Pyrexia of Unknown Origin

1. Infection

2. Malignancy

3. Non-Infectious Inflammatory Disease

4. Miscellaneous and Undiagnosed

Petersdorf and Beeson set the original bar in 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 revised it in 1991, replacing the week in hospital with three outpatient visits or three days of inpatient investigation, and adding the nosocomial, neutropenic and HIV-associated categories. The purpose of the threshold is not academic. It exists to stop the expensive, low-yield investigation of fever that would have declared itself if given a fortnight.

A surprising proportion of referred PUO is not PUO. Some patients have a normal circadian temperature variation misread as fever, some have measured only at home with an unreliable thermometer, and a few have 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.

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. The practical consequence is that the search should be for a site to sample rather than for a blood test. Lymph node, pleura, peritoneum, marrow and liver are all more informative than another round of serology. When tissue is obtained, it must go for GeneXpert and mycobacterial culture as well as histopathology: granuloma on histology alone does not distinguish tuberculosis from sarcoidosis, fungal infection or lymphoma.

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. The corollary matters as much: when there are no clues, repeat the history and examination rather than repeating the tests. Clues appear over time, and the examination that was normal in week two is often abnormal in week four.

Ultrasound of the abdomen is cheap, available and reasonable first. CECT of chest and abdomen is the workhorse of second-stage imaging and finds most occult abscesses, lymphadenopathy and solid tumours. FDG PET-CT is useful where it is available and affordable, particularly for large vessel vasculitis and for identifying a site to biopsy, but 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 and should be requested when there is a reason, not as a routine sweep.

A very high ferritin will be quoted in favour of adult-onset Still's disease and of haemophagocytic lymphohistiocytosis. It is an acute phase reactant and rises in infection, in malignancy and in liver disease as well. It is a reason to look harder at those two diagnoses, not a reason to make either of them. Still's disease in particular remains a diagnosis of exclusion, and the exclusions that matter most are lymphoma and tuberculosis.

Several empirical strategies are used in PUO, and each has arguments on both sides. Empirical antibiotics may treat a culture-negative endocarditis, but they also render subsequent cultures unhelpful. Corticosteroids may produce a striking response in giant cell arteritis or Still's disease, but they also produce 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 it 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.

What is common to all of them is that the decision should be deliberate rather than incidental. 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.

A short course of naproxen has been described as separating neoplastic fever, which settles, from infective fever, which does not. It 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.

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. It should be communicated to the patient as such, because the alternative is an anxious search that continues indefinitely and does its own harm.

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 patient who is haemodynamically unstable belongs in a sepsis pathway, not in a PUO workup, 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.