Fever, Blanching Maculopapular Rash, and Leukocytosis
Immediate Action Required
Start doxycycline 100 mg twice daily immediately without waiting for laboratory confirmation if this patient has any combination of fever, rash, headache, and tick exposure or residence in an endemic area. 1
The presence of leukocytosis with a blanching maculopapular rash distinguishes this presentation from typical tickborne rickettsial diseases, which usually present with normal or low white blood cell counts, making drug hypersensitivity syndrome and certain viral infections more likely—however, Rocky Mountain Spotted Fever (RMSF) remains life-threatening and must be excluded first. 2
Critical Life-Threatening Diagnoses to Exclude First
Rocky Mountain Spotted Fever (RMSF)
- RMSF has a 5-10% case-fatality rate with 50% of deaths occurring within 9 days of illness onset, making immediate empiric treatment essential even when the presentation is atypical. 1
- The classic presentation begins with small (1-5 mm) blanching pink macules on ankles, wrists, or forearms appearing 2-4 days after fever onset, progressing to maculopapular with central petechiae. 1
- Up to 40% of RMSF patients report no tick bite history, and up to 20% never develop a rash, so absence of these features does not exclude the diagnosis. 1, 3
- Less than 50% of patients have rash in the first 3 days of illness. 1
Key distinguishing feature for RMSF: The total white blood cell count is typically normal in RMSF patients, but increased numbers of immature bands are generally observed—not frank leukocytosis. 2
Meningococcemia
- Meningococcemia presents with rapid progression from maculopapular to petechial rash with clinical deterioration and markedly elevated inflammatory markers. 3
- Both RMSF and meningococcemia can begin as maculopapular rash and progress to petechial rash, but meningococcemia progresses more rapidly. 2
- Administer intramuscular ceftriaxone immediately if meningococcal disease cannot be excluded. 3
Most Likely Diagnoses Given Leukocytosis
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
The combination of fever, maculopapular rash, and leukocytosis (particularly with eosinophilia) strongly suggests DRESS syndrome rather than tickborne illness. 4, 5
Critical features of DRESS:
- Fever, generalized maculopapular rash, and leukocytosis with eosinophilia. 4, 5
- Elevation of liver enzymes is common. 4
- Symptoms typically appear 2-8 weeks after drug initiation. 5
- Can progress to multiple organ failure if not recognized and treated. 4
- Management requires immediate discontinuation of the offending drug and systemic corticosteroids. 4, 5
Viral Exanthems
- Viral exanthems are the most common cause of maculopapular rashes, particularly enteroviral infections. 1
- Epstein-Barr virus causes maculopapular rash, especially if the patient received ampicillin or amoxicillin. 1
- Human herpesvirus 6 (roseola) presents with macular rash following high fever resolution. 1
- Parvovirus B19 presents with "slapped cheek" appearance with possible truncal involvement. 1
Diagnostic Algorithm
Step 1: Immediate Risk Stratification
Obtain complete blood count with differential, comprehensive metabolic panel, and peripheral blood smear immediately. 1
Look for these critical laboratory findings:
For RMSF/Ehrlichiosis:
- Thrombocytopenia (up to 94% in ehrlichiosis). 2
- Hyponatremia. 2, 1
- Elevated hepatic transaminases. 2
- Leukopenia (up to 53% in ehrlichiosis)—not leukocytosis. 2
For DRESS:
- Leukocytosis with eosinophilia. 4, 5
- Atypical lymphocytes. 5
- Elevated liver enzymes and hyperbilirubinemia. 4
Step 2: History Assessment
Obtain medication history for the past 2-8 weeks, focusing on common DRESS-inducing drugs (allopurinol, sulfasalazine, anticonvulsants, antibiotics). 4, 5
Assess tick exposure or travel to endemic areas (but remember 40% of RMSF patients deny tick exposure). 1, 3
Determine timing of rash relative to fever onset:
- Rash appearing during active fever suggests bacterial causes (RMSF, scarlet fever) or drug reaction. 3
- Rash appearing after fever resolves suggests viral exanthem (roseola). 3
Step 3: Rash Characteristics
Examine for progression to petechiae, which occurs by days 5-6 in RMSF and suggests urgent need for doxycycline. 2, 6
Check palms and soles for involvement, which occurs in approximately 50% of RMSF cases but typically late in disease. 2
Look for eschar (dark, scabbed plaque overlying shallow ulcer), which suggests Rickettsia parkeri rickettsiosis rather than RMSF. 2
Management Decision Tree
If thrombocytopenia, hyponatremia, or normal/low WBC with tick exposure:
Start doxycycline 100 mg twice daily immediately for presumed RMSF. 1
- Clinical improvement expected within 24-48 hours. 1
- Delay in treatment is the most important factor associated with death from RMSF. 2
If leukocytosis with eosinophilia and recent drug initiation:
Discontinue suspected offending drug immediately and initiate systemic corticosteroids for presumed DRESS. 4, 5
- Monitor for progression to multiple organ failure. 4
If clinical features suggest viral exanthem without red flags:
Provide supportive care with antipyretics and hydration. 3
- Monitor for clinical deterioration suggesting bacterial superinfection. 3
If diagnosis uncertain and patient appears ill:
Administer both doxycycline and ceftriaxone empirically, as reliably distinguishing between RMSF and meningococcal infection based on initial presentation is difficult. 2
Common Pitfalls to Avoid
- Never dismiss the possibility of RMSF based on absence of tick bite history—40% of patients report no tick exposure. 1, 3
- Never wait for laboratory confirmation before starting doxycycline if RMSF is suspected—early serology is typically negative. 3
- Never rely on the presence of leukocytosis to exclude RMSF—while typical RMSF presents with normal WBC, atypical presentations occur. 2
- Never attribute fever and rash to viral exanthem without excluding life-threatening bacterial causes first. 3
- Geography should not exclude RMSF—cases occur nationwide despite the name. 3