Pyrexia of Unknown Origin (PUO)

Definitions:

Original criteria were an illness of at least 3 weeks duration with fever over 38.3C on several occasions that
was undiagnosed after 1 week of hospital study
This has now been modified to include patients who are diagnosed after 2 outpatient visits or 3 days in
hospital
Additional categories:
o Nosocomial PUO in hospital patients with fever of >38.3C on several occasions caused by a process
not present or incubating on admission where initial cultures are negative and diagnosis unknown
after 3 days' investigation
o Neutropenic PUO includes patients with fever as above with <500 neutrophils/ml with initial
negative cultures and diagnosis uncertain after 3 days
o HIV-associated PUO includes HIV positive patients with fever as above (for 4 weeks as outpatients
or 3 days as inpatient with an uncertain diagnosis after 3 days investigation where at least 2 days have
been allowed for cultures to incubate).

Common causes of PUO:

In adults:
o Infections and cancer (25-40%)
o Autoimmune disorders (10-20%)
Children:
o Infections (30-50%)
o Cancers (5-10%)
o Autoimmune disorders (10-20%)
Granulomatous diseases, e.g. granulomatous, hepatitis, Crohn's disease, Ulcerative colitis, and factitious are
common causes
TB and endocarditis are commonest systemic infections with mycoses and viral diseases, especially EBV and
CMV, toxoplasmosis, brucellosis, Q fever, cat-scratch fever, salmonellosis and malaria have all been
implicated
Primary HIV infection or opportunistic infections due to AIDS, especially mycobacterial, can present as PUO
Localised infections, e.g. occult abscess can be difficult to diagnose in liver, spleen, kidney, brain and bones.
Collection of pus in the abdomen, cholangatis, osteomyelitis, UTI, dental abscess or pus in paranasal sinuses
can all cause prolonged fever.
Neoplasms commonest causes of PUO are lymphoma and leukaemia. Other conditions include
angioimmunoblastic lymphoma, Castleman's disease, tumours of the liver, renal cell carcinomas, atrial
myxoma.
Autoimmune disorders most commonly Still's disease, SLE, cryoglobulinaemia, polyartitis nodosa. In
patients >50 years of age giant cell arteritis and polymyalgia rheumatica.
Undiagnosed 10-15% of patients remain undiagnosed despite extensive investigations and in 75% of these
the fever resolves spontaneously. In the remainder, other signs and symptoms make the diagnosis clear.

Investigations:

Confirm temperature by taking it yourself

Look for signs usually accompanying fever, e.g. tachycardia, chills
Take thorough history family, occupation, sexual, dietary, exposure to animals and chemicals, travel.

Routine laboratory studies:

Blood cultures (preferably before starting antibiotics) culture for 5 days to detect slow growing organisms
Culture urine, sputum, stool, CSF, morning gastric aspirates if TB suspected.
Chest X-ray, abdominal CT, echocardiography (endocarditis/atrial myxoma)
Invasive procedures for abnormal findings lumbar puncture for headache, skin biopsy for rash, lymph
aspiration or biopsy for lymphadenopathy; in HIV positive patients bone marrow aspiration or biopsy.

Abnormal liver function tests liver biopsy even if normal size. In deteriorating patients consider laparotomy
or laparoscopy.