What is the initial approach to managing pyrexia of unknown origin with elevated C-Reactive Protein (CRP) levels?

Causes of Pyrexia of Unknown Origin with Raised CRP Levels

Primary Diagnostic Categories

Pyrexia of unknown origin (PUO) with elevated CRP broadly falls into four major categories: infectious (most common), inflammatory/autoimmune, neoplastic, and miscellaneous causes, with infection accounting for the largest proportion of cases. 1, 2, 3

Infectious Causes

• Bacterial infections including occult abscesses, endocarditis (particularly prosthetic valve endocarditis), tuberculosis, and opportunistic mycobacterial infections are leading infectious causes 4, 1
• Enteric fever (typhoid/paratyphoid) should be considered in travelers from endemic areas, presenting with fever and gastrointestinal symptoms 4
• Bacterial dysentery from Shigella, Salmonella, or Campylobacter can cause fever with bloody diarrhea and elevated inflammatory markers 4
• Opportunistic mycobacterial disease (MAC, M. kansasii) particularly in immunocompromised patients, may present as disseminated disease or lymphadenitis with PUO 4
• Melioidosis, brucellosis, Q fever, and leptospirosis are important considerations in patients with relevant travel or occupational exposures 4

Inflammatory/Autoimmune Causes

• Giant cell arteritis should be suspected when ESR >40 mm/h with new-onset headache, jaw claudication, or visual symptoms, requiring urgent specialist referral within 24 hours 5, 6
• Polymyalgia rheumatica presents with bilateral shoulder/hip girdle pain, morning stiffness >45 minutes, and typically ESR >40 mm/h 6
• Still's disease (systemic JIA/AOSD) manifests with spiking fever, rash, arthritis, and markedly elevated CRP and ESR 6
• Rheumatoid arthritis and other connective tissue diseases show concordant elevation of inflammatory markers 6
• Inflammatory bowel disease with CRP >5 mg/L in symptomatic patients suggests active endoscopic inflammation 4, 7, 5

Neoplastic Causes

• Solid tumors have median CRP values around 46 mg/L, lower than acute bacterial infections but still significantly elevated 5
• Lymphomas and leukemias can present with fever and elevated inflammatory markers without obvious localizing signs 1, 3

Miscellaneous Causes

• Drug fever from various medications can cause persistent fever with elevated CRP 1, 3
• Thromboembolic disease including deep vein thrombosis and pulmonary embolism 1
• Factitious fever should be considered when clinical findings are inconsistent 2, 3

Initial Diagnostic Approach

Immediate Assessment

When CRP ≥10 mg/L is present with fever, immediately examine for sources of infection or inflammation, measure vital signs including temperature, and obtain blood cultures if infection is suspected. 7, 5

• Check for fever, tachycardia, hypotension, or altered mental status suggesting severe infection or sepsis 5, 6
• Perform systematic screening for respiratory, abdominal, urinary tract, soft tissue, and bloodstream infection sources 5
• Document recent trauma, surgery, travel history (with exact dates and locations), or known inflammatory conditions 4, 5

Essential Laboratory Workup

• Blood cultures (multiple sets) before antibiotic initiation if infection suspected 7, 5
• Complete blood count with differential to assess for leukocytosis, left-shift, neutropenia, or anemia 5, 6
• Liver function tests (AST/ALT) to exclude hepatic inflammation or fatty liver disease 7, 5
• Urinalysis and urine culture to identify urinary tract infection 5, 6
• Comprehensive metabolic panel for renal function and electrolyte abnormalities 6

Interpretation of CRP Magnitude

The magnitude of CRP elevation provides diagnostic clues: acute bacterial infections typically show CRP ~120 mg/L, inflammatory diseases ~65 mg/L, solid tumors ~46 mg/L, non-bacterial infections ~32 mg/L, and stable cardiovascular disease ~6 mg/L. 5

• CRP >10 mg/L warrants thorough evaluation, but approximately 20% of smokers have CRP >10 mg/L from smoking alone 5
• Obesity, age, sex, and race significantly affect baseline CRP levels and must be considered 5
• Serial CRP measurements are more valuable than single values for diagnosis and monitoring treatment response 5

Advanced Diagnostic Strategies

Imaging Modalities

FDG-PET/CT has emerged as a highly valuable tool for identifying occult sources of infection and inflammation in PUO, with particularly high sensitivity and specificity when CRP levels are elevated. 4

• FDG-PET/CT shows significantly improved diagnostic accuracy for fever of unknown origin when CRP is elevated, and should be considered early in immunosuppressed or neutropenic patients 4
• Chest radiography to exclude pulmonary infection or malignancy, though sensitivity is limited in early disease 4, 6
• CT imaging of chest, abdomen, and pelvis may identify abscesses, lymphadenopathy, or malignancy 4
• Echocardiography (preferably transesophageal) if endocarditis suspected, particularly in patients with prosthetic valves or cardiac devices 4

Specialized Testing Based on Clinical Context

• Autoantibody panel (RF, anti-CCP, ANA, ANCA) if joint symptoms or systemic features suggest autoimmune disease 6
• Procalcitonin if available to help differentiate bacterial infection from other causes 5
• Mycobacterial cultures from blood, sputum, or tissue if tuberculosis or atypical mycobacteria suspected 4
• Serological testing for specific infections based on exposure history (brucella, Q fever, leptospirosis) 4

Critical Clinical Pitfalls

False Reassurance from Normal Tests

• A single normal CRP does not rule out infection, and CRP may be completely normal even during disease flares in some conditions 4, 7
• CRP has a 31.4% false-negative rate in high pretest probability scenarios for conditions like ulcerative colitis 5
• Neutropenia, immunodeficiency, and NSAID use can affect CRP concentrations and lead to falsely reassuring results 5

Misinterpretation of Elevated CRP

• Do not assume CRP >10 mg/L always indicates acute infection—it can be associated with chronic conditions, demographic factors, and lifestyle factors 7, 5
• ESR should be interpreted cautiously in anemia and azotemia, which artificially elevate ESR independent of inflammation 6
• Discordance between CRP and ESR occurs in 12-20% of patients and has specific clinical associations requiring careful evaluation 6

Laboratory Safety Considerations

Laboratory staff must be warned when considering enteric fever, brucella, Q fever, melioidosis, or viral hemorrhagic fevers, as these require upgraded infection control procedures for sample processing. 4

Monitoring and Follow-up

Serial Assessment Strategy

• Average two CRP measurements taken 2 weeks apart for stable assessment in non-acute situations 7, 5
• Repeat CRP after clinical recovery to confirm normalization, as CRP normalizes more quickly than ESR during resolution of inflammation 7, 5
• In patients achieving symptomatic remission, repeat CRP measurement in 3-6 months to ensure sustained response 5

When Diagnosis Remains Elusive

Up to 50% of PUO patients have no cause found despite adequate investigations, but this undiagnosed cohort has a reassuringly good prognosis. 1

• Continue careful clinical observation for new symptoms and signs rather than empiric antimicrobial therapy in stable patients 2
• Consider narrow-spectrum antimicrobial therapy only in patients with clearly progressive disease despite extensive negative investigations 2
• Early use of FDG-PET/CT may prevent missed diagnoses by identifying inflammation before it is suppressed by extended antibiotic therapy 4