What are the differential diagnoses and management plan for a 3-year-old child with fever, rash, and unilateral leg pain, who has a normal Complete Blood Count (CBC) and negative dengue serology?

Differential Diagnoses and Management for 3-Year-Old with Fever, Rash, and Unilateral Leg Pain

This child requires immediate empiric treatment with doxycycline for presumed tickborne rickettsial disease, specifically Rocky Mountain Spotted Fever (RMSF) or Human Monocytic Ehrlichiosis (HME), given the potentially fatal outcome if treatment is delayed. 1

Critical Differential Diagnoses

High-Priority Life-Threatening Conditions

Rocky Mountain Spotted Fever (RMSF)

• RMSF presents with fever and rash appearing 2-4 days after fever onset, initially as small blanching pink macules on ankles, wrists, or forearms 2, 3
• The rash progresses to maculopapular with central petechiae, spreading to palms, soles, arms, legs, and trunk 2
• Critical pitfall: Up to 20% of RMSF patients never develop a rash, and less than 50% have rash in the first 3 days of illness 2
• Case-fatality rate is 5-10%, with 50% of deaths occurring within 9 days of illness onset 1, 2
• Normal CBC does NOT exclude RMSF—normal WBC is frequently observed early in the disease course 1
• The unilateral leg pain could represent early vascular involvement or myalgia, both characteristic of rickettsial diseases 1
• Absence of tick bite history should NOT dissuade diagnosis: up to 40% of RMSF patients report no tick bite 1

Human Monocytic Ehrlichiosis (HME)

• Rash occurs in only approximately 30% of adults and children, varying from petechial to maculopapular to diffuse erythema 2, 4
• Rash appears later in disease course (median 5 days after onset) and rarely involves palms and soles 2
• Case-fatality rate is 3% 2
• Can present with severe localized myalgia, as demonstrated in a case report of a 7-year-old with severe calf muscle pain and markedly elevated CPK 5

Meningococcemia

• Must be considered in any child with fever and rash, particularly if petechial elements develop 1
• Requires immediate blood cultures and empiric antibiotics while pursuing rickettsial workup 1

Moderate-Priority Infectious Causes

Viral Exanthems

• Enteroviruses are the most common cause of maculopapular rashes, typically involving trunk and extremities while sparing palms, soles, face, and scalp 2, 3
• Human herpesvirus 6 (roseola) presents with macular rash following high fever 2, 3
• Epstein-Barr virus causes maculopapular rash, especially if patient received ampicillin or amoxicillin 2, 3
• Parvovirus B19 presents with "slapped cheek" appearance with possible truncal involvement 2, 3

Streptococcal Disease with Exanthem

• Group A Streptococcus can present with fever, rash, and arthralgia 1
• Requires throat culture or rapid strep test 1

Lower-Priority Considerations

Kawasaki Disease

• Presents with fever >5 days, rash, conjunctival injection, oral changes, extremity changes, and lymphadenopathy 1, 6
• Unilateral leg pain would be atypical unless representing arthritis 6

Juvenile Idiopathic Arthritis

• Can present with fever, rash, and arthritis, but typically has more prominent joint swelling 6
• Intermittent fever pattern ("quotidian fever") is characteristic 6

Drug Reaction

• Nonspecific drug eruptions present as fine reticular maculopapular rashes or broad, flat erythematous macules and patches 2, 3
• Query specifically about recent antibiotic use, NSAIDs, anticonvulsants, or any new medications within past 2-3 weeks 3

Immediate Management Plan

Step 1: Empiric Treatment (Do NOT Wait for Laboratory Results)

Initiate doxycycline immediately 1, 2, 4

• Dosing: 2.2 mg/kg body weight orally twice daily (maximum 100 mg per dose) 1
• Duration: Minimum 5 days and continue until patient is afebrile for 24-48 hours 1
• Rationale: Doxycycline is the drug of choice for all tickborne rickettsial diseases in patients of all ages, including children aged <8 years 1, 4
• Critical point: Delay in treatment increases mortality significantly; treatment must begin based on clinical suspicion 1, 3
• Expected response: Clinical improvement within 24-48 hours of initiating doxycycline 2, 4

Consider empiric coverage for meningococcemia if petechiae present

• Ceftriaxone 50-100 mg/kg/day IV while pursuing diagnostic workup 1

Step 2: Immediate Diagnostic Workup

Laboratory tests to order STAT 1, 2, 3

• Complete blood count with differential (looking for leukopenia, thrombocytopenia—though normal CBC does NOT exclude diagnosis)
• Comprehensive metabolic panel (looking for hyponatremia, elevated hepatic transaminases AST/ALT)
• Blood culture (to rule out bacterial sepsis/meningococcemia)
• Acute serology for R. rickettsii, E. chaffeensis, and A. phagocytophilum (though results will not be available for days and should NOT delay treatment)
• PCR for E. chaffeensis and A. phagocytophilum using EDTA whole blood if available from reference laboratory 1, 4
• Creatine phosphokinase (CPK) level given the leg pain—severe myositis can occur with ehrlichiosis 5

Additional testing based on clinical presentation

• Rapid Streptococcus pharyngitis screen if pharyngitis present 1
• Peripheral blood smear examination for morulae within leukocytes (visible in only 1-20% of cases) 4

Step 3: Detailed History to Guide Differential

Specific questions to ask 1

• Tick exposure history (outdoor activities, hiking, camping, playing in brushy areas or backyard, pet exposure)
• Geographic location and recent travel
• Timing of rash appearance relative to fever onset
• Pattern of rash progression (where it started, direction of spread)
• Characteristics of leg pain (unilateral vs bilateral, severity, ability to bear weight)
• Recent medication use (antibiotics, NSAIDs, anticonvulsants)
• Sick contacts
• Immunization status

Step 4: Clinical Monitoring

Monitor for severe complications 2, 4

• Meningoencephalitis
• Acute respiratory distress syndrome (ARDS)
• Disseminated intravascular coagulation (DIC)
• Multiorgan failure
• Pulmonary hemorrhage

If no clinical improvement within 24-48 hours of doxycycline 4

• Consider coinfection with other tickborne pathogens (Borrelia burgdorferi, Babesia microti)
• Consider alternative diagnoses
• Reassess for complications

Step 5: Follow-up Serology

Convalescent serology 1, 4

• Obtain 2-4 weeks after symptom onset to confirm diagnosis retrospectively
• Rising IgG antibody titers between acute and convalescent samples confirm diagnosis 1

Critical Pitfalls to Avoid

1. DO NOT wait for laboratory confirmation before starting doxycycline—serology is typically negative in the first week of illness 1, 4

2. DO NOT exclude RMSF based on absence of tick bite history—40% of patients report no tick bite 1

3. DO NOT exclude RMSF based on normal CBC—normal WBC is frequently observed early in disease 1

4. DO NOT exclude RMSF based on absence of rash—20% never develop rash 2

5. DO NOT use penicillins, cephalosporins, aminoglycosides, erythromycin, or sulfa-containing drugs for suspected rickettsial disease—these are not effective against rickettsiae, ehrlichiae, or anaplasmae 1

6. DO NOT delay treatment based on geographic considerations—RMSF should be considered endemic throughout the contiguous United States 1