What are the possible causes of a markedly elevated C‑reactive protein (CRP) in an otherwise asymptomatic patient with recurrent fever and a normal complete blood count (CBC)?

Differential Diagnosis of CRP 125 mg/L with Recurrent Fever and Normal CBC

A CRP of 125 mg/L with recurrent fever strongly suggests bacterial infection as the primary cause, given that bacterial infections show a median CRP of ~120 mg/L. 1, 2

Immediate Diagnostic Priorities

Obtain blood cultures immediately before starting any antibiotics, as this CRP level with fever indicates potential bacteremia or occult bacterial infection requiring urgent evaluation. 1

Most Likely Causes in Order of Probability

Bacterial infections are the leading consideration:

• Occult bacterial infections including endocarditis, deep-seated abscesses (hepatic, splenic, renal, psoas), osteomyelitis, or pyelonephritis can present with recurrent fever and markedly elevated CRP despite normal CBC. 1, 2
• Tuberculosis must be strongly considered, particularly if the patient has risk factors (immunosuppression, travel history, prior TB exposure), as TB can present with recurrent fever and very high CRP while maintaining normal CBC. 3
• Persistent CRP >100 mg/L strongly suggests the presence of an abscess or septic complication. 2

Inflammatory diseases (median CRP ~65 mg/L) are the second consideration:

• Giant cell arteritis requires urgent evaluation if the patient has new-onset headache, jaw claudication, visual disturbances, or temporal artery tenderness, as this requires treatment within 24 hours to prevent permanent blindness. 1, 4
• Adult-onset Still's disease classically presents with recurrent fever, markedly elevated CRP, and normal or only mildly elevated white blood cell count. 1
• Other systemic inflammatory conditions (rheumatoid arthritis, inflammatory bowel disease) typically show CRP ~65 mg/L. 1, 2

Malignancy (median CRP ~46 mg/L):

• Solid tumors or lymphoma can present with fever of unknown origin and elevated CRP, though 125 mg/L is higher than typical for malignancy alone. 1, 2
• Consider occult malignancy if other causes are excluded after systematic evaluation. 1

Essential Immediate Workup

Laboratory evaluation:

• Blood cultures (at least two sets from different sites) before antibiotics. 1
• Procalcitonin to help differentiate bacterial from non-bacterial causes. 1
• Liver enzymes (AST/ALT) to exclude hepatic pathology. 1
• Serum albumin and creatinine to assess for chronic disease states. 1
• ESR in combination with CRP yields highest sensitivity and specificity for detecting underlying pathological inflammation. 1

Imaging studies:

• Chest radiograph to identify pulmonary sources of infection or inflammation, including tuberculosis. 1
• CT chest/abdomen/pelvis if initial workup is unrevealing, to search for occult abscesses, malignancy, or lymphadenopathy. 1

Tuberculosis screening:

• Interferon-gamma release assay (IGRA) or tuberculin skin test given the case example showing TB reactivation presenting with fever and CRP 147.6 mg/L. 3
• Consider bronchoscopy with BAL and PCR for MTB if pulmonary infiltrates are present. 3

Critical Pitfalls to Avoid

• Do not attribute CRP of 125 mg/L to lifestyle factors alone: While smoking can elevate CRP (approximately 20% of smokers have CRP >10 mg/L), a level of 125 mg/L is far too high to attribute solely to non-pathological factors. 2
• Normal CBC does not exclude serious bacterial infection: Certain infections (endocarditis, TB, deep abscesses) can present with normal white blood cell counts. 1, 2
• Single normal CRP does not rule out infection: Serial measurements are more valuable than single values for diagnosis and monitoring. 2
• Do not delay empiric antibiotics if sepsis is suspected: Check for fever, hypothermia, hemodynamic instability, and signs of organ dysfunction requiring urgent intervention. 1

Monitoring Strategy

Serial CRP measurements should be obtained every 24-48 hours:

• CRP that fails to decrease or continues to rise after 48 hours of appropriate therapy suggests treatment failure or incorrect diagnosis. 5
• In bacterial infections, CRP typically peaks at 36-50 hours and decreases rapidly with resolution of inflammation. 5, 6

Do not use serial CRP testing to monitor treatment effects directly; instead, target the underlying cause while using CRP trends to confirm therapeutic response. 1