What are the differential diagnoses and initial management for a centripetal rash?

Centripetal Rash: Differential Diagnosis and Initial Management

Immediate Life-Threatening Diagnoses to Exclude First

Rocky Mountain Spotted Fever (RMSF) is the most critical diagnosis to consider in any patient with centripetal rash (spreading from extremities to trunk), and empiric doxycycline 100 mg twice daily must be initiated immediately if fever, headache, and tick exposure or endemic area exposure are present—even without laboratory confirmation. 1

Key Clinical Features of RMSF

• The classic RMSF rash begins 2–4 days after fever onset as small (1–5 mm) blanching pink macules on ankles, wrists, or forearms (peripheral distribution), then spreads centripetally to palms, soles, arms, legs, and trunk while sparing the face 1, 2
• The rash evolves from maculopapular to lesions with central petechiae by day 5–6 of illness 1, 2
• Critical pitfall: Less than 50% of patients have rash in the first 3 days, and up to 20% never develop a rash—absence of rash does not exclude RMSF 1, 2
• Up to 40% of RMSF patients report no tick bite history, making exposure history unreliable 1
• The case-fatality rate is 5–10%, with 50% of deaths occurring within 9 days; delayed treatment is the most important factor associated with death 1

Red Flags Requiring Immediate Doxycycline

The CDC recommends initiating doxycycline immediately if ANY of the following are present: 1

• Fever + rash + headache + tick exposure or endemic area exposure
• Thrombocytopenia and/or hyponatremia (present in up to 94% and 53% of cases, respectively) 1
• Leukopenia (present in up to 53% of RMSF cases) 1

Other Tickborne Rickettsial Diseases with Centripetal Spread

Human Monocytic Ehrlichiosis (HME)

• Rash occurs in only approximately 30% of adults (up to 66% in children), appearing as petechial, maculopapular, or diffuse erythema 1, 2
• Rash appears later in disease course (median 5 days after onset) and rarely involves palms and soles 1
• Case-fatality rate is 3% 1
• Prominent gastrointestinal manifestations help distinguish HME from RMSF 1

Rickettsia parkeri Rickettsiosis

• Approximately 90% develop a sparse maculopapular or vesiculopapular rash with palmar/plantar involvement in about half of cases 1
• Distinguishing feature: An inoculation eschar at the bite site is present in nearly all patients and is often the first manifestation 1

Immediate Diagnostic Workup for Suspected Tickborne Disease

When RMSF or ehrlichiosis is suspected, obtain immediately: 1

• Complete blood count with differential (looking for leukopenia, thrombocytopenia)
• Comprehensive metabolic panel (looking for hyponatremia, elevated hepatic transaminases)
• Acute serology for Rickettsia rickettsii, Ehrlichia chaffeensis, and Anaplasma phagocytophilum
• Peripheral blood smear to look for morulae within granulocytes (Anaplasma)

Do not wait for laboratory confirmation to initiate doxycycline—clinical improvement is expected within 24–48 hours of starting treatment 1

Non-Infectious Causes of Centripetal Rash

Drug Hypersensitivity Reactions

• Drug eruptions can present as fine reticular maculopapular rashes or broad, flat erythematous macules and patches, sometimes with petechial components 3
• Query about new medications within the past 2–3 weeks, particularly antibiotics (especially ampicillin/amoxicillin), NSAIDs, or anticonvulsants 3
• Management: Discontinue the offending agent immediately and provide symptomatic treatment with antihistamines for pruritus 3

Viral Exanthems

• Enteroviral infections are the most common cause of maculopapular rashes, characteristically presenting with trunk and extremity involvement while sparing palms, soles, face, and scalp 1, 3
• Parvovirus B19 presents with "slapped cheek" appearance on face with possible truncal involvement 1
• EBV causes maculopapular rash, especially if the patient received ampicillin or amoxicillin 1, 3
• Human herpesvirus 6 (roseola) presents with macular rash following resolution of high fever 1, 4

Pediatric Considerations: Kawasaki Disease

In children with fever ≥5 days plus centripetal rash (especially with groin/perineal accentuation), Kawasaki disease must be excluded due to risk of coronary artery aneurysms if untreated. 1

Diagnostic Criteria

Requires fever ≥5 days plus 4 of 5 features: 1

• Bilateral conjunctival injection
• Oral mucosal changes (strawberry tongue, cracked lips)
• Cervical lymphadenopathy ≥1.5 cm
• Extremity changes (erythema of palms/soles, edema, later desquamation)
• Polymorphous rash (typically maculopapular, truncal, with groin accentuation)

If suspected, obtain ESR, CRP, serum albumin, and urinalysis 1

Algorithmic Approach to Centripetal Rash

Step 1: Assess for Fever and Systemic Symptoms

• If fever + headache + myalgia present: Assume RMSF until proven otherwise; start doxycycline immediately 1
• If afebrile with pruritus: Consider drug reaction or viral exanthem as primary differentials 3

Step 2: Examine Rash Distribution and Morphology

• Peripheral onset (wrists/ankles) spreading centrally with palmar/plantar involvement: RMSF is most likely 1, 2
• Truncal with groin accentuation in a child with fever: Consider Kawasaki disease 1
• Trunk and extremities sparing palms/soles/face: Viral exanthem or drug reaction more likely 1, 3

Step 3: Check for Petechiae

• Petechiae present, especially on palms/soles: Advanced RMSF, meningococcemia, or endocarditis—requires immediate intervention 2
• No petechiae: Does not exclude early RMSF (petechiae develop by day 5–6) 1, 2

Step 4: Obtain Exposure History

• Tick exposure or endemic area (April–September, grassy/wooded areas): Strongly supports tickborne disease 1
• New medications in past 2–3 weeks: Supports drug hypersensitivity 3
• Recent viral prodrome: Supports viral exanthem 1, 4

Critical Pitfalls to Avoid

• Never wait for the classic triad of fever, rash, and tick bite in RMSF—it is present in only a minority of patients at initial presentation 2
• Absence of rash does not exclude RMSF: Up to 20% never develop a rash, and fewer than 50% have rash in the first 3 days 1, 2
• Absence of tick bite history does not exclude RMSF: Up to 40% report no tick bite 1, 2
• In darker-skinned patients, petechial and maculopapular rashes may be difficult to recognize, increasing risk of delayed diagnosis 1, 2
• Do not misdiagnose pityriasis rosea as drug-induced allergy, leading to unnecessary medication discontinuation—look for herald patch and Christmas tree pattern 1, 4

High-Risk Populations Requiring Lower Threshold for Treatment

• Immunosuppressed patients 1
• Elderly (≥60 years) 1
• Children <10 years 1

These groups have higher case-fatality rates for RMSF and other tickborne diseases and may present with atypical or absent rash 1

Expected Clinical Response and Red Flags for Re-evaluation

• If RMSF treated with doxycycline: Clinical improvement expected within 24–48 hours 1
• If viral exanthem or drug reaction: Spontaneous resolution expected within 5–14 days 1, 3

Red flags requiring immediate re-evaluation: 3, 2

• Development of fever in previously afebrile patient
• Progression of petechiae to purpura or ecchymoses
• Development of systemic symptoms (headache, altered mental status, severe myalgia)
• New involvement of palms and soles
• Lack of improvement after 48 hours of doxycycline (consider coinfection with Borrelia burgdorferi or Babesia microti) 1