What is the diagnosis and treatment for a patient with fever, chills, fatigue, mouth irritation, and new onset nausea?

Differential Diagnosis and Management Approach

Most Likely Diagnosis: Tick-Borne Illness (Lyme Disease or Anaplasmosis)

Given the constellation of fever, chills, fatigue, mouth irritation, and nausea over one week, the most likely diagnosis is a tick-borne illness, specifically early Lyme disease or human granulocytic anaplasmosis (HGA), and empiric treatment with doxycycline should be initiated immediately without waiting for laboratory confirmation. 1

Critical Initial Assessment

Key Historical Elements to Obtain

• Recent tick exposure or outdoor activities in endemic areas (within past 3 weeks for HGA, past 30 days for Lyme disease) 2, 1
• Presence of expanding rash with or without central clearing, which would be diagnostic of erythema migrans and requires no laboratory confirmation 1
• Severity of fever pattern: High-grade fever (>102°F) persisting >48 hours suggests possible coinfection with Anaplasma or Babesia 2, 1
• Travel history to malaria-endemic regions, which would shift the differential significantly 2

Physical Examination Priorities

• Examine entire skin surface for erythema migrans lesions (expanding red rash, may have central clearing) 1
• Assess for splenomegaly, which increases likelihood of malaria if travel history is positive 2
• Evaluate mouth irritation for characteristic lesions versus nonspecific findings 3

Essential Laboratory Testing

• Complete blood count: Thrombocytopenia (<150,000/mL) and leukopenia strongly suggest tick-borne illness or malaria 2
• Liver function tests: Elevated transaminases support tick-borne illness or malaria 2
• Blood smear examination if thrombocytopenia present: Look for intragranulocytic inclusions (HGA) or intraerythrocytic parasites (malaria/babesiosis) 2

Immediate Treatment Decision Algorithm

Scenario 1: Tick Exposure + Erythema Migrans Present

Start doxycycline 100 mg orally twice daily for 14 days immediately without laboratory confirmation, as the rash is diagnostic 1

Scenario 2: Tick Exposure + No Rash + Thrombocytopenia/Leukopenia

Start doxycycline 100 mg orally twice daily for 10 days for presumed HGA, as delay in treatment increases risk of complications 2

• This regimen also covers concurrent Lyme disease if coinfection exists 2

Scenario 3: Travel to Malaria-Endemic Area + Fever + Thrombocytopenia

Urgent thick and thin blood smears must be obtained, and if positive or high clinical suspicion with severe features, initiate antimalarial therapy immediately 2

• Severe malaria requires intravenous artesunate 2

Scenario 4: No Clear Exposure History

Obtain blood cultures and consider broader infectious workup, but if thrombocytopenia and elevated liver enzymes are present, empiric doxycycline is reasonable while awaiting results 2

Monitoring for Coinfection

Red Flags Requiring Treatment Modification

• Fever persisting >48 hours despite doxycycline: Strongly suggests Babesia coinfection, requiring addition of atovaquone plus azithromycin or clindamycin plus quinine 2, 1
• Worsening thrombocytopenia or new anemia: Consider Babesia coinfection 2, 1
• No clinical improvement within 24-48 hours: Re-evaluate for alternative diagnoses 2

Alternative Diagnoses to Consider

If Mouth Irritation is Prominent

• Drug reaction with eosinophilia and systemic symptoms (DRESS): Recent antibiotic use (amoxicillin/clavulanic acid) can cause fever, rash, oral lesions, and elevated liver enzymes 4
• Viral infection: Human herpesvirus-6 can present with fever, oral lesions, and leukopenia 4

If COVID-19 Prevalence is High

• SARS-CoV-2 infection: Fever, chills, fatigue, nausea can precede respiratory symptoms by several days 2
• Testing should be considered if GI symptoms are prominent in high-prevalence settings 2

If Brucellosis Risk Factors Present

• Unpasteurized dairy consumption or animal exposure: Fever with afternoon sweating pattern, chills, and fatigue are characteristic 3
• Treatment requires doxycycline 100 mg twice daily plus rifampin 600-900 mg daily for 6 weeks 3

Critical Pitfalls to Avoid

Do Not Use These Antibiotics for Lyme Disease

First-generation cephalosporins, fluoroquinolones, and macrolides are ineffective for Lyme disease treatment 1

Do Not Delay Treatment Waiting for Serology

Two-tier Lyme serology is insensitive in early disease because antibodies have not yet developed, and negative testing does not rule out infection 1

Do Not Assume Fever Improvement Means Treatment Failure

In brucellosis, fever may persist for 7-14 days despite appropriate therapy, and this represents ongoing inflammatory response rather than treatment failure 3

Expected Clinical Course

With Appropriate Doxycycline Treatment

• Clinical improvement should occur within 24-48 hours for HGA 2
• Erythema migrans may take several weeks to completely resolve even with appropriate treatment 1
• Full symptom resolution may take several weeks for brucellosis despite appropriate therapy 3

When to Escalate Care

• Development of neurological symptoms: Suggests disseminated Lyme disease, HGA complications, or neurobrucellosis requiring parenteral therapy 2, 3
• Respiratory distress or hypoxemia: Consider severe COVID-19, SARS, or other respiratory pathogens 2
• Signs of shock: Requires immediate intensive care and broad-spectrum antibiotics for presumed sepsis 5