# Internal Medicine/Fever of Unknown Origin
## Introduction to Fever of Unknown Origin (FUO)

Fever of Unknown Origin (FUO) is a complex and perplexing clinical syndrome characterized by a persistent fever of 101°F (38.3°C) or higher for three weeks or longer, accompanied by diagnostic uncertainty. It presents a formidable diagnostic challenge for healthcare providers, as patients with FUO often undergo an extensive battery of tests and evaluations in the quest to identify the underlying cause of their fever.
FUO is not a singular diagnosis but rather a symptom of an underlying condition. It can affect individuals of all ages, from pediatric patients to the elderly, and it is imperative to differentiate FUO from self-limited febrile illnesses. The elusive nature of FUO demands a systematic and comprehensive approach to diagnosis, which often involves multidisciplinary collaboration among physicians, including internists, infectious disease specialists, rheumatologists, and oncologists.

## Common Causes of FUO

Uncovering the source of a fever in FUO cases is akin to solving a complex puzzle, and there is a wide array of potential contributing factors. Here are some common categories of causes:
Infectious Causes: Infectious etiologies are perhaps the most prevalent culprits behind FUO. These may include latent infections, such as tuberculosis, abscesses, or endocarditis, which can evade conventional diagnostic tests. Additionally, chronic viral infections and atypical pathogens may manifest as FUO.
Inflammatory Diseases: Autoimmune and rheumatic diseases are noteworthy contributors to FUO. Conditions like systemic lupus erythematosus, systemic vasculitides, or polymyositis can incite recurrent fever episodes. The diversity of inflammatory diseases associated with FUO underscores the importance of a meticulous clinical evaluation and targeted laboratory testing.
Neoplasms: Malignancies, both hematologic and solid tumors, can present with unexplained fevers. Lymphomas, carcinomas, and histiocytic disorders are examples of cancers that may be masked by fever, emphasizing the necessity of cancer screening in FUO cases.
Miscellaneous Causes: Beyond infections, inflammation, and malignancies, a wide range of miscellaneous factors can contribute to FUO. These may encompass metabolic abnormalities, hypersensitivity reactions, and genetic disorders. For instance, conditions like Gaucher disease, milk protein allergy, or metal fume fever should not be overlooked in the diagnostic workup.

## Diagnostic Imaging in the Workup of FUO

Accurate diagnosis of FUO often necessitates the utilization of advanced diagnostic imaging techniques, with FDG-PET/CT (Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography) being a pivotal tool. Key considerations in this context include:
The Superiority of FDG-PET/CT: Among various imaging modalities, FDG-PET/CT has emerged as a frontrunner due to its superior diagnostic performance. It excels in detecting areas of abnormal metabolic activity, making it particularly effective for identifying underlying causes of FUO.
High Diagnostic Yield: Studies and meta-analyses consistently report a high diagnostic yield for PET and PET/CT in the evaluation of FUO patients. Sensitivity and specificity figures of around 85% and 50%, respectively, highlight its effectiveness.
Proper Timing and Biomarker Use: The timing of FDG-PET/CT is crucial in its diagnostic value. Elevated biomarkers like C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) can enhance the contribution of PET/CT to the diagnostic process. When both CRP and ESR are normal during the scan, the diagnostic outcome may only be contributory when fever is present.
Cost-Effectiveness: While FDG-PET/CT is a relatively expensive procedure, its judicious use at an early stage of the diagnostic workup can prove cost-effective. It can facilitate early diagnosis, reduce hospitalization duration, and eliminate unnecessary tests.

## Conventional Scintigraphic Imaging

In situations where FDG-PET/CT is not available or appropriate, conventional scintigraphic methods can be considered. These methods include gallium scintigraphy and leukocyte scintigraphy. However, their diagnostic performance is generally inferior to PET/CT.

## Later-Stage Diagnostic Tests

In some cases, more invasive diagnostic tests become necessary as initial evaluations fail to yield a diagnosis. These procedures may include:
Lymph Node Biopsy: Especially when lymphadenopathy is present, a lymph node biopsy may be required, even if affected lymph nodes are challenging to access.
Skin Biopsy: For patients with skin lesions, a skin biopsy is a valuable diagnostic tool.
Chest and Abdominal CT Scans: While not the initial choice, chest and abdominal CT scans can be considered as later-stage screening procedures due to their noninvasive nature and high sensitivity. These scans can help identify potential sources of fever.
Bone Marrow Aspiration/Biopsy: Bone marrow studies are useful in detecting hematological disorders, lymphomas, or bone marrow infections.
Temporal Artery Biopsy: In cases where giant cell arteritis is suspected, temporal artery biopsy remains a crucial diagnostic step, particularly for patients aged 55 and older.
Liver Biopsy: Liver biopsies were historically performed but have limited diagnostic value in FUO, except for cases with specific liver-related symptoms or infections like miliary tuberculosis.

## Diagnostic Challenges and Second Opinions

Addressing persisting FUO can be a complex task. Here are important considerations:
Waiting for New Diagnostic Clues: In cases where the initial diagnostic workup is inconclusive, it may be prudent to wait for new potential diagnostic clues to emerge rather than ordering more screening investigations.
Second Opinions in Expert Centers: When no definitive diagnosis is reached despite extensive evaluation, seeking a second opinion at an expert center dedicated to FUO can significantly enhance the chances of identifying the underlying cause. Studies have shown that such consultations have resulted in diagnoses for a substantial percentage of previously undiagnosed FUO cases.

## Treatment Approaches for FUO

Managing FUO often requires a tailored approach based on the underlying condition. Here are some important considerations:
Empirical Therapeutic Trials: The use of antibiotics, glucocorticoids, or antituberculous agents as empirical treatment should generally be avoided unless there is rapid deterioration in the patient's condition and a strong clinical indication.
Antibiotics and Antituberculous Therapy: Antibiotics should be used judiciously, as they can affect the ability to culture certain bacteria or mycobacteria. Indications for empirical antibiotic therapy may include hemodynamic instability or neutropenia. Positive tuberculosis tests may necessitate antituberculous therapy.
Colchicine, NSAIDs, and Glucocorticoids: In specific conditions like familial Mediterranean fever (FMF) and adult-onset Still's disease, medications such as colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or glucocorticoids can be effective in managing recurrent fever episodes.
Interleukin-1 Inhibition: Interleukin-1 (IL-1) inhibitors, such as anakinra, have demonstrated efficacy in treating various autoinflammatory syndromes associated with FUO. Consideration of IL-1 inhibition may be appropriate for cases that remain undiagnosed after extensive diagnostic evaluations.

## Prognosis of Unexplained FUO

While the journey to diagnosing FUO can be arduous, the prognosis for patients with unexplained fever is generally favorable. Mortality rates associated with FUO have progressively declined over recent decades. The majority of fevers in these cases are caused by treatable diseases. The prognosis is, of course, highly dependent on the underlying condition, but early diagnosis and timely intervention play pivotal roles in determining patient outcomes.
This comprehensive approach to understanding FUO encompasses the intricacies of diagnosis, the importance of appropriate imaging and diagnostic tests, the challenges faced in managing undiagnosed cases, and the potential for favorable outcomes with prompt intervention. It underscores the collaborative nature of medicine and the need for a holistic approach when addressing this perplexing clinical syndrome.