What is the differential diagnosis for a patient presenting with a generalized erythematous rash, considering potential causes such as autoimmune disorders (e.g., lupus, rheumatoid arthritis), infections (viral, bacterial, or fungal), and drug reactions?

Differential Diagnosis for Generalized Erythematous Rash

Immediately Exclude Life-Threatening Conditions First

If the patient has fever with the rash, initiate doxycycline 100 mg twice daily immediately if Rocky Mountain Spotted Fever (RMSF) is suspected—do not wait for laboratory confirmation, as the case-fatality rate is 5-10% with most deaths occurring within 9 days. 1

Critical Red Flags Requiring Immediate Action

• RMSF triad: Fever + rash + headache with tick exposure (or endemic area exposure), thrombocytopenia, or hyponatremia warrant immediate empiric doxycycline 1, 2
• Critical pitfall: Up to 40% of RMSF patients report no tick bite history, and 20% never develop a rash—absence of these features does NOT exclude the diagnosis 1, 2, 3
• Timing matters: RMSF rash appears 2-4 days after fever onset as small (1-5 mm) blanching pink macules on ankles, wrists, or forearms, then progresses to maculopapular with central petechiae spreading to palms, soles, arms, legs, and trunk while sparing the face 1, 2, 3
• Meningococcemia: Maculopapular rash rapidly progressing to petechial/purpuric lesions requires immediate antibiotics 3
• Toxic shock syndrome: Diffuse erythema with desquamation and multiple organ failure 1

Immediate Laboratory Workup if RMSF Suspected

• Complete blood count with differential (looking for leukopenia, thrombocytopenia) 1, 2
• Comprehensive metabolic panel (looking for hyponatremia, elevated hepatic transaminases) 1, 2
• Acute serology for R. rickettsii, E. chaffeensis, and A. phagocytophilum 1, 2
• Peripheral blood smear for morulae within granulocytes 1

Expected response: Clinical improvement within 24-48 hours of doxycycline; lack of response suggests alternative diagnosis or coinfection 1, 2

Categorize by Rash Morphology and Clinical Context

Maculopapular Erythematous Rashes (Most Common Pattern)

Viral Exanthems

• Enteroviral infections: Most common cause of maculopapular rashes with trunk and extremity involvement while sparing palms, soles, face, and scalp 1, 2
• Human herpesvirus 6 (roseola): Macular rash following high fever resolution 1, 2
• Epstein-Barr virus: Maculopapular rash, especially if patient received ampicillin or amoxicillin 1, 2
• Parvovirus B19: "Slapped cheek" appearance on face with possible truncal involvement 1, 2

Drug Reactions

• Nonspecific drug eruptions: Fine reticular maculopapular rashes or broad, flat erythematous macules and patches 1, 2
• Acute generalized exanthematous pustulosis (AGEP): Acute onset erythematous and edematous eruptions with sterile pustules, accompanied by fever, typically caused by antibiotics (especially beta-lactams) or diltiazem 4, 5
• DRESS syndrome: Generalized skin rash with hypereosinophilia, lymphocytosis, and internal organ involvement—more severe than simple drug eruption 4

Erythrodermic Pattern (>90% Body Surface Area)

Erythrodermic psoriasis presents with generalized erythematous inflammatory patches and plaques covering >90% BSA, often with superficial exfoliation, pitting edema of lower extremities, and systemic symptoms (chills, night sweats, arthralgias) 6

Differential for Erythroderma

• Atopic dermatitis 6
• Contact dermatitis 6
• Seborrheic dermatitis 6
• Cutaneous T-cell lymphoma 6
• Pityriasis rubra pilaris 6

Distinguishing features for psoriasis: Personal or family history of psoriasis, areas of indurated plaques with silvery scale, lack of "skip" areas, absence of significant palmoplantar keratoderma 6

Critical action: Obtain blood for flow cytometry, Sézary cell count, and T-cell receptor gene rearrangement to exclude cutaneous T-cell lymphoma; screen for HIV 6

Polymorphous Exanthem with Fever

Kawasaki disease (primarily pediatric but consider in young adults): Fever ≥5 days PLUS ≥4 of the following 6, 1, 3:

