---

Fever with Rash - Types and Differential Diagnosis

---

Approach to the Patient

• Immune status and medications taken in the past month
• Travel history, immunization status
• Animal/arthropod bite exposure
• Recent dietary exposures and sick contacts
• Sexual history
• Site of rash onset and direction/rate of spread
• Harrison's Principles of Internal Medicine 22E, p. 181

---

Lesion Morphology - Definitions

---

Classification by Rash Type + Key Differentials

1. Centrally Distributed Maculopapular Eruptions (Most Common)

• Harrison's Principles of Internal Medicine 22E, pp. 181-189

---

2. Peripheral Eruptions

---

3. Confluent Desquamative Erythematous Eruptions ("Sunburn-like")

---

4. Vesiculobullous Eruptions

---

5. Urticaria-like Eruptions

---

6. Nodular Eruptions

---

7. Purpuric Eruptions (Non-blanchable)

---

8. Eruptions with Eschars

---

Summary Table: Quick Differential by Morphology

• Harrison's Principles of Internal Medicine 22E (2025), Chapter 21; Goldman-Cecil Medicine Table 259-2

---

Red Flags Requiring Immediate Action

1. Petechial/purpuric rash + fever - rule out meningococcemia; give ceftriaxone before LP if septic
2. Peripheral petechiae spreading centripetally - rule out RMSF; start doxycycline empirically
3. Diffuse erythroderma + hypotension - toxic shock syndrome
4. Eschar + fever + travel to Asia - scrub typhus
5. Bullous eruption + mucosal involvement - SJS/TEN (stop all suspect drugs immediately)
6. Fever + rash + immunocompromised host - broad differential including fungi, atypical organisms

---

Key Diagnostic Mnemonic: "VIRUS"

• Varicella (chickenpox)
• Infectious mononucleosis (EBV)
• Rubella (German measles) / Roseola (HHV-6)
• Urticarial drug reaction
• Scarlet fever / Secondary syphilis

---

---

Clinical Case Analysis: 55-Year-Old Male, Fever ×4 Days + Peripheral Maculopapular Rash ×1 Day

Clinical Summary

• Age/Sex: 55-year-old male
• Fever: 4 days (rash appeared on day 4 - "fever then rash" pattern)
• Rash type: Maculopapular
• Distribution: Peripheral (wrists, ankles, hands, feet, face)

---

Priority Diagnoses (Most to Least Urgent)

🔴 1. Rocky Mountain Spotted Fever (RMSF) - R. rickettsii

• Rash begins on wrists and ankles, spreads centripetally
• Initially erythematous macules → evolves to maculopapular → petechial over days
• Palms and soles involved later in disease
• Fever precedes rash by 2-4 days (matches this case exactly)
• Tick bite history (often not recalled); outdoor exposure
• Associated: severe headache, myalgias, nausea, occasionally confusion
• Do not wait for rash to become petechial before treating - start doxycycline empirically

• Harrison's Principles of Internal Medicine 22E, Chapter 21

---

🔴 2. Dengue Fever

• Fever 4-7 days, then maculopapular rash appears on days 3-5 - highly consistent with this presentation
• "Islands of white in a sea of red" - characteristic appearance
• Classic triad: high fever, severe headache ("break-bone fever"), retro-orbital pain + myalgia/arthralgia
• Rash may begin peripherally and spread to trunk
• Look for: thrombocytopenia, leukopenia, raised hematocrit, positive tourniquet test
• Risk: dengue hemorrhagic fever in those >65, diabetics, or with cardiopulmonary disease
• Rosen's Emergency Medicine; Goldman-Cecil Medicine

---

🟡 3. Secondary Syphilis

• Rash characteristically involves palms and soles - highly specific
• Maculopapular, copper-colored
• Fever + malaise common
• May be pruritic or non-pruritic
• Look for: mucous patches, condylomata lata, generalized lymphadenopathy
• History: sexual exposure 3-5 months prior (primary chancre may have been missed/painless)
• Diagnosis: RPR/VDRL → confirm with TPPA/FTA-ABS
• Harrison's 22E; Tintinalli's Emergency Medicine

