Management by Grade

Grade 1 (Rash <10% BSA, asymptomatic):

• Continue current therapy if not drug-induced 3
• Topical emollients and mild-to-moderate potency topical corticosteroids 3
• Counsel to avoid skin irritants 3

Grade 2 (Rash 10-30% BSA or >30% BSA with mild symptoms):

• Consider holding offending agent, monitor weekly 3
• Topical emollients, oral antihistamines, medium-to-high potency topical corticosteroids 3
• Consider prednisone 0.5-1 mg/kg tapered over 4 weeks 3
• If no improvement after 4 weeks, regrade as Grade 3 3

Grade 3 (Rash >30% BSA with moderate-severe symptoms):

• Hold offending agent immediately 3
• Consult dermatology urgently 3
• High-potency topical corticosteroids, oral antihistamines 3
• Oral prednisone 1 mg/kg/day tapered over at least 4 weeks 3
• May consider phototherapy for severe pruritus 3

Grade 4 (Life-threatening, requiring hospitalization):

• Immediate hold of offending agent 3
• Admit immediately with direct oncology/dermatology involvement 3
• IV methylprednisolone 1-2 mg/kg with slow taper 3
• Monitor closely for progression to severe cutaneous adverse reactions 3
• Consider burn unit admission for extensive epidermal detachment 1

Critical Pitfalls to Avoid

Diagnostic Errors:

• Sending patients home before rash appears when fever and systemic symptoms are present 1
• Missing evolution of blanching rash to non-blanching 1
• Delaying treatment while awaiting diagnostic confirmation in suspected meningococcemia 1
• Failing to examine all mucosal surfaces 3
• Not recognizing that up to 20% of RMSF cases never develop rash 3

Treatment Errors:

• Using alcohol-containing lotions on xerotic skin (worsens dryness) 1
• Applying high-potency steroids to face (risk of atrophy and telangiectasia) 1
• Using topical steroids continuously for >2-3 weeks without reassessment 1
• Frequent washing with hot water (increases irritation) 1
• Applying over-the-counter anti-acne medications to drug-induced rashes 1

Medication-Specific Cautions:

• Hydroxyzine can cause QT prolongation - use cautiously in patients with cardiac risk factors 7
• Hydroxyzine potentiates CNS depressants - reduce dosages of concomitant narcotics, barbiturates 7
• Start elderly patients on low doses of hydroxyzine due to increased sedation risk 7