Medicine chapters
Pyrexia of unknown origin
Pyrexia of unknown origin (PUO) is a prolonged fever that stays unexplained despite proper investigation. Learn the definitions, the main cause groups, a step-by-step workup and why blind treatment should be avoided.
- PUO classically means a fever above 38.3 °C on several occasions, lasting more than 3 weeks, with no diagnosis after a set period of good investigation (originally 1 week in hospital).
- The big groups are infection (in Pakistan especially tuberculosis, enteric fever, brucellosis, abscesses, endocarditis), malignancy (especially lymphoma), connective tissue/vasculitic disease (Still disease, giant cell arteritis, SLE) and miscellaneous (drug fever, factitious fever); a share stay undiagnosed.
- Work up step by step: detailed and repeated history and examination, then targeted tests (cultures, imaging, PET-CT, biopsy); avoid blind antibiotics or steroids, and note that undiagnosed PUO usually has a good prognosis.
On this page
Overview
Most fevers are short and explained by history, examination and simple tests. A few patients have a fever that goes on for weeks without an obvious cause. This is pyrexia (fever) of unknown origin (PUO / FUO).
PUO is usually a common disease presenting unusually, rather than a rare disease. A careful, repeated history and examination finds most diagnoses. Blind treatment can hide the cause.
Definitions
Classic definition (Petersdorf and Beeson, 1961)
- Temperature above 38.3 °C on several occasions
- Duration of more than 3 weeks
- No diagnosis after 1 week of investigation in hospital
Updated categories (Durack and Street)
The "1 week in hospital" rule was replaced by 3 outpatient visits or 3 days in hospital of proper investigation, and four groups were described:
| Category | Setting | Usual causes |
|---|---|---|
| Classic PUO | As above | Infection, malignancy, connective tissue disease |
| Healthcare-associated (nosocomial) | Fever starting in hospital, not present on admission | Line infection, C. difficile, drug fever, PE, sinusitis, acalculous cholecystitis |
| Neutropenic | ANC below 0.5 × 10⁹/L | Bacterial and fungal infection (see the febrile neutropenia chapter) |
| HIV-associated | Known HIV infection | TB, MAC, CMV, cryptococcus, lymphoma |
- Kumar's practical definition: fever persisting beyond 2 weeks that remains unexplained after careful, thorough investigation. Patients with known HIV or immunosuppression are usually excluded from classic PUO, because their causes and workup differ.
Before labelling PUO, confirm there really is a fever. Some people have a normal exaggerated evening rise in temperature, and factitious fever (manipulated readings) must be considered. Observed recordings may need admission.
Aetiology
| Group | Approximate share | Main causes |
|---|---|---|
| Infection | 20–40% (higher in developing countries) | Tuberculosis (extrapulmonary, miliary), enteric fever, brucellosis, abscess (liver, subphrenic, pelvic, dental, psoas), infective endocarditis (especially culture-negative), osteomyelitis, EBV and CMV, toxoplasmosis, primary HIV, malaria, visceral leishmaniasis (kala-azar), amoebic liver abscess, Lyme disease |
| Malignancy | 10–30% | Lymphoma (Hodgkin and non-Hodgkin), leukaemia, renal cell carcinoma, hepatocellular carcinoma, liver metastases, atrial myxoma |
| Connective tissue / vasculitis | 15–20% | Adult-onset Still disease, SLE, giant cell arteritis / polymyalgia rheumatica, granulomatosis with polyangiitis, polyarteritis nodosa |
| Miscellaneous | 10–25% | Drug fever, thyrotoxicosis, inflammatory bowel disease, sarcoidosis, granulomatous hepatitis, recurrent PE, factitious fever, familial Mediterranean fever, alcoholic hepatitis |
| Undiagnosed | 5–25% | No cause found despite full workup |
In Pakistan and other developing countries, infection, especially tuberculosis, is the commonest cause of PUO. In older patients in high-income countries, malignancy and connective tissue disease become relatively more common.
Useful clinical clues
| Clue | Think of |
|---|---|
| Raw milk, contact with goats or sheep, sweats, back pain, orchitis | Brucellosis |
| Weight loss, night sweats, contact with TB | Tuberculosis |
| Night sweats, itching, lymph nodes, Pel-Ebstein fever, alcohol-induced node pain | Hodgkin lymphoma |
| Very high ferritin, evanescent salmon-pink rash with fever spikes, sore throat, arthritis, neutrophilia | Adult-onset Still disease |
| Age over 50, headache, scalp tenderness, jaw claudication, visual symptoms, high ESR | Giant cell arteritis |
| New murmur, embolic phenomena, prosthetic valve | Infective endocarditis |
| Recent abdominal surgery, right upper quadrant pain | Abscess (subphrenic, liver) |
| Haematuria, flank mass | Renal cell carcinoma |
| Massive spleen, pancytopenia, from an endemic area | Visceral leishmaniasis |
| Fever started with a new medicine; eosinophilia, rash, relative bradycardia | Drug fever (beta-lactams, sulphonamides, phenytoin, allopurinol) |
| Health worker, inconsistent readings, no tachycardia with "fever" | Factitious fever |
Drug fever is a common, often missed cause. It usually settles within 48–72 hours of stopping the culprit.
Diagnosis: a stepwise approach
Step 1: History and examination (repeat them)
- Full travel, occupational, animal, food (raw milk), sexual, drug and family history.
