Definition
Petersdorf and Beeson defined pyrexia of unknown origin (PUO) in 1961. It is defined as:
• A temperature greater than 38.3°C on several occasions.
• Accompanied by more than three weeks of illness.
• Failure to reach a diagnosis after one week of inpatient investigation.

This timing allowed exclusion of patients with protracted but self-limited viral illnesses, giving time for studies to be completed. This has now been modified to include patients who are diagnosed after two outpatient visits or three days in hospital.

Additional categories have now been added including:
• Nosocomial PUO in hospital patients with fever of 38.3°C on several occasions, caused by a process not present or incubating on admission, where initial cultures are negative and diagnosis unknown after three days of investigation.
• Neutropenic PUO includes patients with fever as above with <1 x 109 neutrophils, with initial negative cultures and diagnosis uncertain after three days.[3]
• HIV-associated PUO includes HIV-positive patients with fever as above for four weeks as outpatients or three days as inpatients, with an uncertain diagnosis after three days of investigation, where at least two days have been allowed for cultures to incubate.

Common causes of pyrexia of unknown origin
Most cases are unusual presentations of common diseases - eg, tuberculosis, endocarditis, gallbladder disease and HIV infection, rather than rare or exotic diseases.[
• In adults: infections and cancer (25-40% of cases each) account for most PUOs.Autoimmune disorders account for 10-20% of cases
• In children, at least 50% of cases are due to viral infections. Cancers, autoimmune diseases and miscellaneous conditions make up the remainder.

Bacterial
• Abscesses
• There may be no localising symptoms.
• Previous abdominal or pelvic surgery, trauma or history of diverticulosis or peritonitis increase the likelihood of an occult intra-abdominal abscess.
• They are most commonly in the subphrenic space, liver, right lower quadrant, retroperitoneal space or the pelvis in women.

• Tuberculosis
• When dissemination has occurred - eg, in patients who are immunocompromised - the initial presentation is more likely to consist of constitutional symptoms than localising signs. CXR may be normal.
• Urinary tract infections (UTIs) are rare causes.
Perinephric abscesses occasionally fail to communicate with the urinary system, resulting in a normal urinalysis.

• Endocarditis is a rare cause of PUO:
• Culture-negative endocarditis is reported in 5-10% of endocarditis cases.
• The HACEK group is responsible for 5-10% of cases of infective endocarditis and is the most common cause of Gram-negative endocarditis among people who do not abuse intravenous drugs:
• This is a group of Gram-negative bacilli - Haemophilus spp., (H. parainfluenzae,H. aphrophilus and H. paraphrophilus), Actinobacillus actinomycetemcomitans,Cardiobacterium hominis, Eikenella corrodens and Kingella spp.
• They are part of the normal oropharyngeal flora, are slow growers and prefer a carbon dioxide-enriched atmosphere.
• Because of their fastidious growth requirements, they have been a frequent cause of culture-negative endocarditis.

• Previous antibiotic therapy is the most frequent reason for negative blood cultures.

• Hepatobiliary infections - eg, cholangitis - can occur without local signs and with only mildly elevated or normal LFTs, especially in the elderly.

• Osteomyelitis usually causes localised pain or discomfort at least sporadically.
• Brucellosis should be considered in patients with persistent fever and a history of contact with cattle, swine, goats or sheep, or patients who consume raw milk products.

• Borrelia recurrentis is transmitted by ticks. It is responsible for causing relapsing fever.
• Other spirochetal diseases that can cause PUO include Spirillum minor (rat-bite fever),Borrelia burgdorferi (Lyme disease) and Treponema pallidum (syphilis).

Other causes like Viral, Neoplasms ,Fungal etc - to follow.

G Mohan.