Introduction
Investigating Pyrexia of Unknown Origin (PUO) requires a structured approach balancing non-invasive screening, advanced molecular tests, and targeted nuclear imaging. Random ordering of expensive panels without clinical reasoning often delays diagnosis. This article outlines a tiered imaging and lab algorithm to systematically resolve occult fevers.
Phase-Wise Diagnostic Approach
Phase 1: Basic Screen (CBC, ESR, CRP, Blood Cultures, Chest X-Ray)
Phase 2: Targeted Cross-Sectional Imaging (CT Chest/Abdomen/Pelvis, Echo)
Phase 3: Molecular & Metabolic Scans (18F-FDG PET/CT, Serologies, Biopsy)
Phase 1: Initial Essential Investigations
Hematology & Acute Phase Reactants: CBC with differential, ESR, CRP, Ferritin.
Microbiology: Blood cultures ($\times 3$ sets from different sites with strict aseptic technique), Urinalysis and Urine culture, Sputum AFB.
Biochemistry: Liver Function Tests, Renal Function Tests, Electrolytes, Lactate Dehydrogenase (LDH).
Basic Imaging: Chest Radiograph and Abdominal Ultrasonography.
Phase 2: Non-Invasive Anatomical Cross-Sectional Imaging
Contrast-Enhanced CT (Chest, Abdomen, Pelvis): Identifies occult abscesses, retroperitoneal lymphadenopathy, deep vein thrombosis, or occult solid tumors.
Echocardiography: Transthoracic (TTE) followed by Transesophageal Echocardiography (TEE) to exclude infective endocarditis and atrial myxoma.
Phase 3: Functional Imaging & Invasive Sampling
$^{18}\text{F-FDG PET/CT}$: Combines metabolic activity assessment with anatomical localization. Highly effective in identifying hypermetabolic vascular inflammation (large vessel vasculitis), occult infections, and early-stage lymphomas.
Bone Marrow Aspirate & Biopsy: Indicated when cytopenias are present or in suspected disseminated TB, leishmaniasis, or lymphoma.
Targeted Tissue Biopsy: Biopsy of enlarged lymph nodes, temporal artery, or focal liver/splenic lesions.
Comparison of Functional Imaging Modalities in PUO
| Modality | Diagnostic Utility | Primary Indications |
| $^{18}\text{F-FDG PET/CT}$ | High sensitivity for hypermetabolic focus. | Vasculitis, Lymphoma, Occult Abscesses. |
| Leukocyte Scintigraphy ($^{111}\text{In}$ / $^{99m}\text{Tc}$) | Specific for neutrophil infiltration. | Bacterial Abscesses, Osteomyelitis. |
| Gallium-67 Citrate Scan | Binds to transferrin and inflammatory exudates. | Granulomatous diseases, Chronic infections. |
Diagnostic Summary: Functional nuclear imaging with $^{18}\text{F-FDG PET/CT}$ has largely replaced older radioisotope scans due to its high spatial resolution and ability to guide subsequent biopsies directly.