Pyrexia of Unknown Origin (PUO)
by Petersdorf and Beeson in 1961
“Temperature higher than 38.3°C (101°F) on several
occasions , persisting without diagnosis for at least 3
weeks, in spite of at least 1 week investigation in
Durack and Street’s classification:
• PUO associated with HIV infection
Temperature ˃ 38.3°C, on several occasions,
stipulating 3 OPD visits or 3 days in hospital with out
elucidation of a cause or 1 week of intelligent and
Temperature ˃ 38.3°C, on several occasions in a
hospitalized patient who is receiving acute care
and in whom infection was not manifest or
incubating on admission. 3 days of investigation
include at least 2 days of cultures.
Temperature ˃ 38.3°C on several occasions in a
patient whose neutrophil count is ˃ 500 / µL or is
expected to fall to that level in 1 to 2 days. The
specific cause of fever is not identified after
3days of investigation including at least 2 days of
incubation of cultures.
HIV associated PUO:
Temperature ˃ 38.3°C on several occasions over
a period of ˃ 4 weeks for out patients or > 3 days
for hospitalized patients with HIV, specific cause
of fever is not identified after 3days of
investigation including at least 2 days of
incubation of cultures.
• Chronic or sub acute course
• Median duration of 40 days
• Etiology:- infection
-connective tissue disorders
• Relative frequencies depends on age, geographic
• Overall infection is leading cause (25 to 50 %)
• In age > 65 yrs infection has become 2nd or 3rd , in a
study by Knockart and associates.
Causes of Fever in the Returned Traveler *
al (n = 587)
al (n = 195)
Malaria 32 42
Hepatitis 6 3
Respiratory infection 11 2.6
Urinary tract infection/pyelonephritis 4 2.6
Dysentery 4.5 5.1
Dengue fever 2 6.2
Enteric fever 2 1.5
Tuberculosis 1 2
Rickettsial infection 1 0.5
Acute HIV infection 0.3 1.0
Amebic liver abscess 1 0
Other miscellaneous infections 4.3 9.2
Miscellaneous noninfectious causes 6 1
Undiagnosed 25 24.6
• After 3 days of hospitalization
• Risk factors encountered in hospital
-urinary& respiratory instrumentation
-I V devices
• Infected intravascular line
• Septic phlebitis
• Abcess/ hematoma/infected foreign bodies in post operative patients
• Prostatic abscess in men
• Infected urinary catheters
• Clostridium difficile colitis
•Sinuses of intubated patients
• Acalculous Cholecystitis
• DVT/ pulmonary embolism
• Drug fever
• Transfusion reactions
• Alcohol/ drug withdrawl
• Adrenal insufficiency
Non infectious causes:
• Gout/ pseudogout
• Intracranial mass effects in stroke patients
• Persistent post operative fever
• Strong predisposition infections.
• Atypical clinical manifestations
• Absence of radiological abnormalities.
• 50 – 60 % are infective, 20 % are bacteremic.
• Only 35 % of patients respond to broad spectrum antibiotics.
• Review history & repeat physical examination
• Specific investigations
• Repeat sampling of blood & other body fluids.
• Skin tests
• Blood for antibodies – HIV antibodies, CMV
antibodies, EBV antibodies.
• Serological tests for toxoplasmosis, psittacosis and
rickettsial infections, syphillis.
• Serology for rheumatologic disorders like antinuclear
and antineutrophilic cytoplasmic antibodies,
• Quatiferon TB Gold in tube and T spot TB – detects
ϒ interferon release.
• Direct examination of blood smears: malaria,
trypanosomiasis ,babesia, leishmania, relapsing fever
rat bite fever, ehrlichiosis.
• Intra cellular organisms, bacteria, inclusion bodies,
Blood for culture:
• Detect fastidious organism e.g. nutritionally variant
streptococci, HACEK group.
• Media containing pyridoxal and L-cystein.
• 3 to 6 samples
• Incubated with and without CO2.
• Biopsy of liver and bone marrow
• Lymph node biopsy
• Blind biopsy of 1 or both temporal artery in
patient > 50 yrs
• Exploratory laparotomy
• Empirical treatment with corticosteroids or NSAIDS
• Antimycobacterial agents in AIDS & neutropenic
• Blind therapy- delay in correct diagnosis
• Therapy withheld until cause is found
• Empirical corticosteroids or anti inflammatories in
• Vital sign instability & neutropenia –
Fluoroquinolones + piperacillin,
vancomycin + ceftazidime/cefepime/
carbapenem with or without aminoglycoside,
Management of Nosocomial PUO:
• Change of IV lines, catheters
• Empirical treatment:
Vancomycin for MRSA
Broad spectrum Gram negative coverage
Piperacillin + tazobactum
Ticarcillin + clavulinic acid
• Poorest prognosis - elderly & malignant
• Delay in diagnosis affects prognosis of
intraabdominal infections, miliary tuberculosis,
disseminated fungal infections & recurrent
• Undiagnosed PUO for prolonged duration – good
• Harrison’s principles of internal medicine
• Mandell, Bennet & Dolin’s, principle of
infectious disease 6th edition.
• Mims’ Medical microbiology 4th edition.