Description
Pyrexia of Unknown Origin (PUO) remains one of the most intriguing and diagnostically challenging clinical presentations in internal medicine. This session offers a comprehensive, case-based exploration of PUO, guiding learners through a systematic, evidence-based approach to diagnosis. Participants will engage with real-world clinical cases that highlight the complexity and nuances of prolonged fever without an identifiable source. The session will cover the evolving definitions of PUO, classification into major subtypes (classic, nosocomial, neutropenic, and HIV-associated), and a structured roadmap for investigations—including clinical history-taking, physical examination pearls, essential lab workups, and the judicious use of imaging and invasive diagnostics. Emphasis will be placed on narrowing differentials using organ system-based thinking, understanding red flag indicators, and recognizing when to reconsider diagnoses or stop investigations. Through practical case discussions, attendees will gain deeper insights into common and rare causes of PUO—from infections and malignancies to autoimmune disorders and drug fevers. The session is designed to strengthen diagnostic reasoning and reduce cognitive bias in evaluating febrile patients.
Summary Listen
- **Definition and Subtypes of PEO:** Fever of unknown origin (PEO) is defined as a fever above 101°F for over three weeks without a diagnosis after a week of inpatient evaluation or three outpatient visits/days of hospitalization. Subtypes include classical PEO in immunocompetent patients, nosocomial PEO (fever after 48 hours of hospitalization), neutropenic PEO (absolute neutrophil count less than 500), and HIV-related PEO.
- **Major Categories of PEO:** PEO falls into four major categories: infections, neoplasms (lymphomas, leukemias), non-infectious inflammatory conditions (connective tissue disorders, vasculitis), and miscellaneous causes (drug fever, deep vein thrombosis, hormonal imbalances). Proper categorization aids in targeted investigations.
- **Diagnostic Challenges in PEO:** Diagnosing PEO is challenging due to numerous etiologies, requiring a structured approach to avoid over-investigation or over-reliance on imaging. Emerging autoimmune entities like Still's disease and VEXAS syndrome complicate diagnosis. Diagnostic bias can lead to a focus on preconceived diagnoses.
- **Stepwise Evaluation Strategies for PEO:** A stepwise approach includes confirming PEO criteria, reevaluating history and examination, Tier 1 investigations (CBC, ESR, CRP, ultrasounds, cultures), and stratifying by category. Tier 2 tests (auto-inflammatory panels, CT scans, PET-CTs) are reserved for cases where Tier 1 yields no clues. Continuous re-examination is vital.
- **Interpretation of Ferritin Levels:** Ferritin levels are valuable in differentiating inflammatory from infectious conditions. Levels of 500-1500 can be normal in infections or malignancies, while levels over 5000 suggest auto-inflammatory conditions like AOSD or macrophage activation syndrome. Levels over 10,000 are highly suggestive of AOSD or MAS.
- **When to Repeat Imaging:** Repeat imaging should be considered after 7-10 days of persistent unexplained fever, new symptoms (cough, pain, weight loss), evolving lab pathologies, or suspected internal abscesses. CT scans are preferred for detailed organ images. PET-CT is reserved for PEO lasting over three weeks with suspicion of inflammatory or malignant etiology after a negative CT scan.
- **Interpreting CRP and ESR:** CRP rises rapidly during acute inflammation, while ESR rises slowly and is more indicative of chronic inflammation. Isolated high ESR suggests malignancies or vasculitis. Isolated high CRP suggests early infection or acute inflammation. Elevated ESR and CRP indicate a systemic inflammatory process.
- **Role and Caution with Steroids:** Steroids can be useful for stable PEO patients with suspected inflammatory conditions. However, they should be avoided if there is suspicion of tuberculosis, fungal infection, deep abscess, or if biopsies are planned, as they can mask infections, malignancies, and alter biopsy results.
- **Common Misdiagnoses and Approach:** Common misdiagnoses include disseminated tuberculosis, culture-negative endocarditis, factitious fever, drug-induced fever, and occult abscesses. In stable patients with persistent fever and normal cultures, reconsider the diagnosis, but not the antibiotics. Avoid starting antitubercular therapy without pathology or PCR confirmation.
Sample Certificate
About the Speakers
Dr. Meghanath Yenni
Consultant Physician, Medicover Hospitals, Andhra Pradesh
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