This week in Morning Report, one of our residents on service in AACU presented the case of a young person presenting with a few weeks of fevers of unclear etiology after multiple initial outpatient investigations. Although this patient’s symptom timeline did not strictly meet criteria for ‘Fever of Unknown Origin’, we used this case to go over an approach to this much-discussed Internal Medicine topic!

Let’s recap our key learning from this case.

1. The definition of ‘Fever of Unknown Origin’ dates back several decades

FUO was originally defined by Petersdorf and Beeson in their 1961 paper, which included the following criteria:

• The fever must be > 38.3 C on several occasions
• It must last for at least 3 weeks
• There must be no clear diagnosis after 1 week of in-hospital investigation

As you can imagine, both the incidence and the understanding of ‘Fever of Unknown Origin’ have changed significantly over time! For example, we talked about the fact that:

• Previously difficult-to-grow organisms (e.g. HACEK organisms) are now readily cultured as our laboratory processing techniques have evolved
• Our understanding of many rheumatological conditions has increased significantly over the past few decades, so many previously ‘unknown’ conditions are now better defined
• We have more ready access to imaging and screening, so previously difficult-to-pin-down diagnoses like extrapulmonary TB or grumbling abscesses are now detected sooner
• 1 week of in-hospital investigation is no longer realistic! Given our evolving emphasis on reducing inpatient hospitalizations and encouraging outpatient care for investigations, most stable patients with FUO will actually be managed in the ambulatory setting

2. One of the seminal papers on FUO has a very Toronto connection!

Drs. Mourad, Palda, and Detsky (highly regarded GIM staff at our academic hospitals!) wrote a great paper, ‘A Comprehensive Evidence-Based Approach to Fever of Unknown Origin‘ in Arch Internal Med, 2003, that I strongly recommend you read. Their systematic review identified that a majority of FUO diagnoses fall into 3 large categories of disease – infectious, inflammatory, and malignant:

It is interesting to watch how these categories have shifted over time based on our points above re: improved diagnostic capacity for infectious causes, and improved understanding and recognition of inflammatory conditions!

3. Not all sustained fevers are fevers of unknown origin

A key point of understanding FUO is to respect the classification, and to ensure that a minimum threshold of investigations is sent off before a case qualifies as ‘FUO’. Mourad et al. propose the following diagnostic workup:

• Comprehensive History: This should include a thorough exposure history and geographic history. In our case, we discussed unique geographic factors including immigration and travel history, and exposures to potential zoonoses. Always ask about place of birth, recent travel and nature of travel, exposures to nature, wildlife, farms, and farm animals (and if you’re an ID keener, you’ll get into the real nitty gritty, like asking about exposure to specific bodily fluids from cattle…)
• Physical Examination: Careful head-to-toe examination, not forgetting examination of skin and joints!
• CBC with differential, and peripheral blood smear
• Routine bloods including LDH, liver enzymes, bili
• Urinalysis, urine microscopy
• BCx x 3, Urine Cultures
• HIV test and Hepatitis Serologies
• CMV, +/- EBV/Monospot given the right host
• Inflammatory serologies: ANA, RF
• CXR
• I would also add: inflammatory markers (ESR, CRP – although these are nonspecific), ensuring extended-incubation blood cultures are sent, and (these days) CoVID swab + routine NP swab

The above investigations should give you a starting point for ‘buckets’ of diagnoses, which we discussed next.

4. The DDx of FUO is broad, but easily remembered in big ‘buckets’

I hate memorizing lists, so I’m a big fan of buckets (conceptual and otherwise). Here’s how I approach the ‘big 3’ categories of FUO, and then some ‘extra stuff’ after:

5. If you STILL don’t have a diagnosis, time (and a few other investigations) may give you the answer

If your patient is otherwise stable, monitoring them longitudinally (e.g., in the GIM Ambulatory clinic) and asking them to keep a careful fever diary can be extremely valuable, as can repeating some of the investigations above to look for change. Sometimes timecourse and evolution of symptoms can uncover the diagnosis better than a shotgun-approach to investigation!

It is also reasonable to consider the following testing if your above approach and DDx doesn’t clarify the diagnosis (as a directed, rather than screening/initial set of investigations):

• CT Chest/Abdo/Pelvis: Should be considered if initial investigations are unrevealing, to look for hidden abscesses, lymphadenopathy, intrathoracic/intra-abdominal lymphoma, or extrapulmonary TB
• CT Head +/- LP: Consider if there are any suspicious or subtle CNS findings
• Nuclear medicine (gallium/indium scans) and PET: These are more controversial as they are extremely nonspecific, but can be considered in the right clinical context

Thank you to our AACU resident for sharing this case with us — I hope you found this Morning Report useful!

Note: These recaps are based on real-life cases presented during weekly Morning Report; however, no real patient information/investigations/images/identifying details are presented. Any clinical information presented has been modified and completely de-identified for privacy.