Approaching persistent fever of unknown origin: HM17 insights

Persistent fever of unknown origin is a working diagnosis rather than a final label. It means that a patient has a sustained febrile illness, yet the history, examination and initial tests have not explained it. For hospitalists, the task is to turn broad uncertainty into testable hypotheses while continually checking for deterioration. Diagnostic discipline matters because early treatment of dangerous infection can save life, while premature closure on a common cause can direct treatment wrongly.

Hospital Medicine 2017 was held from 1 to 4 May 2017 at Mandalay Bay Resort and Casino in Las Vegas, Nevada. Its programme covered research, best practice, innovation, patient care and continuing professional development. The HM17 conference resources provide context for that educational focus and access to learning and networking opportunities. For Australian hospitalists, the transfer is practical: combine diagnostic curiosity with the realities of public hospitals, private pathology, regional transfers and notifiable-disease duties.

Fever is a physiological sign, not a diagnosis. A reliable method starts with urgency, defines the syndrome, takes a focused exposure history, performs a repeatable examination and orders tests that could change management. Each step should generate the next, while a mismatch between temperature, pulse, symptoms and laboratory findings triggers reconsideration.

This sequence avoids two common errors: labelling every prolonged fever without examining alternatives, or pursuing every rare test at once. It also creates continuity across shifts. The same fever may reflect infection, inflammation, malignancy, drug reaction or an unrecognised exposure, so notes should record what changed, what was excluded and which assumption still needs testing.

Defining the syndrome and identifying urgency

The classic definition of fever of unknown origin requires temperatures above 38.3°C on several occasions, illness lasting more than three weeks and no diagnosis after a week of hospital evaluation. Applying that definition rigidly can delay care, because some infections declare themselves quickly and immunosuppressed patients may not mount typical fever. Contemporary practice uses shorter diagnostic windows, including classic, neutropenic and hospital-acquired syndromes, while retaining the requirement that the cause remains unexplained.

Urgency comes first. Rapid progression, hypotension, confusion, hypoxaemia, rash, neck stiffness, prosthetic material or recent surgery should trigger immediate assessment for time-critical disease. Meningococcal sepsis, infective endocarditis, malaria, invasive streptococcal infection and necrotising soft-tissue infection must not wait for a complete work-up. Use a lower threshold in pregnancy, neutropenia, transplantation, rheumatic disease, recent healthcare exposure and injection-related infection. Obtain cultures and start treatment in parallel when waiting would be unsafe.

Taking a focused exposure history

An exposure history must be concrete. Australian patients may have camped or bushwalked in northern Queensland, worked with livestock on a rural property, swum in freshwater near Darwin, gardened near Melbourne, or travelled from Sydney to Thailand or Indonesia. Ask about mosquito bites, water, soil, animals, undercooked food, unpasteurised dairy, mushrooms, new sexual contacts, dental treatment, tattoos, veterinary work and sick people at home. Geographies should be mapped to specific activities and dates because incubation windows make timing decisive.

Review medication and vaccination histories, including antibiotics taken before admission, non-prescribed drugs and recent dose changes. Record operations, transfusions, implants, indwelling devices, endoscopy, hospital contacts and outbreaks in aged-care or childcare settings. Occupational hazards, animal bites, insect exposure and household illness often matter more than a remote travel date. Previous records and microbiology results should be obtained early, with consent and secure transfer, so a supposedly new finding can be checked against an older one.

Reading patterns and first-line evidence

Initial evidence should establish severity and direction rather than name the disease. A full blood count with differential and film, electrolytes, renal and liver function, inflammatory markers, urinalysis, chest imaging and carefully timed blood cultures form a practical baseline. Repeat key results and examine trends; a high C-reactive protein identifies inflammation but does not separate bacterial infection from vasculitis or malignancy. A normal result shortly after treatment began may carry little weight.

Temperature alone is especially weak at discriminating causes. Pulsatile fever, new murmur and embolic skin lesions point towards endocarditis; eosinophilia with rash suggests drug reaction or a parasitic process; weight loss, nodes and organ enlargement shift attention towards malignancy or tuberculosis. Serial examination often reveals more than repeated broad screening. Targeted findings should be reviewed with infectious-disease, rheumatology, haematology and oncology colleagues when the pattern warrants their input.

