What initial lab tests should be run for a patient presenting with a new onset rash, fever, and fatigue?

Initial Laboratory Testing for PrEP Patient with New Onset Rash, Fever, and Fatigue

Order a complete blood count (CBC) with differential, comprehensive metabolic panel including hepatic transaminases, and HIV testing immediately, as these are the foundational tests for evaluating fever with rash and can identify life-threatening conditions while guiding empiric treatment decisions. 1

Essential First-Line Laboratory Tests

Complete Blood Count with Differential

• Thrombocytopenia, leukopenia, and elevated atypical lymphocytes are critical findings that narrow the differential diagnosis significantly 1
• Thrombocytopenia with normal or slightly increased white blood cell count suggests Rocky Mountain spotted fever (RMSF), which has a 5-10% case-fatality rate if untreated 1
• Leukopenia with thrombocytopenia points toward ehrlichiosis (3% case-fatality rate) or anaplasmosis (<1% case-fatality rate) 1
• The CDC emphasizes that these hematologic abnormalities appear early and are among the most useful diagnostic clues 1

Comprehensive Metabolic Panel

• Elevated hepatic transaminases occur commonly in tickborne rickettsial diseases and help differentiate between specific etiologies 1
• Hyponatremia is characteristic of RMSF and ehrlichiosis 1
• Renal function assessment is essential as acute renal failure represents a severe late-stage manifestation of RMSF 1

HIV Testing (Antigen and Antibody)

• HIV seroconversion illness presents with fever, rash, and fatigue and is critical to identify in PrEP patients 1, 2
• Many rapid tests do not detect seroconversion illness, so fourth-generation antigen/antibody testing is necessary 1
• PrEP patients have ongoing HIV exposure risk, making this test non-negotiable 1

Additional Critical Testing Based on Clinical Context

Blood Cultures

• Obtain at least two sets of blood cultures before initiating antibiotics 1
• Blood cultures can be positive in early leptospirosis (<5 days from symptom onset) and should be transferred at room temperature to reference laboratory 1
• Essential for identifying bacterial sepsis and guiding targeted antimicrobial therapy 1

Inflammatory Markers

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) should be checked when systemic inflammation is suspected 2
• These markers help distinguish infectious from non-infectious causes and assess disease severity 2

Peripheral Blood Smear

• Examine for morulae in leukocytes, which when present are diagnostic for ehrlichiosis, though sensitivity is only 1-20% 1
• This simple test can provide immediate diagnostic information while awaiting confirmatory testing 1

Pathogen-Specific Testing to Order Simultaneously

Tickborne Disease Panel

• Do not delay empiric doxycycline while awaiting these results if clinical suspicion is moderate to high 1, 2
• Order acute phase serology for rickettsial diseases (though negative early serology does not exclude diagnosis) 1
• PCR for Ehrlichia chaffeensis and Anaplasma phagocytophilum on whole blood 1
• Convalescent serology (3-6 weeks later) is required for definitive diagnosis 1

SARS-CoV-2 Testing

• PCR testing for SARS-CoV-2 should be performed based on community transmission levels 1
• COVID-19 can present with fever, rash, and fatigue 1

Critical Clinical Pitfalls to Avoid

• Never delay treatment for suspected RMSF or meningococcemia while awaiting laboratory confirmation - mortality increases significantly with diagnostic delays 1, 2
• Lack of rash or late-onset rash in RMSF is associated with increased mortality, so do not exclude the diagnosis based on rash characteristics alone 1
• Approximately 10% of RMSF patients never develop a rash, and children develop rash earlier and more frequently than adults 1, 2
• Negative acute serology for rickettsial diseases is common early in illness and should not prevent empiric treatment 1
• Skin pigmentation may make rashes difficult to recognize, requiring careful examination 1

Risk Stratification Based on Initial Results

High-Risk Laboratory Patterns Requiring Immediate Action

• Thrombocytopenia + fever + rash = presumptive RMSF until proven otherwise - initiate doxycycline immediately 1, 2
• Leukopenia + thrombocytopenia + elevated transaminases suggests ehrlichiosis - also requires immediate doxycycline 1
• Any petechial or purpuric rash with fever requires immediate evaluation for meningococcemia and RMSF 2

Moderate-Risk Patterns

• Maculopapular rash with normal CBC may represent viral exanthem, drug reaction, or early rickettsial disease 3
• Elevated atypical lymphocytes suggest viral illness including HIV seroconversion, EBV, or CMV 1

Special Considerations for PrEP Patients

• PrEP patients may have higher-risk sexual behaviors warranting consideration of secondary syphilis (obtain RPR/VDRL) 1
• Recent travel history is essential - if travel to endemic areas occurred, add malaria testing (three tests over 72 hours may be needed) 1, 2
• Tick exposure assessment is critical even without recalled tick bite, as many patients with confirmed rickettsial disease do not recall exposure 1
• Medication history must include all recent drug exposures as drug reactions are among the most common causes of fever with rash 3