---

🟡 4. Scrub Typhus - Orientia tsutsugamushi

• Fever 5-14 days, then maculopapular rash appears on trunk → spreads peripherally
• Pathognomonic eschar (tâche noire) at mite bite site - check hairline, axilla, groin, behind ears
• Headache, lymphadenopathy, hepatosplenomegaly
• Age 55 in a rural/forested setting = high suspicion
• Diagnosis: Weil-Felix (OX-K positive, low sensitivity), IFA, PCR
• Treatment: doxycycline

---

🟡 5. Typhoid Fever (Enteric Fever) - Salmonella typhi

• Fever builds over days 1-4 (step-ladder pattern) - matches this case
• "Rose spots" appear in ~30% of patients - faint, blanchable, salmon-colored, 2-4mm
• Relative bradycardia at peak fever (pulse-temperature dissociation)
• Constipation early, diarrhea later; abdominal pain; hepatosplenomegaly
• Travel to endemic areas (South Asia, Sub-Saharan Africa)
• Diagnosis: blood culture (gold standard), Widal test (low specificity)
• Harrison's 22E; Sherris & Ryan's Medical Microbiology 8E

---

🟡 6. Chikungunya Fever

• Mosquito-borne flavivirus
• Maculopapular rash within first 5 days of fever - consistent with this case
• Hallmark: severe debilitating polyarticular arthralgia (small joints) - persists weeks to months
• Clinically similar to dengue but arthralgia is more prominent and hemorrhagic complications less common
• Diagnosis: PCR (acute phase), IgM serology
• Goldman-Cecil Medicine, Chapter on Post-Travel Care

---

🟢 7. Infectious Mononucleosis (EBV)

• Maculopapular rash + fever + pharyngitis + lymphadenopathy (classic triad)
• Rash dramatically worsens if given ampicillin/amoxicillin
• Hepatosplenomegaly common
• Check: atypical lymphocytes on peripheral smear, heterophile antibody (Monospot), EBV serology

---

🟢 8. Drug Reaction / DRESS

• Drug started within last 2-8 weeks (can be delayed)
• DRESS: Drug Reaction with Eosinophilia and Systemic Symptoms
• Maculopapular rash, fever, facial edema, lymphadenopathy, liver/kidney involvement
• Common culprits: allopurinol, anticonvulsants (carbamazepine, phenytoin), sulfonamides, dapsone
• Eosinophilia on CBC is a key clue

---

🟢 9. Lyme Disease (Erythema Migrans)

• Single or multiple annular "bulls-eye" lesions - pathognomonic
• Tick bite (usually Ixodes); endemic areas
• Associated: arthralgia, fatigue, cranial nerve palsy (Bell's palsy), AV block
• Note: erythema migrans is typically a single expanding lesion, not a peripheral scattered rash

---

🟢 10. Erythema Multiforme

• Symmetric target/iris lesions on elbows, knees, palms, soles, face
• Triggered by HSV (most common), Mycoplasma, drugs
• Fever and malaise common
• Mucosal involvement = Stevens-Johnson spectrum (check for oral/ocular lesions)

---

Systematic Approach: History Questions to Ask NOW

---

Investigations to Order (First-Line)

---

Clinical Decision Framework

Peripheral maculopapular rash + 4 days fever
         |
         ├── Tick bite / outdoor exposure?
         │         ├── YES → RMSF (start doxycycline empirically, don't wait for labs)
         │         └── Scrub typhus (check for eschar)
         │
         ├── Tropical travel / mosquito exposure?
         │         ├── Dengue (NS1, CBC, thrombocytopenia)
         │         └── Chikungunya (prominent arthralgia?)
         │
         ├── Palms/soles prominently involved?
         │         └── Secondary syphilis (RPR, sexual history)
         │
         ├── Step-ladder fever + relative bradycardia?
         │         └── Typhoid (blood culture)
         │
         ├── Recent medications?
         │         └── DRESS / drug reaction (eosinophilia, liver enzymes)
         │
         └── Pharyngitis + lymphadenopathy?
                   └── EBV (Monospot, atypical lymphocytes)

---

Red Flags to Watch For in This Patient

1. Rash becoming petechial/non-blanchable - RMSF progression or meningococcemia - treat immediately
2. Thrombocytopenia + rising hematocrit - dengue hemorrhagic fever
3. Hypotension - septic shock; escalate care
4. Mental status change - rickettsia, typhoid, dengue encephalopathy
5. Facial edema + eosinophilia - DRESS syndrome - stop all suspect drugs immediately

---