Fever of unknown origin is one of the most difficult challenges in clinical medicine. Its epidemiology has changed over time with advanced diagnostics and imaging available. A multidisciplinary approach, the advent of newer diagnostics and imaging can help in improving the evaluation & management.

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Fever of unknown origin (FUO) is a known entity and is considered to be a diagnostic challenge for a physician. Detailed clinical history and laborious physical examination are the main tools. Rheumatological disorders are the second common underlying cause after infections.

Among all, thirty per cent of FUO have underlying rheumatological conditions. Many rheumatological disorders can have fever as either an initial manifestation or as a part of other systemic manifestations. The advent of nuclear imaging tools like PET-CT has greatly changed the landscape of FUO evaluation protocol in resourceful settings.

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Definition of fever of unknown origin

Fever of unknown origin (FUO) can be defined as a documented fever of ≥101°F on three different occasions over the duration of >3 weeks, and no diagnosis can be made after extensive evaluation in an immunocompetent patient.

1. Fever ≥38.3°C (101°F) on ≥3 occasions.
2. Duration of illness: 3 weeks.
3. No diagnosis despite extensive evaluation including:
   1. Extensive medical history and physical examination.
   2. Laboratory: Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), haemoglobin, platelet count, leukocyte count including differentiation, sodium, potassium, calcium, creatinine, serum protein electrophoresis, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), antinuclear antibodies (ANAs), rheumatoid factor (RF), microscopic urinalysis, ferritin.
   3. Microbiology: Blood cultures, urine culture, tuberculin skin test, or interferon-gamma release assay.
   4. Imaging: Chest X-ray, abdominal ultrasound, or chest and abdominal CT scans.
4. No known immunocompromised state:
   1. Neutropenia (leukocyte count <1000/cu.mm and/or granulocyte count <500/cu.mm) during at least 1 week within 3 months before the start of the fever.
   2. Known human immunodeficiency virus (HIV) infection.
   3. Known hypogammaglobulinemia (IgG <50% of normal value).
   4. Use of 10 mg prednisone or equivalent dose of steroids during at least 2 weeks in the 3 months before the start of the fever.

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Causes of FUO

Overall causes for fever of unknown origin are one of the following:

• Infections
• Autoimmune conditions/ Rheumatological conditions
• Malignancies
• Miscellaneous conditions include drug fever

Infection should always be considered the first cause of fever as it's more common than any other aetiologies. Incidence may vary among various countries. Developing countries have higher chances of infectious causes for FUO than developed countries. Common chronic infections like tuberculosis, brucellosis, viral hepatitis, subacute bacterial endocarditis or atypical chronic infections like malleidiosis, fungal infections etc. or partially treated infections are usual causes.

Thirty per cent of FUO have underlying primary rheumatological conditions. Fever as an isolated initial manifestation or as part of other systemic features is common in rheumatological conditions like systemic vasculitis, systemic lupus erythematosus, rheumatoid arthritis, adult-onset Still’s disease, Bechet's disease, polymyalgia rheumatica, granulomatous disorders like sarcoidosis etc or macrophage activation syndrome/hemophagocytic lymphohistiocytosis (HLH) as an initial manifestation secondary to underlying rheumatological conditions.

Mainly haematological malignancies are known to present as FUO, but solid malignancies like renal cell carcinoma, hepatocellular carcinoma and benign tumour-like hepatoma can have FUO like presentation. Haematological malignancies are known to present as FUO secondary to HLH.

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FUO evaluation and diagnostic clues

Evaluation for FUO includes:

• Detailed clinical history
• Comprehensive physical examination
• Relevant laboratory investigations and imaging directed from potential diagnostic clues

There is no test that can certainly rule out infection. Potential diagnostic clues help in making a diagnosis. Any relevant abnormalities found during history and examination is said to be potential diagnostic clues, and in the majority of cases guides further investigation and management. Multidisciplinary approaches including rheumatology can expedite the process in presence of relevant potential diagnostic clues.

Clinical history like joint pain or swelling, diffuse myalgia or muscle weakness, oral ulcer or other mucosal lesions, skin rashes, photosensitivity, a pattern of fever, eye inflammation like uveitis, scleritis, diminution of vision, temporal headache, scalp pain, limb-girdle pain & stiffness, sicca features, carotidynia, testicular pain etc. can be potential diagnostic clues. Acalculous cholecystitis as FUO is common in systemic lupus and is commonly overlooked.

Age matters a lot. Among old people, malignancies are more common than autoimmune aetiologies. Among rheumatological aetiologies, elderlies have different causes like giant cell arteritis and polymyalgia rheumatica. Young people can have Takayasu, lupus, rheumatoid, sarcoid etc.

Infections and malignancies are great mimickers of rheumatological disorders. Various negative potential diagnostic clues should also be taken into consideration like the presence of chills, rigour and night sweat with fever favours more infection rather than rheumatological conditions. Significant weight loss, night sweats, fever, excessive fatiguability, pruritus after hot bath suggest malignancies prior to rheumatological conditions.

Comprehensive physical examination should be carried out with a special focus on examining peripheral artery pulse and bruit, ophthalmological examination, tongue and oral mucosa, lymphadenopathies, skin and nails, musculoskeletal examination to look for synovitis, can give certain essential potential diagnostic clues.

Non-specific laboratories like hemogram, urinalysis, renal, liver function test and inflammatory markers like ESR, CRP, Ferritin etc can give additional diagnostic clues when seen along with clinical context.

For example, leukocytosis, thrombocytosis will be seen in patients of vasculitis, adult-onset Still's disease while cytopenia will be seen with lupus, hemophagocytic lymphohistiocytosis. Eosinophilia can be seen with Hyper IgD syndrome, Eosinophilic granulomatous polyangiitis or can be reactionary or can be secondary to fungal infections or drug-related fever.

Elevated inflammatory markers with polyclonal gammopathy in protein electrophoresis will narrow diagnostics to underlying chronic rheumatological or infectious conditions. Similarly, various other non-specific tests like lactate dehydrogenase can be increased in haematological malignancies or autoimmune aetiologies like hepatitis, hemolytic anaemia, myositis etc.

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What tests should you order?

1. Special tests like rheumatoid factor, antinuclear antibodies and angiotensin-converting enzyme levels are more sensitive and less specific tests and should always be correlated with clinical context. There are various specific antibodies like anti smith antibody, anti-dsDNA antibody etc are available which have higher specificity and can be of help in making diagnoses if correlated incorrect context.
2. Imaging is a great tool and is considered a second-line tool for FUO evaluation. Radionuclide imaging can localise the pathologic foci or can differentiate between biologically inactive from active lesions and guides invasive procedures.
3. The advent of PET-CT scan has changed the approach. PET-CT has higher sensitivity to conventional gallium scans or labelled WBC scans. PET-CT has improved diagnostic impact in FUO cases especially for underlying rheumatological cases. Early consideration of PET-CT might be of importance for early diagnosis.
4. Imaging like CT chest/abdomen/pelvis and MRI with or without contrast can also be a valuable tool in resource-limited settings.
5. Endoscopic procedures may be helpful in the diagnosis of gut infections like tuberculosis, Whipple's or autoimmune causes like inflammatory bowel disease, sarcoidosis.
6. Other invasive testing such as lumbar puncture or biopsy of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising Rheumatologist from Bangalore.