Differential Diagnosis and Diagnostic Workup for Fever and Rash
Immediate Life-Threatening Considerations
If tickborne rickettsial disease is suspected based on outdoor exposure, thrombocytopenia, or geographic risk, initiate doxycycline 100 mg twice daily immediately without waiting for laboratory confirmation, as delay in treatment leads to severe disease and death. 1, 2
Other critical diagnoses to exclude immediately include:
- Meningococcemia - requires emergent empiric antibiotics 1
- Toxic epidermal necrolysis - mortality risk of 5% 3
- Staphylococcal toxic shock syndrome - can be rapidly fatal 3
Algorithmic Approach by Rash Morphology
Step 1: Categorize the Rash Type
Petechial/Purpuric Rash:
- Meningococcemia - non-blanching petechiae, rapidly progressive, requires immediate blood cultures and empiric ceftriaxone 1, 4
- Rocky Mountain Spotted Fever (RMSF) - petechiae develop by day 5-6, involves palms/soles, indicates advanced disease 1
- Thrombotic thrombocytopenic purpura - check coagulation studies immediately 5
Maculopapular Rash (Most Common Pattern):
- RMSF - begins on ankles/wrists/forearms 2-4 days after fever onset, spreads centrally, becomes petechial 1
- Measles - most common viral cause in adults 3
- Drug reactions - most common noninfectious cause, requires medication history 3
- Ehrlichiosis - rash in 30% of adults, 60% of children, appears median 5 days after illness onset 1
Vesiculobullous/Pustular:
- Varicella - third most common cause overall 3
- Rickettsia parkeri - vesiculopapular rash with eschar 1
Diffuse Erythema:
- Adult-onset Still's disease - fourth most common cause, can be fatal 3
- Toxic shock syndrome - requires immediate recognition 3
Step 2: Assess Critical Clinical Features
Timing of rash relative to fever:
- Rash 2-4 days after fever onset suggests RMSF 1
- Rash before fever or simultaneous onset suggests viral exanthem or drug reaction 6
- Late rash (>5 days) or absent rash does NOT exclude RMSF - <50% have rash in first 3 days 1
Distribution pattern:
- Palms and soles involvement - RMSF, Rickettsia parkeri, ehrlichiosis, drug reactions 1
- Peripheral-to-central spread - RMSF classic pattern 1
- Eschar present - Rickettsia parkeri or R. species 364D, NOT typical for RMSF 1
Patient age:
- Children <15 years develop rash earlier and more frequently than adults with RMSF 1
- Lack of rash in adults associated with delayed diagnosis and increased mortality 1
Step 3: Obtain Essential History
Exposure and epidemiologic factors:
- Tick exposure or outdoor activities in wooded/grassy areas - most patients do NOT recall tick bites, so absence of history does not exclude rickettsial disease 1, 2
- Travel within past year to tropical/subtropical regions - most infections symptomatic within 21 days 2
- Geographic location and season - critical for rickettsial diseases 1
- Medication history - drug reactions are leading noninfectious cause 3
- Pet illness or death - can indicate shared exposure to rickettsial disease 1
- Immunocompromised status - broader differential including opportunistic infections 2
Symptom characteristics:
- Incubation period: RMSF 3-12 days (shorter with severe disease), ehrlichiosis 5-14 days, anaplasmosis similar 1
- Associated symptoms: headache, myalgia, nausea/vomiting, photophobia, abdominal pain 1
- Mental status changes suggest encephalitis or advanced rickettsial disease 1
Step 4: Initial Laboratory Workup
Immediate laboratory tests (obtain before antibiotics):
- Complete blood count with differential and peripheral smear - look for thrombocytopenia, leukopenia, morulae in granulocytes (anaplasmosis) or monocytes (ehrlichiosis) 1, 5, 2
- Comprehensive metabolic panel with liver enzymes - elevated transaminases characteristic of rickettsial diseases 1, 5, 2
- At least two sets of blood cultures (one peripheral, one from central line if present) before antibiotics 2
- Coagulation studies if considering TTP 5
Key laboratory patterns:
- Rickettsial diseases: thrombocytopenia, leukopenia or normal WBC with left shift, elevated transaminases, hyponatremia 1
- Ehrlichiosis: leukopenia, thrombocytopenia, increased transaminases, morulae visible in only 1-20% 1
- Anaplasmosis: leukopenia, thrombocytopenia, elevated transaminases, mild anemia, morulae in granulocytes 1
Additional testing based on exposure:
- Three malaria tests over 72 hours if travel to endemic areas 2
- Chest radiograph for all febrile patients 2
- PCR for rickettsial pathogens from whole blood - more sensitive than serology acutely 1
Step 5: Advanced Diagnostics if Initial Workup Unrevealing
- CT imaging for patients with recent surgery or if posterior lung pathology suspected 2
- 18F-FDG PET/CT if other tests fail and patient stable for transport 2
- Bone marrow examination if considering hemophagocytic lymphohistiocytosis (check ferritin, triglycerides, fibrinogen) 5
- Tissue biopsy for persistent undiagnosed rash 6
Critical Management Pitfalls to Avoid
Never delay doxycycline for suspected rickettsial disease while awaiting serologic confirmation - early serologic testing is often negative, and treatment within first 3 days is most effective 1, 2. The classic triad of fever, rash, and tick bite is present in only a minority at initial presentation 1.
Do not exclude rickettsial disease based on absence of tick bite - most patients do not recall tick exposure 1, 2.
Do not wait for rash to develop - absence of rash should not preclude RMSF diagnosis, as <50% have rash in first 3 days and some never develop rash 1.
Recognize coinfection potential - Ixodes scapularis transmits Anaplasma, Borrelia burgdorferi, and Babesia; if anaplasmosis treated with doxycycline responds but Lyme disease treated with beta-lactam does not, consider coinfection 1. Leukopenia or thrombocytopenia in Lyme disease suggests Anaplasma coinfection 1.
Skin pigmentation may obscure rash - maintain high clinical suspicion in patients with darker skin tones 1.
Immunocompromised patients require lower threshold for hospitalization and empiric therapy - may present with atypical or more severe manifestations 2.