Choosing targeted investigations wisely

Targeted investigations should follow the leading hypotheses and local pre-test probability. Echocardiography is important when endocarditis is plausible; CT or ultrasound may define an abscess, obstruction or concealed source; and FDG-PET can help locate lymphoma, large-vessel inflammation or occult malignancy. Biopsy of an enlarged node, liver lesion, skin lesion, temporal artery or bone marrow may provide the answer when repeated blood tests have not. When diagnosis requires tissue, obtain material before antibiotics where safe, but never delay treatment for sepsis.

Australian access is shaped by a mixed market: state-funded public pathology and imaging operate beside private providers, while Medicare rebates, the Pharmaceutical Benefits Scheme and local formularies influence affordability and treatment choice. The Therapeutic Goods Administration and the Australian Register of Therapeutic Goods govern which medicines may be marketed, so clinicians should not assume an overseas product is available locally. Many nationally notifiable diseases, including malaria and dengue, can also trigger duties under state and territory public-health legislation.

Geography changes the pathway as well as the differential. A patient in the Northern Territory or rural New South Wales may need transfer, overnight travel or a telehealth consultation with a tertiary team before a scan or biopsy can be arranged. Public-health notifications should follow approved local procedures. The Privacy Act 1988 and Australian Privacy Principles govern private health information, while public services also operate under state records legislation, making lawful information-sharing part of safe escalation.

A repeatable bedside checklist

A short paired checklist helps clinicians hand over the case without losing its pattern.

The history and examination pass should cover:

• Plot temperature spikes, rigors, weight change and symptoms against medication times, operations and hospital milestones.
• Specify travel, freshwater, insects, animals, food, work, sexual and household exposures, with relevant dates.
• Review prescribed and non-prescribed medicines, vaccines, allergies, devices, dental work and recent hospital contacts.
• Examine skin, nails, eyes, nodes, joints, heart, abdomen, scars and implanted material; repeat the examination daily.

The initial investigation pass should include:

• Repeat the full blood count with film, electrolytes, renal and liver function, inflammatory markers and urinalysis as indicated.
• Obtain multiple blood-culture sets from peripheral sites before antibiotics when the patient is stable and culture will not delay treatment.
• Choose focused tests from the exposure history, such as malaria films, dengue testing, HIV and hepatitis serology, or targeted bacterial and fungal studies.
• Compare new imaging and microbiology with previous results, documenting the specific question that each new test is intended to answer.

Microbiological input should shape the list before results are interpreted. Local protocols, regional pathogens and recent antimicrobial exposure matter, especially for patients transferred from Darwin, Cairns or rural hospitals. Unstable patients receive immediate treatment, often after a rapid culture draw. In a stable patient, a clinician-directed pause in empirical treatment may allow cultures and the clinical pattern to clarify, with close monitoring for deterioration. A structured review at 24 to 48 hours should ask whether the fever, examination and evidence have moved together or point to a missed source. This supports antimicrobial stewardship without delaying treatment for sepsis.

The lessons worth carrying forward

Hospital Medicine 2017’s emphasis on research, best practice and innovation supports a disciplined, evidence-led response to persistent fever. Those themes translate well to Australian hospital medicine when local epidemiology, antimicrobial stewardship and transfer constraints are incorporated from the outset. Uncertainty is managed through structured reassessment rather than reflexive test ordering.

For hospitalists, the most useful diagnostic habits are unglamorous: document trends, take an exposure history that includes ordinary Australian life, seek permission for every invasive step, and involve specialists early enough to influence sampling and treatment. Electronic records, discharge summaries and community pathology can reveal prior patterns that a single admission misses. Clear documentation of negative findings is equally valuable because it narrows the next differential.

The lesson to remember is to pair diagnostic curiosity with clinical urgency: define the syndrome, take a focused history, examine repeatedly, investigate in sequence, and keep reassessing the evidence as the patient changes.