Pyrexia of Unknown Origin (PUO) Pathway

1. Infection

2. Malignancy

3. Non-Infectious Inflammatory Disease

4. Miscellaneous and Undiagnosed

1. What the Definition Is Actually For

The threshold exists to stop the expensive, low-yield investigation of a fever that would have declared itself if given a fortnight.

• Petersdorf and Beeson, 1961: fever above 38.3 C, which is 101 F on the charts most Indian wards actually use, on several occasions, lasting more than three weeks, and undiagnosed after a week of investigation in hospital.
• Durack and Street, 1991: the week in hospital replaced by three outpatient visits or three days of inpatient investigation, and the nosocomial, neutropenic and HIV-associated categories added.

2. Confirm the Fever Before Investigating It

A surprising proportion of referred PUO is not PUO: a normal circadian variation misread as fever, a reading taken only at home on an unreliable thermometer, or no documented fever at all. Before ordering imaging, ask for temperature charted by a health worker, four hourly, alongside the pulse.

• A fever above 102 F (39 C) with a pulse under 90 raises relative bradycardia.
• A fever with no rise in pulse and no rise in acute phase markers raises the possibility that the reading itself is not genuine.

3. Tuberculosis Is the First Thought in India, and Tissue Is What Settles It

Indian series consistently place infection as the largest group in classic PUO, and tuberculosis as the commonest single infection within it, much of it extrapulmonary and much of it with a normal chest radiograph. So the search is for a site to sample rather than for another blood test.

• Lymph node, pleura, peritoneum, marrow and liver are all more informative than another round of serology.
• Tissue goes for GeneXpert and mycobacterial culture as well as histopathology. Granuloma on histology alone does not distinguish tuberculosis from sarcoidosis, fungal infection or lymphoma.

4. The Clue-Driven Workup Outperforms the Checklist

Ordering every test in a long list is slower and less productive than following the clues that are present.

• A murmur directs to blood cultures and echocardiography.
• A large spleen directs to marrow, and to visceral leishmaniasis in an endemic area.
• New headache in a patient over 50 with a very high ESR directs to the temporal artery.
• Where there are no clues, repeat the history and examination rather than the tests. Clues appear over time, and the examination that was normal in week two is often abnormal in week four.

5. Sequence the Imaging, and Know What Each Test Is For

• Ultrasound of the abdomen: cheap, available and reasonable first.
• CECT of chest and abdomen: the workhorse of second-stage imaging, and it finds most occult abscesses, lymphadenopathy and solid tumours.
• FDG PET-CT: useful where available and affordable, particularly for large vessel vasculitis and for identifying a site to biopsy. It is not available in most Indian district settings and a workup should not stall waiting for it.
• Echocardiography: answers a specific question about the valves. Request it when there is a reason, not as a routine sweep.

6. Ferritin, and the Limits of a Single Number

A very high ferritin will be quoted in favour of adult-onset Still's disease and of haemophagocytic lymphohistiocytosis. It is also an acute phase reactant, and rises in infection, in malignancy and in liver disease, which makes it a reason to look harder at those rather than a reason to make either diagnosis. Still's disease remains a diagnosis of exclusion, and the exclusions that matter most are lymphoma and tuberculosis.

7. Empirical Therapy: What to Weigh

Each strategy has arguments on both sides, and what is common to all of them is that the decision should be deliberate rather than incidental.

• Antibiotics may treat a culture-negative endocarditis, and also render subsequent cultures unhelpful.
• Corticosteroids may produce a striking response in giant cell arteritis or Still's disease, and also a partial and temporary response in lymphoma, and can allow tuberculosis to disseminate.
• A trial of antitubercular therapy is widely used in India, where the pretest probability of tuberculosis is high, and may be the only practical option when tissue cannot be obtained. Against that: both lymphoma and Still's disease can defervesce transiently on any of these agents, so a fall in temperature does not confirm the diagnosis, and a full course commits the patient to months of hepatotoxic treatment.
• The naproxen test, a short course said to separate neoplastic fever, which settles, from infective fever, which does not, is a weak discriminator in modern series and should not be used to rule anything in or out. It appears here because it is still asked about in examinations and still occasionally used on the wards, not because it should decide management.

Record what is being treated, what response would count as a success, by what date it will be judged, and what will happen if the response does not come. Where tissue can still be obtained, obtaining it before starting is almost always the more informative order.

8. Not Reaching a Diagnosis Is a Recognised Outcome

In every published series a substantial minority of PUO is never diagnosed, and most of those patients do well. Once malignancy, tuberculosis, endocarditis and the treatable inflammatory diseases have been reasonably excluded in a patient who is stable and gaining weight, structured observation with a defined review date is a legitimate plan rather than a failure. Say so to the patient, because the alternative is an anxious search that continues indefinitely and does its own harm.

9. When This Pathway Is the Wrong One

• Fever of less than two weeks belongs in the Acute Undifferentiated Febrile Illness Pathway, which sequences investigations by day of illness and is built for the tropical infections that dominate that window.
• A haemodynamically unstable patient belongs in a sepsis pathway, whatever the duration of fever.
• Neutropenic fever is a medical emergency in which the first antibiotic matters more than the diagnosis, and empirical cover should not wait for this tool.