• Polymorphous exanthem (nonspecific diffuse maculopapular eruption, urticarial, scarlatiniform, or erythroderma) with perineal accentuation and early desquamation 6, 3
• Bilateral bulbar conjunctival injection without exudate 6
• Oral/lip changes: erythema, cracking, strawberry tongue, diffuse oropharyngeal erythema 6
• Extremity changes: erythema of palms/soles, edema of hands/feet (acute); periungual peeling (subacute, weeks 2-3) 6
• Cervical lymphadenopathy ≥1.5 cm diameter, usually unilateral 6

Critical action: If suspected, obtain ESR, CRP, serum albumin, urinalysis immediately—untreated disease causes coronary artery aneurysms 1, 3

Bullous/Vesicular Patterns

Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN): Painful rash initially on face and chest with target lesions (particularly atypical targets), purpuric macules, blisters, and epidermal detachment involving mucous membranes (eyes, mouth, nose, genitalia) 6

Immediate Actions for Suspected SJS/TEN

• Discontinue all potential culprit drugs immediately 6
• Document percentage of body surface area with erythema versus epidermal detachment separately (detachment has prognostic value) 6
• Obtain skin biopsy from lesional skin for routine histopathology 6
• Obtain second biopsy from periblister lesional skin unfixed for direct immunofluorescence to exclude immunobullous disorders 6

Differential for Bullous Eruptions

• Erythema multiforme major 6
• Pemphigus vulgaris 6
• Mucous membrane pemphigoid 6
• Bullous pemphigoid 6
• Generalized bullous fixed drug eruption 6
• Staphylococcal scalded skin syndrome 6

Systematic Diagnostic Approach

History Elements to Elicit

• Timing: Date of rash onset and progression pattern 6, 7
• Prodromal symptoms: Fever, malaise, upper respiratory symptoms, sore throat, sore eyes/mouth 6, 3
• Medication history: All drugs taken over previous 2 months including OTC and complementary therapies, with dates started and stopped; note any brand switches 6
• Tick/environmental exposure: Travel to endemic areas, camping, dog ownership (dogs serve as sentinels for RMSF), summer months 1, 2
• Personal/family history: Atopy, psoriasis, recurrent HSV infections, previous drug allergies 6, 7

Physical Examination Specifics

• Palms and soles: Involvement suggests RMSF, secondary syphilis, meningococcemia, ehrlichiosis, certain enteroviruses 1, 2, 3
• Mucous membranes: Examine eyes, mouth, nose, genitalia for erosions, conjunctival injection, oral changes 6
• Distribution pattern: Centripetal spread (RMSF), perineal accentuation (Kawasaki), sun-exposed areas, extensor versus flexor surfaces 6, 1, 7
• Individual lesion characteristics: Color, size, shape, scale, blanching, Koebner phenomenon 7
• Nikolsky sign: Detachable epidermis suggests SJS/TEN 6

Laboratory Testing Strategy

• If fever present: CBC with differential, CMP, acute rickettsial serology, peripheral smear 1, 2
• If erythroderma: Flow cytometry, Sézary cell count, T-cell receptor gene rearrangement, HIV screening 6
• If suspected Kawasaki: ESR, CRP, serum albumin, urinalysis 1, 3
• If bullous eruption: Skin biopsy for histopathology and direct immunofluorescence, swabs for bacteriology 6

Special Population Considerations

Immunocompromised Patients

Expanded differential includes: Drug eruption, cutaneous infiltration with underlying malignancy, chemotherapy/radiation-induced reactions, Sweet syndrome, erythema multiforme, leukocytoclastic vasculitis, graft-versus-host disease (allogeneic transplant recipients) 1

Critical action: Biopsy or aspiration of lesion should be implemented as an early diagnostic step 1

Higher mortality risk: Elderly (≥60 years), children <10 years, and immunosuppressed patients have higher case-fatality rates for tickborne diseases 2

Critical Pitfalls to Avoid

• Never wait for serologic confirmation before starting doxycycline if RMSF suspected—IgM/IgG are not detectable before the second week of illness 1
• Do not exclude RMSF based on absence of rash or tick bite history 1, 2, 3
• Palms/soles involvement is NOT pathognomonic for RMSF—occurs in multiple conditions 3
• In prolonged fever with rash, always consider Kawasaki disease to prevent coronary complications 3
• Petechial rash requires immediate evaluation for meningococcemia and other life-threatening causes 3
• Do not delay treatment decisions in erythrodermic psoriasis—favor therapies with rapid, predictable responses over long-term safety considerations during acute crisis 6