2nd August 2023

Fever of Unknown Origin (FUO)

Note that roughly 75% of patients with pyrexia will not receive a diagnosis. Therefore, a risk stratified approach is the best method in standing any chance of finding an underlying cause.

Differential Diagnoses

Whilst infection is responsible for most pyrexial scenarios, other strong contributors include malignancy (especially lymphomas) and connective tissue diseases such as rheumatoid arthritis and Kawasaki disease (see table 3). Be astute to not be caught out by the occult pulmonary embolism or drug induced fever – ironically, antimicrobials and anti-epileptics are chief culprits here.

Table 3: A broad overview of non-infective causes of FUO

Focusing on Infection

The list of potential infectious diseases is exhaustive. Therefore, marrying the pattern of pyrexia with associated symptoms and clinical history will help guide your diagnosis.

For example, abscesses and TB may result in a daily temperature spike, as can Schistosomiasis. Additionally, the recently returned traveller with a high enteric fever is far more likely to have Salmonella typhi infection than cytomegalovirus colitis in the absence of immunosuppressive predisposition.

Of the 25% of fevers with an established diagnosis in the UK, the most important identifiable imported cause is Malaria. Malaria classically presents with intermittent fevers and should resolve after a course of appropriate treatment. If a patient complains of recurrent feverish episodes years after initial malaria diagnosis and supposed treatment – be sure to rule out Plasmodium ovale or Plasmodium vivax as their hypnozoites may have been stirred into acute infective action.

Work Up

Investigations, such as full blood count (leucocytosis vs eosinophilia), blood films, rapid molecular testing and CXR, will guide your diagnosis. Dental abscesses and infective endocarditis are uncommon causes of FUO but warrant further investigations, such as via an orthopantomogram and echocardiogram, respectively, if suspected.

Whilst blood cultures are useful in identifying bacterial septicaemia, they may miss the underlying cause. Note that it is important to exclude infective causes in a pyrexial and unwell patient despite negative blood cultures –consider Q fever, caused by the obligate intracellular bacterial pathogen Coxiella burnetii –a favoured question in exams!