Fever Of Unknown Origin (FUO)

I am sure you have all watched at least one episode of House, the series in which a witty Hugh Laurie is presented with difficult to solve cases almost every day. Obviously in reality these kind of cases are incredibly rare, but there is one kind of 'difficult to solve' problem in medicine which appears far more often than you think, the febrile illness without an obvious origin, FUO.

Definition and Diagnosis:

Fever greater than 38.3 degrees on several occasions, persisting without diagnosis for at least 3 weeks despite of at least 1 week investigation in hospital. (Later updated to 3days Inpatient investigation or 3days of Outpatient investigation).

Can be further classified into:

Classical (as defined above)

Nosocomial (the fever was absent on admission to the hospital)

Neutropenic (Patient is neutropenic as well, less than 500 neutrophils per mm3)

HIV associated (Patient has confirmed HIV infection)

You cannot conclude a patient has a FUO until you have performed the following basic investigations:

History, Physical exam, Complete blood count, Blood Cultures, Complete metabolic panel and Liver function tests, Urinanalysis and culture, Chest X-ray.

Etiology:

Three catergories of illness can cause FUO; 

infections, malignancies and connective tissue disorders.

There is a long list of the possible causes (See image) but don’t forget Drug Fevers in which a fever can be the sole feature of an adverse drug reaction (most commonly with antibiotics).

Age is very important when considering the etiology, for example in younger patients infections will be much more common (in children around one third of FUO are caused by self limited viral illnesses) and in the elderly (haematological malignancies and solid tumours will be much more common).

Also neutropenia associated FUO will be much more likely linked to a bacterial infection (although never forget genetic neutropenia exists such as cyclic neutropenia and benign familial neutropenia).

Malaria and respiratory infections are a common cause in returned travellers.

First steps:

Re do history and physical exam, a careful history is critical for diagnosis! 

Ask about: animal exposure, immunosupression, drugs and toxins, localising symptoms (for example, jaw claudication is consistent with giant cell arteritis, nocturia with prostatitis etc.). 

Note that the degree of fever, nature of fever curve and response to antipyretics has no specificity to guide the diagnosis. 

After a careful history the following exams will be useful (obviously performed in a targeted nature, guided by your suspiscions):

LEVEL 1 testing:

ESR, CRP, LDH, TST/IGRA, HIVab/RNA, 3 blood cultures for separate sites, Rheumatoid factor, creatine phosphokinase, heterophile antibody test, antinucleaur antibodies, serum protein electrophoresis, procalcitonin can be helpful

LEVEL 2 testing:

CT abdomen, CT chest (if these turn out to be negative move to FDG-PET, although be aware of its high false positive rate)

Level 3 testing: 

Biopsies and Endoscopies

Treatment:

Treatment should be withheld as long as possible until the cause of the fever is determined and empirical antibiotic treatment is not appropriate! However you must obviously consider the patients condition and febrile neutropenic patients have a much higher percentage of bacterial infections and so empiric treatment can be appropriate after cultures have been obtained.

Summary:

• Most cases of FUO are due to unusal represantations of common diseases rather than exotic diseases
• Reassess the patient frequently and the don’t underestimate the importance of a very careful history and physical exam (it is in fact critical).
• Almost any infective agent can be responsible for FUO
• Look out for Malignancy red flags in the history and physical exam such as symptoms (night sweats, weight loss, pruritus, rectal bleeding), radiation exposure, cigarette smoking, lymphadenopathy, hepatosplenomagaly, petechiae.

A long list of the possible causes of FUO #fever #medicine #fuo #medED #study #medicalschool