- Medication timeline: when did each drug start in relation to the fever?
- Examine skin, eyes (fundi), lymph nodes, temporal arteries, thyroid, heart (murmurs), abdomen (liver, spleen, masses), breasts, testes, spine, joints, teeth, rectum and pelvis.
- Repeat the examination regularly: new signs (a murmur, a rash, a node) often appear later.
Step 2: First-line investigations
- FBC and film (including malaria film), ESR, CRP.
- U&E, LFTs, CK, LDH, ferritin.
- Blood cultures: at least three sets, repeated, with prolonged incubation if Brucella or fastidious organisms (HACEK) are suspected.
- Urinalysis and urine culture (including for TB if pyuria with no growth).
- Chest X-ray.
- Serology guided by exposure: Brucella, HIV, EBV, CMV, hepatitis, toxoplasma, Widal is not reliable on its own.
- ANA, rheumatoid factor, ANCA, complement; thyroid function.
- Mantoux / IGRA (supportive only), sputum for AFB and GeneXpert.
- Ultrasound abdomen (liver abscess, nodes, spleen, kidneys).
Step 3: Directed investigations
| Investigation | Purpose |
|---|---|
| CT chest, abdomen and pelvis | Abscesses, nodes, tumours, kidney masses |
| Echocardiography (transthoracic, then transoesophageal) | Endocarditis, atrial myxoma |
| PET-CT (FDG) | Finds hidden inflammation, infection or tumour when other tests are negative; also shows a site to biopsy; useful in large-vessel vasculitis |
| Labelled white-cell scan | Occult abscess |
| MRI | Spine (Pott disease, discitis), brain |
Step 4: Tissue diagnosis
- Bone marrow aspirate and biopsy with culture: TB, brucella, leishmaniasis, typhoid, lymphoma, leukaemia.
- Lymph node biopsy (excision preferred): lymphoma, TB, sarcoid; more than one biopsy may be needed.
- Liver biopsy: granulomatous hepatitis, TB, lymphoma.
- Temporal artery biopsy: giant cell arteritis.
- Bronchoscopy with lavage: when sputum is unhelpful and a chest cause is suspected.
Bone marrow biopsy with culture can diagnose several PUO causes at once (TB, brucellosis, typhoid, leishmaniasis, lymphoma and leukaemia).
Do not "scan everything" first. Let the history, examination and early results guide the imaging, and use biopsy to confirm.
Management
- Treat the cause once found.
- Until then, give symptomatic treatment only (paracetamol, fluids).
- Avoid empirical antibiotics: they can partly treat and hide infections such as endocarditis, TB or abscesses, and make cultures negative.
- Avoid empirical steroids: they may suppress fever and inflammation without treating the cause, worsen infections (TB, fungi) and hide lymphoma (making biopsy non-diagnostic).
- Exceptions: an unstable or rapidly deteriorating patient (for example possible sepsis, endocarditis, miliary TB, or giant cell arteritis threatening vision) may need treatment after samples are taken.
- A therapeutic test of anti-TB treatment is sometimes used in high-burden areas when TB is strongly suspected but unproven, with careful follow-up.
- Stop unnecessary drugs to exclude drug fever.
Prognosis
- When no cause is found after thorough investigation and long follow-up, most patients recover spontaneously, and the long-term outlook is good.
- Outcome is worse in older patients and in those whose PUO is due to malignancy.
"I'M Coming Mad": Infection, Malignancy, Connective tissue disease, Miscellaneous.
Expect: the Petersdorf definition (more than 38.3 °C, more than 3 weeks, 1 week of inpatient study) and Durack categories (classic, nosocomial, neutropenic, HIV); tuberculosis as the commonest cause in developing countries; lymphoma as the commonest malignant cause; clues to Still disease (very high ferritin), giant cell arteritis, brucellosis, endocarditis and drug fever; repeated blood cultures and bone marrow biopsy; PET-CT for occult causes; why empirical antibiotics and steroids are avoided; good prognosis of undiagnosed PUO.
Quick revision
- Classic PUO: more than 38.3 °C, more than 3 weeks, no diagnosis after proper study.
- Groups: classic, nosocomial, neutropenic, HIV-associated.
- Causes: infection (TB first in Pakistan), malignancy (lymphoma), connective tissue (Still, GCA, SLE), miscellaneous (drugs, factitious).
- Confirm fever is real; repeat history and examination.
- Blood cultures at least three times; prolonged for Brucella.
- CT, echo, PET-CT; biopsy of marrow, node, liver, temporal artery.
- No blind antibiotics or steroids in a stable patient.
- Undiagnosed PUO: usually resolves; good prognosis.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Levinson's Review of Medical Microbiology and Immunology).
FAQ
What is the classic definition of PUO?
Fever above 38.3 °C on several occasions for more than 3 weeks, with no diagnosis after one week of investigation in hospital. Newer definitions accept 3 outpatient visits or 3 inpatient days of proper study.
What is the commonest cause of PUO in Pakistan?
Infection, particularly extrapulmonary or miliary tuberculosis; enteric fever, brucellosis and abscesses are also important.
Why should steroids not be given before a diagnosis is made?
They can mask fever and inflammation, worsen hidden infections such as TB, and make lymphoma hard to diagnose on biopsy.
What happens to patients in whom no cause is ever found?
Most get better on their own over time, and their long-term prognosis is good.