In a patient from a rural Asia‑Pacific area presenting with 5–14 days of fever, headache, myalgia, an eschar and possible maculopapular rash, how should I diagnose scrub typhus and what empiric therapy should be initiated?

Scrub Typhus Diagnosis and Empiric Treatment

Immediate Action: Start Doxycycline Now

In a patient from rural Asia-Pacific with fever, headache, myalgia, and an eschar, initiate doxycycline immediately without waiting for laboratory confirmation—delay in treatment can lead to severe disease and death. 1, 2

Diagnostic Approach

Clinical Diagnosis (Sufficient to Start Treatment)

The combination of clinical features is highly suggestive and warrants immediate empiric therapy 2:

• Fever (most consistent symptom, onset 6-10 days post-exposure) 2
• Eschar (painless necrotic lesion with black crust surrounded by erythema)—present in only 60% of cases, so absence does not exclude diagnosis 2
  • Check hidden areas: axilla, groin, inguinal region, scalp 3
• Headache and myalgia (nearly universal) 2
• Maculopapular rash (when present, supports diagnosis) 4

Laboratory Testing (Do Not Delay Treatment)

Order these tests but start antibiotics before results return 2:

Serological tests (primary diagnostic method):

• IgM ELISA: 80.3% sensitivity, excellent specificity 5
• Immunofluorescence assay (IFA): 93.4% sensitivity, reference standard 5, 3
• Rapid diagnostic tests: excellent sensitivity and specificity 6

Critical limitation: Serological tests remain negative in early disease (<7 days), so negative results do not rule out scrub typhus 6, 5

Molecular testing (when available):

• Nested PCR: 75.2% sensitivity, most sensitive test in early disease (<7 days) when serology is negative 6, 5
• Can detect cases missed by serology alone 5

Confirmatory testing: Paired sera 2-4 weeks apart showing ≥4-fold rise in titer 4, 3

Avoid: Weil-Felix test (only 54.2% sensitivity, inadequate) 5

Supportive Laboratory Findings

Common abnormalities that support diagnosis 3:

• Elevated liver transaminases
• Thrombocytopenia
• Leukocytosis

Empiric Treatment Protocol

First-Line Therapy: Doxycycline

Adults: 1, 2

• Doxycycline 100 mg twice daily (oral or IV)
• Continue for at least 3 days after fever subsides
• Minimum course: 5-7 days

Children <45 kg: 1, 2

• Doxycycline 2.2 mg/kg twice daily (oral or IV)
• Use in all children including those <8 years—short-course doxycycline does not cause dental staining 1

Route selection: 2

• Use IV for hospitalized patients with multi-organ dysfunction, vomiting, or altered mental status
• Otherwise oral is acceptable

Expected Response and Alternative Diagnoses

Typical response: Fever resolves within 24-48 hours 4, 1, 2

If no improvement within 48 hours: 4, 1

• Strongly reconsider diagnosis
• Consider alternative or co-infections (malaria, dengue, enteric fever, leptospirosis)
• Exception: Severely ill patients with multi-organ dysfunction may require >48 hours 2

Alternative Agent (Second-Line)

Chloramphenicol: 12.5-25 mg/kg every 6 hours IV 1, 2

• Use only if doxycycline contraindicated
• Less effective than doxycycline

Azithromycin: 6

• Alternative for mild illness
• Less data supporting use

Critical Pitfalls to Avoid

1. Never delay treatment waiting for laboratory confirmation—mortality up to 4% if treatment delayed 4, 1

2. Do not exclude scrub typhus based on absent eschar—only present in 60% of cases 2

3. Do not rely on negative early serology—antibodies not detectable in first week 6, 5

4. Do not withhold doxycycline from children <8 years—it is the drug of choice for all ages 1, 2

5. Do not assume treatment failure at 24 hours—severely ill patients may need >48 hours to respond 2

Severe Disease Management

For patients with multi-organ dysfunction 2:

• Hospitalize immediately
• IV doxycycline mandatory
• Longer treatment courses required (>7 days)
• Careful fluid management—avoid overhydration (pulmonary complications in 36% of cases)
• Monitor for complications: ARDS (15%), acute renal failure (9%), CNS involvement (20%)