What is the best course of action for an adult patient with a history of autoimmune disorders, presenting with a feverish feeling despite normal white blood cell (WBC) counts and no apparent infection?

Management of Subjective Fever with Normal White Blood Cell Counts in Adults with Autoimmune Disorders

In an adult patient with autoimmune disorders experiencing subjective fever despite normal WBC counts, you should obtain blood cultures immediately, perform a complete blood count with differential focusing on band count and neutrophil percentage, and pursue targeted diagnostic testing based on systematic clinical evaluation—because normal WBC counts do not exclude serious bacterial infection, particularly in immunocompromised patients. 1, 2

Initial Diagnostic Approach

Immediate Laboratory Evaluation

• Obtain at least two sets of blood cultures (ideally 60 mL total blood) from different anatomic sites before any antibiotic administration, as this is the highest-yield initial test for identifying occult bacteremia 2, 1

• Order a complete blood count with differential immediately, even though the total WBC is normal, because specific findings can indicate bacterial infection 1, 2:

  • An elevated total band count (>1,500/mm³) has the highest likelihood ratio (14.5) for detecting bacterial infection 1
  • Neutrophil percentage >90% has a likelihood ratio of 7.5 for bacterial infection 1
  • A "left shift" (band neutrophils ≥6%) has a likelihood ratio of 4.7 for infection 1
  • These findings can indicate serious bacterial infection even when total WBC count is normal 1

Biomarker Testing Strategy

• If the clinical probability of bacterial infection is low to intermediate, measure procalcitonin (PCT) or C-reactive protein (CRP) in addition to clinical evaluation 2, 3

  • PCT begins rising 4 hours after bacterial exposure, peaking at 6-8 hours 2
  • Normal PCT is <0.05 ng/mL 2
  • However, PCT can be elevated in severe viral illness, reducing its discriminatory power 2

• If clinical probability of bacterial infection is high, do NOT wait for biomarker results—proceed directly with empiric treatment after obtaining blood cultures 2, 3

Systematic Clinical Evaluation

Critical History Elements

• Document all medications started within the past 3 weeks, as drug-induced fever has a mean lag time of 21 days after drug initiation and is a common cause of fever in patients on immunosuppressive therapy 3, 4

• Obtain detailed travel history within the past 3 weeks, as enteric fever and rickettsial infections are common causes of prolonged fever in returned travelers 3, 4

• Ask specifically about tick exposure or outdoor activities in wooded areas, as tickborne rickettsial diseases (ehrlichiosis, anaplasmosis) can present with nonspecific fever and normal or low WBC counts 1, 3

• Document presence of any indwelling devices (central lines, urinary catheters, vascular grafts), as these are common sources of occult infection 4

Targeted Diagnostic Testing Based on Symptoms

• If there are any urinary symptoms or unexplained fever, obtain urinalysis with leukocyte esterase dipstick 1, 2:

  • The absence of pyuria (negative leukocyte esterase) effectively excludes urinary tract infection 1
  • If pyuria is present, then obtain urine culture 1

• If there are respiratory symptoms or suspected pneumonia, perform chest radiography and viral pathogen testing including SARS-CoV-2 PCR based on community transmission levels 1, 2

• If there is altered mental status or any neurological signs, perform lumbar puncture after appropriate imaging if focal signs are present, as CNS infection must be excluded 1, 2, 4

Special Considerations for Autoimmune/Immunosuppressed Patients

Key Clinical Pitfalls

• Do not assume normal WBC count excludes infection in immunosuppressed patients—up to 75% of patients with prolonged fever may have normal WBC counts, particularly in those on immunosuppressive therapy 4

• Maintain high index of suspicion for opportunistic infections, including cytomegalovirus reactivation, which can present with fever and normal WBC counts in immunosuppressed patients 1

• Consider autoinflammatory disease flare as a cause of subjective fever in patients with known autoimmune disorders, but only after excluding infection 5

When to Initiate Empiric Antibiotics

• Start empiric antibiotics immediately if any of the following are present 3:

  • Signs of hemodynamic instability or septic shock
  • Altered mental status suggesting sepsis or meningitis
  • Respiratory distress
  • Suspected cholangitis

• Stable patients without signs of sepsis can be observed for 1-2 hours before antibiotics, but blood cultures must be obtained first and close monitoring maintained 3

Addressing the Subjective Fever Component

• Take the complaint of subjective fever seriously—studies show that 4 out of 5 adult patients who believe they have fever actually have objective temperature elevation ≥38.0°C, with sensitivity of 89-90% and specificity of 94-95% 6

• Verify fever objectively with proper temperature measurement, as subjective fever may be an important clue requiring further evaluation even when initial temperature is normal 6, 4

• Consider administering acetaminophen 1000 mg orally every 4-6 hours (maximum 4 g/day) for symptomatic relief while diagnostic workup proceeds 3